Download Novel therapeutics and pharmacology, biological approaches 132

Novel therapeutics and pharmacology, biological approaches
anemia (3). No serious angiographic complications occurred. Although these
are preliminary results in a small sample, IA carboplatin and IV etoposide
appears to be active against brain metastases and warrants further study.
| 601P | Quality of life and prognostic factor in patients with
brain metastases from solid tumors following whole
brain radiotherapy.
Moh'd Suleiman, Gianfranco Pesce, Jacques Bernier, Sabine Bieri. Division
of Radio-Oncology, Institute of Southern Switzerland, Ospedale San
Giovanni, Bellmzona, Switzerland
The purpose is to evaluate mean survival rate (MSR), quality of life (OoL) and
prognostic factors (Pf) of patients (pts) with BM from solid tumors, treated with
whole brain radiotherapy (WBRT) in our institution between Nov 98 and Dec 99.
Thirty-five pts (18M, 17F) with BM from solid tumors were treated with WBRT.
Mean total dose was 32.8 Gy (range 8.6-45.0) with a median of 14 fractions
(range 3-18). Median age, 59 years (range 41-78). Primary sites: breast 10
(28.6%), lung 17 (48.6%). Less frequent tumors 8 pts (22.9%). CT scan or MRI
revealed single lesion in 10 pts (28.6%), the remaining had multiple lesions
(71.4%). Systemic disease was controlled (stable since 3 mo) in 9 pts (25.7%),
not stable in 26 (74 3%). QoL evaluations have been completed. MSR of all
pts was 2.9 mo (SD 2.52, range 0.37-9.97). MSR in elderly pts (>65 yrs)
was 1.83 mo (SD 1.64, range 0 37-6 5) and in young pts 3.44 mo (SD 2.73,
range 0.40-9.97). Pts with good PS (WHO 0-I, nr 17) had MSR of 4.22 (SD
2 83, range 0.63-9.97); those with low PS (WHO ll-lll, nr 18) had MSR 1.65
(SD 1.33, range 0.37-5 83) When systemic disease was controlled MSR was
5.46 (SD 3.12, range 1.03-9.97), and with progressive disease MSR was 2.01
(SD 1.53, range 0.37-5.83). All pts tolerated well WBRT The evaluation of
QLQ-C30 (16 pts) showed a pre-treatment Global Health Status of 59% and
56% after WBRT There was no improvement in other categories.
Conclusion: WBRT could be helpful for pts with good prognostic factors,
but should be avoided in elderly pts or pts bearing other bad prognostic factors
(advanced age, low PS, progressive disease) that could outline a short life
expectancy QoL in our series showed no improvement after WBRT.
| 602P | Phase II study of Temozolomide in heavily pretreated
patients with brain metastases from solid tumors.
Chnstos Christodoulou, Dimitnos Bafaloukos, Pans Kosmidis,
Epaminondas Samantas, Aristotle Bamias, Pavlos Papakostas,
Athanasios Karabelis, Charalabos Bacoyiannis, Dimosthenis Skarlos.
Hellenic Co-operative Oncology Group, Athens, Greece
To determine the antitumor efficacy, safety profile and influence of Temozolomide to clinical neurological performance status in heavily pretreated patients
with brain metastases from solid tumors. From May 1998 to October 1999
28 patients with brain metastases from solid tumors with median age 56
years (33-75) were enrolled in this multicenter phase II study There were 12
patients with NSCLC, 5 patients with SCLC, 4 patients with breast cancer
and 7 patients with various solid tumors Most of these patients, had multiple
metastatic sites, poor performance status and had been heavily pretreated.
They received Temozolomide 150 mg/m2 di-5 every 28 days Seventy-four cycles (1-11) were given in total One patient with NSCLC had PR for 11.4 months
both in brain and pnmary site Four patients (2 with SCLC, 1 with melanoma
and 1 with vaginal cancer) had disease stabilization for 8.2, 4.26, 1.25 and
4.13 months respectively. Time to progression was 3 months (0.4-12.8). The
median survival was 4.5 months (0.5-15.5) From 22 patients who underwent
clinical neurological evaluation 1 was definitely better, 9 possibly better, 2
unchanged, 3 possibly worse and 7 definitely worse The treatment was well
tolerated. No grade 4 toxicity was observed whilst, 4 patients had grade 3
nausea and 4 patients grade 3 vomiting (one refused to continue). Temozolomide demonstrated activity in brain metastases of patients with NSCLC and it
deserves to be tested in a group of patients with more favorable characteristics
as monotherapy or in combination with other active drugs e.g. cisplatin.
NOVEL THERAPEUTICS AND PHARMACOLOGY,
BIOLOGICAL APPROACHES
603O NCIC CTG IND.122: A multicentre phase I
dose-escalation study of ZD1839 with
pharmacodynamic (PD) endpoints: Feasibility of serial
tumour sampling.
Lesley Seymour', Hal Hirte 1 , Shaniah Stafford1, Glenwood Goss',
Wilson Miller1, Hal Belfer1, Gerald Batist1, Patricia Hanna',
Sarah Matthews 1 , Steven Averbuch 2 . ' IND Program, NCIC CTG, Kingston,
Canada; 2 AstraZeneca, Wilmington, DE, USA
ZD1839 (Iressa*") is an orally active, selective epidermal growth factor receptor
tyrosine kinase inhibitor. This 3-centre phase I dose-seeking study is the
132
second NCI-C CTG study to include mandatory serial tumour sampling.
Endpoints: pharmacokinetics, toxicity, efficacy and PD assessment. Patients
(pts) are pre-registered, screened, biopsied and receive ZD1839 for 28 days
(3-6 pts/dose level [DL]; 150-1000 mg/day); on day 29 pts are re-biopsied.
Tumour samples are shipped centrally; EGFR expression, mutations and
phosphorylation, Ki67 and apoptosis are measured. 19 pts have entered 5
DLs (3 pts - 150 mg/d, 3 pts - 225 mg/d, 4 pts - 300 mg/day, 5 pts - 400
mg/day, 4 pts - 600 mg/day); 15 are currently evaluable. Pt charactenstics:
performance status was ECOG 0/1/2 in 1/12/2 pts; median age 61 yrs; 3
pts each had colon, endometrial and 1 pt had breast, cervix, mesothehoma,
melanoma, gastric, NSCLC, ovary, pancreas and esophageal cancer 9 pts had
>3 sites of disease One pt experienced transient grade 3 diarrhea. Toxicity
included grade 1 or 2 sweating, fatigue, anorexia, taste changes, alopecia,
diarrhea, acneiform rash, pruritus and dry skin No dose-limiting toxicity has
been reported to date. Median duration of treatment for DL 1-4 is 12.6, 10, 8.5
and 3 9 weeks, respectively. All 19 pts underwent initial tumour biopsy; 11 pts
had repeat biopsy at 28 days (1 pt refused, 1 pt with mesothelioma did not have
malignant cells in biopsy, 2 pts were taken off study early, 4 pts are too early).
Biopsies included skin/subcut (4 pts), superficial nodes (2 pts), liver (5 pts),
lung (2 pts), pelvic mass (2 pts). Preliminary analysis of samples reveals the
techniques to be feasible and reproducible. While organisationally challenging,
the inclusion of PD endpoints and serial tumour sampling in multicentre phase
I trials is feasible and does not preclude timely accrual.
| 60401 An intermittent phase I and pharmacokinetic study of
BBR3464, a novel cationic triplatinum complex.
Hilary Calvert', Cristiana Sessa2-7, James Carmichael3, Paula Calvert1,
Massimo Zucchetti4-7, Silvia Marsoni7, Sabine Van den Bosch 2 ,
Angela Robinson1, Elena Verdi 5 , Gabnella Camboni5. ' Cancer Research
Unit • Medical School, University of Newcastle upon Tyne, Newcastle upon
Tyne, United Kingdom, 2 Oncology, Oncology Institute of Southern
Switzerland, Bellmzona, Switzerland; 3 Clinical Oncology, The Cancer
Research Campaign (CRC), Nottingham, United Kingdom;4 Oncology, Mario
Negri Institute for Pharmacological Research, Milan, Italy;5 Novuspharma,
Monza (Ml), Italy; 6 European Institute of Oncology, Milano, Italy, 7 Southern
Europe New Drugs Organization (SENDO), Milano, Italy
BBR3464 is a novel triplatinum more potent than cisplatin (CDDP), active in
CDDP-resistant and insensitive xenografts, which achieves a higher proportion
of major DNA adducts. 32 patients (pts) with advanced solid tumours, for
which efficacious therapy was unavailable, received BBR 3464 on a single
intermittent schedule every 28 (15 pts) and subsequently, to increase the dose
intensity, every 21 days (17 pts). In both schedules the drug was given as
1-hour infusion. Total and free platinum in plasma and urine were assessed by
ICP-MS. The starting dose in the q28 days schedule was 0.2mg/sqm, and the
highest 1.1 mg/sqm. At this dose 3 and 5 of 10 patients suffered respectively
from short-lasting neutropenia (gr 4) and delayed diarrhoea (gr 3-4). Alopecia
(gr 1-2) was frequent. Nausea and vomiting were rare, neither neurotoxicity
nor renal toxicity was observed. In the 21 days schedule 2 dose-levels were
tested • 0.9 & 1.1 mg/sqm The study is ongoing- at 1.1 with loperamide at
symptom onset, no gr > 3 diarrhoea was observed so far, while neutropenia
seems to be dose limiting. 2 pts experienced a reversible grade < 2 drop in
their lung diffusion capacity, possibly drug related. Overall, 1 PR (pancreas
- CT scan) and 3 marker responses (2 colon, 1 ovarian) were observed.
BBR3464 showed a linear kinetic with a distribution phase of 3-5 hrs and a
terminal half-life of several days. Approximately 10% of the equivalent dose of
BBR3464 was recovered in 24 hours urine.
BBR3464 given intermittently has shown some activity and has a different
toxicity and pharmacokinetic profile to that of CDDP Lack of nephrotoxicity
and reduced urinary excretion support the use of BBR3464 without hydration.
Neutropenia and diarrhoea are dose limiting Diarrhoea is manageable with
loperamide. The schedule optimal dose-intensity is under evaluation
60501 Cleavage of the HER2 ectodomain is a
4-aminophenylmercuric acetate-activable process that
is inhibited by trastuzumab (Herceptin-) in breast
cancer cells.
Miguel Angel Molina. Jordi Codony-Servat, Federico Rojo, Joaqum Arribas,
Joan Albanell, Jose Baselga. Laboraton de Recerca Oncologica, Hospital Vail
d'Hebron, Barcelona, Spain
HER2/neu is a ligand-less tyrosine-kinase receptor of the ErbB family that is
overexpressed in 25-30% of breast cancers. It undergoes proteolytic cleavage that results in the release of the extracellular domain (ECD) and the
production of a truncated intracellular fragment (p95), an event that could
contnbute to deregulated cell growth. We have previously shown that HER2
cleavage was activable by pervanadate and could be inhibited by TIMP-1. In
order to further characterize HER2 shedding, we have studied the effects of
aminophenylmercuric acetate (APMA), a well-known matrix metalloprotease
activator. APMA at 1 mM induced a rapid and potent cleavage of the receptor
in two HER2-overexpressing breast cancer cell lines, BT-474 and SK-BR-3.
This activation could be blocked with batimastat, a broad-spectrum metallo-
Annah of Oncology. Supplement 4 to Volume 11. 2000
S 2000 Kluwer Academic Publishers. Printed in The Netherlands
Novel therapeutics and pharmacology, biological approaches
protease inhibitor. Trastuzumab (Herceptin * ), a humanized antibody against
HER2 ectodomain, at doses of 10-100 nM, also inhibited basal and induced
HER2 cleavage. This inhibitory effect is specific of trastuzumab, since 2C4,
another antibody against HER2 ECD, did not show any significant effect on
constitutive receptor shedding. The inhibition of HER2 cleavage is not due to
antibody-induced receptor downmodulation, given that trastuzumab inhibited
HER2 cleavage at 30 mm, and receptor downmodulation was not detected until
24 h In addition, trastuzumab effectively prevented HER2 shedding in cells
where receptor internalization was inhibited by hypertonic treatment Finally,
an increase in the phosphotyrosine content of full-length HER2 was associated with APMA-induced cleavage in BT-474 cells, and this increase was less
pronounced if trastuzumab was present. These data indicate that trastuzumab
has a direct inhibitory effect on HER2 shedding that could contribute to its
therapeutic properties.
606O A phase I and pharmacological study of CCI-779, a
rapamycin ester cell cycle inhibitor.
Manuel Hidalgo 12 , Enc Rowinsky1-2, Charles Erlichman3,
Ronald Drengler 12 , Bonnie Marshall", Randy Marks 3 , Tam Edwards'- 2 ,
Joseph Boni", Gary Dukart4, Jan Buckner3 ' University of Texas Health
Science Center at San Antonio, San Antonio, TX, USA;2 Institute for Drug
Development, San Antonio, TX, USA, 3Mayo Clinic, Rochester, MN, USA;
4
Wyeth-Ayerts Research, Radnor, PA, USA
CCI-779 is an ester of rapamycin which inhibits the cell cycle. The agent
inhibits the activity of mTOR (mammalian target of rapamycin) and disrupts
key signal transduction pathways, including those regulated by the p70s6
and PHAS-I kinases resulting in cell cycle arrest at the G1-S boundary This
study is evaluating the feasibility, pharmacokinetics and biological effects of
escalating doses of CCI-779 administered as a 30-minute IV infusion daily
x 5 every 2 weeks to patients (pts) with solid neoplasms Fifty-one pts
have received 262 courses (median 4, range 1-16) at doses ranging from
0 75-19.1 mg/m2/d. Three episodes of DLT have been observed in the 1st
cycle so far consisting of asymptomatic, grade 3 hypocalcemia at the 2.16
mg/m2/d dose level (1 pt), grade 3 elevation in transaminases (1 pt), and
grade 3 vomiting, grade 2 diarrhea and grade 2 asthenia (1 pt) at the 19.1
mg/m2/d Grade 3 thrombocytopenia requiring dose reduction was observed
in 3 heavily-pretreated (HP) pts at the 19.1 mg/m2/d dose level, indicating that
this dose is not well-tolerated in HP subjects At this juncture, HP patients
are receiving 15 mg/m2, while doses continue to be escalated in minimallypretreated pts. Other toxicities noted, generally mild-moderate, some over a
broad dose range, include neutropenia, rash, mucositis, asthenia, fever, and
hypertriglycendemia. Allergic phenomena have also being observed. In 17
pts receiving doses of 0.75-3 12 mg/m2/d, CCI-779 exhibited increasing peak
concentrations with increasing dose, preferential red blood cell partitioning, and
a median terminal half-life of 15.2 h One patient with NSCLC achieved a PR
Minor antitumor responses and/or prolonged (> 4 months) stable disease have
been noted in several drug-refractory cancers including: soft-tissue sarcoma
(3), and cervical (1), uterine (1), and renal cell (3) carcinomas. CCI-779 dose
escalation-expansion continues. The toxicity profile and antitumor activity
observed to date are encouraging.
607O
Phase I study of the gene therapy prodrug, CB1954.
Guv Chung-Fave. Joanna Clark, Rachael Barton, Joanna Baddeley,
David Anderson, Leonard Seymour, David Ferry, David Kerr Institute of
Cancer Studies, Birmingham, United Kingdom
CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide), a substrate for the bacterial
enzyme nitroreductase, is converted into a potent bifunctional alkylating agent.
CB1954 is a candidate prodrug in virus-directed, enzyme prodrug therapy
(VDEPT) protocols. CB1954 was administered by bolus intravenous (IV)
injection on a 3-weekly cycle, or intraperitoneally (IP) followed by 3-weekly IV
injections, with a maximum of six cycles of drug. 30 patients were treated,
age range (23-78 years, median 62 years). 19 patients were males. 22
patients received IV CB1954, 8 patients had IP CB1954, 4 of whom also
received IV drug. 13 cases were colorectal cancers, 4 gastric, 3 oesophageal,
3 mesotheliomas, with ovarian, pancreatic and unknown primaries accounting
for the remainder The first dose level was Smg/m2, no significant toxicity
was seen until the fifth dose level of 24mg/m2. The maximum tolerated dose
IV was 37.5mg/m2 with gastro-intestinal and hepatic dose-limiting toxicities
(DLT). No DLT has been seen in the IP regime at the current dose of 24mg/m2.
No alopecia, marrow suppression or nephrotoxicity was observed No clinical
response was seen. CB1954 pharmacokinetics indicated a linear relationship
between dose and area under the curve for the IV dose range of 3-24mg/m2,
with a non-linear effect at higher doses. Mean elimination half-life was 17
minutes with <5% renal excretion. Animal data suggests biliary excretion
as the main clearance mechanism. Serum levels after IV administration
(SOmg/m2), persisted between 10 and 1/JM for 2 hours. IP administration
{24mg/nf) achieved peritoneal levels between 100 and 1/zM for 18 hours
The IC50 for CB1954 in cancer cells expressing nitroreductase ranges from
0.1 and 10 nM. In summary, CB1954 is a well-tolerated prodrug and sufficient
serum/peritoneal levels are generated for a VDEPT approach to be feasible.
Annals of Oncology, Supplemenl 4 lo Volume 11, 2000
We are now conducting a phase I tnal of adenovirally delivered nitroreductase
and IV CB1954 in patients with primary/secondary liver tumours.
I 608PD | Phase I and pharmacokinetic study of BIBX 1382, an
EGFR inhibitor, as continuous daily oral
administration.
Christian Dittrich'. Uta Bruntsch 2 , Markus Bomer 3 , Karin Weigang 2 ,
Holger Huisman4, Andree Amelsberg 5 , Jantien Wanders4, Axel Hanauske 6 ,
Pierre Fumoleau7. 'LBI-ACR VIE, KFJ-Spital, Vienna, Austria;25th Medical
Clinic, Nurnberg, Germany, 3 Dept. Oncology, Inselspital, Bern, Switzerland;
4
NDDO-Oncology, Amsterdam, Netherlands;5 Boehringer Ingelheim,
Biberach, Germany; s Technical University, Munich, Germany; 7 Centre Rene
Gauducheau, Nantes, France, For the EORTC-Early Clinical Studies Group
(ECSG)
The pyrimido-pynmidine BIBX 1382 inhibits the intracellular tyrosine kinase
domaine of the epidermal growth factor receptor (EGFR), thus specifically
reverting the aberrant enzymatic activity from overexpressed and constitutively
activated EGFR, respectively. A modified Fibonacci scheme was used to
escalate the daily oral dose; the following dosages and cycles (defined as
treatment during 28 days) were applied, respectively 25mg 6, 50mg: 2;
100mg 5; 200mg: 7, 150mg: 3 Over a 10 months accrual phase, 11 pts
(7 females, 4 males) with a median age of 63 years (50-73), WHO PS 0:5,
1 6 and miscellaneous solid tumors were entered The number of cycles
applied per pt was median 1 5 (0-7) Reversible, dose-dependent increase
of liver enzymes (maximal CTC grades: GGT: 4, SGOT: 3, SGPT: 3, aP: 3,
bilirubin: 3) prevented regularly from further dose escalation. Oral medication
yielded plasma levels far below expected to be efficacious. Realistically, target
plasma levels could not be reached via the oral route at reasonable dosage
Meanwhile, a prechnically unknown metabolite was identified from urine of one
patient. Subsequently, this metabolite was found to be abundant in patient
plasma The metabolite was demonstrated to be pharmacologically inactive.
Due to dose limiting increase of liver enzymes, low bioavailabihty of BIBX
1382 and detection of a pharmacologically inactive metabolite this tnal was
discontinued
| 609PD | A phase I and pharmacologic trial of weekly
epothilone B in patients with advanced
malignancies.
A m i t O z a ' . R M Zamek 3 , Lillian Siu 1 , S M Locsin 3 , Malcolm Moore 1 ,
F. Chen 2 , T-L. Chen 2 , Patricia Cohen 2 , John Rothermel2, Eric Rubin 3 .
' Medical Oncology and Hematology, Princess Margaret Hospital, Toronto,
Canada;2 Novartis, New Jersey, USA, 3 RWJ-UMDNJ, The Cancer Institute of
New Jersey, New Brunswick, USA
Epothilone B (EB) is a naturally occurring macrolide that is a more potent
microtubule stabilizer than paclitaxel and exhibits a broad range of preclinical
anti-tumor activity at pg/ml levels. EB is also active in paclitaxel-resistant
models. A phase I dose-escalating trial of weekly intravenous administration
of EB was undertaken to determine toxicities, to identify a maximum-tolerated
dose, and to assess pharmacokinetics Patients receive weekly infusions of
EB every 6 out of 9 weeks and are enrolled in cohorts of 3 or more using
a Fibonacci-based dose escalation strategy. 24 patients have been enrolled
to date at doses ranging from 0.3mg/m2 to 1.85mg/m2. Only one patient has
developed grade 3 toxicity with parasthesia to date at dose level 2 (0 5mg/m2)
Pharmacokinetic results are presented.
Dose
mg/m 2
03
03
0.5
0.5
0.75
0 75
1 1
1 1
Week
AUC| N F
ngh/ml
Cmax
mg/ml
CL
mg/min
Vss
L
Ti/2
H
1
6
1
6
1
6
1
6
28
187
85
312
189
153
204
NA
15
14
14
28
18
19
23
NA
462
254
1201
189
820
185
843
-
64
73
83
103
58
63
59
NA
1179
At the initial dose level, drug accumulation was observed with an accumulation ratio (AUC0-5011 dose e/AUCo-soh dose i) of 2.45. Continued dose escalation
is planned.
© 2000 Kluwer Academic Publishers, Primed in The Netherlands
133
Novel therapeutics and pharmacology, biological approaches
Phase I and pharmacokinetic study of aplidine, a
marine derived compound, given as a 24h infusion
every 2 weeks in patients (pts) with advanced solid
tumors and non-Hodgkin lymphoma (NHL).
E. Raymond 1 , N. Ady-Vago1, V. Ribrag 1 , S. Faivre 1 , F. Lecot 1 , T. Wright2,
L Lopez-Lazaro2, C. Guzman 2 , J Jimeno 2 , J.P. Armand 1 . ' Dept. of
Medicine, Institute Gustave Roussy, Villejuif, France;2 Pharma Mar Clinical
R&D (Tres Cantos, Spain), Tres Cantos, Spain
Aplidine is a cyclodepsipeptide isolated from the marine tunicate, Aphdium
albicans currently undergoing phase I trials. Aplidine interferes with protein
synthesis through a GTP dependant inhibition of the elongation factor 1-<r
and decreases the expression of the VEGF-RI gene. Adult pts with advanced
solid tumors and Non-Hodgkin lymphomas resistant to standard therapy with
appropriate organ functions were included in a phase I trial evaluating aplidine
administered as a 24h infusion every 2 weeks So far, 31 pts have been
treated with 58 courses at doses ranging from 200 to 7000 MQ/m2/2wk.
Tumor types and number of pts are as follows: lung-6, colons, renal-5,
breast-4, pancreas-3, NHL-2, thyroid-2, melanoma-1, uterus-1, prostate-1, and
adrenal-1. No hematological toxicity has been observed. Toxicities including
G1-3 nausea/vomiting and asthenia have been reported. Muscle cramps and
CPK elevations have been observed in pts treated from 5000 /zg/m2/2wk. Two
pts referred pain around the infusion catheter. The MTD has not been achieved
since no dose limiting toxicity was observed. Early hints of activity in pts with
renal cancer and NHL have been observed. Most pts have been sampled
for PK analysis (LC-ESI-MS/MS). Aplidine administered using this schedule
is characterized by linear kinetics up to the studied doses, wide distribution
(median[quartiles] Vss; 539[447-592 L/m2]) and moderate to high clearance
(median[quartiles]; 332(205-453 ml_/(min x m2)] An open 2-compartment
model fits appropriately most plasma concentration profiles. The terminal
half-life is usually in the order of 15-25 h. Potentially active levels are being
consistently reached from 3200 ;tg/m2/2wk onwards. The accrual is ongoing
to determine the dose limiting toxicity and the dose to be recommended in
phase II studies
| 6 1 1 P D | Phase I study of aplidine (APL) in a 1 hour daily
infusion x 5 q 3 weeks in patients (pts) with solid
tumors and low and intermediate grade non
Hodgkin's lymphomas: A National Cancer Institute of
Canada-Clinical Trials Group (NCIC-CTG) study.
Jean Maroun 1 . Karl Belanger2, Lesley Seymour 3 , Denis Souheres2,
Daniel Charpentier1, Rakesh Goel 1 , David Stewart', Eva Tomiak',
Jose Jimeno 4 , Sarah Matthews3. ' Medical Oncology, Ottawa Regional
Cancer Centre, Ottawa, Canada; 2 Hematology/Oncology, Centre Hospitaller
Universitaire de Montreal-Pavilion Notre Dame, Montreal, Canada,
3
NCIC-CTG, Kingston, Canada; " Clinical R&D, Pharma Mar, Madrid, Spam
APL is a cyclic depsipeptide derived from a mediterranean marine tunicate
structurally related to the didemnins with a superior therapeutic index compared
to didemnin B Postulated mechanisms of action include GTP dependent
inhibition of protein synthesis and inhibition of mechanisms involved in signal
transduction. APL blocks the cell cycle at G1 phase. The main objectives of the
study are to determine the maximum tolerated dose (MTD), the dose limiting
toxicity (DLT), the pharmacokinetics of the drug and the recommended dose
for phase 2 studies that can be given in a daily 1 hour IV infusion schedule x 5
days q 3 weeks. The daily starting dose of APL was 80 Mg/m2. Cohorts of 3 pts
are treated at each dose level. Dose level escalation was based on toxicity 20
pts have been treated at 6 dose levels ranging from 80 MQ-720 /ig/m 2 . A total
of 36 cycles were administered. Non-hematological toxicities were grade 1 and
2 with fatigue reported in most pts. Hypersensitivity reactions and transient
neuro-sensory motor changes were each noted in 5 pts. Other toxicities were
grade 1-2 and included nausea, vomiting, anorexia, diarrhea and anxiety.
There were no significant hematological toxicities. Pharmacokinetic analysis
was performed in treatment course 1. APL concentrations were analyzed by
HPLC tandem mass spectrography. Data suggest dose-linear PK with high
interpatient variability. There was a total body clearance of 0 38 L/min and
median t 1/2 of 14.2 hours. Potentially therapeutic plasma concentrations (> 1
^g/ml) have been achieved. No objective responses were documented. 1 pt
with metastatic colon cancer is stable at 6+ months. In conclusion no DLT has
been documented Accrual is ongoing at the present dose level of 720 Mg
612PD
A phase I study of aplidine (APL), a marine derived
compound, given as a 1h infusion weekly x 3 in
advanced solid tumors and non-Hodgkin lymphoma
patients (pts.).
Miguel Angel Izquierdo'. Angela Bowman 2 , Marisa Martinez1,
Beatnce Cicchella 3 , Luis Lopez-Lazaro3, Cecilia Guzman 3 , Jose Germa 1 ,
John Smyth 2 . ' Medical Oncology, Instituto Catalan de Oncologia, Barcelona,
Spam;2 Medical Oncology, Western General Hospital, Edinburgh, United
Kingdom; 3 Clinical R&D, Pharma Mar, Tres Cantos, Spain
APL is a new anticancer cyclodepsipeptide compound isolated in the mediter-
134
ranean tunicate, Aplidium albicans It interferes with protein synthesis through
a GTP dependant inhibition of the elongation factor 1-alpha;. We are conducting a phase I study where APL is given as a 1 hour infusion weekly for 3
weeks every 4 weeks Adult pts with advanced solid tumors or non-Hodgkin
lymphomas refractory to standard therapy with appropriate organ functions are
considered eligible. 23 pts. have been treated with 39 courses at the following
doses: 133 M g/m 2 /wk (3 pts.), 266 Mg/m2/wk (3 pts.), 532 M g/m 2 /wk (3 pts ),
800 ng/m2/wk (3 pts), 1200 /ig/m2/vA (4 pts.), 1800 M&/m2/wk (4 pts.) and
2700 M9/m2/wk (3 pts) Site of disease and number of pts. are as follows:
colon-7, stomach-4, lung-4, renal-2, H&N-2, ovanan-2, melanoma-1 and biliary
tract-1
No hematological toxicities have occurred and no G3-4 toxicities or DLT
have been observed. Other toxicities including G1-2 asthenia, reactions at the
injection site and vomiting have been noted. The MTD has not been achieved
since no significant toxicity was observed. Early hints of activity in gastric
cancer have been noted.
All pts have been sampled for PK analysis (LC-ESI-MS/MS). APL administered using this schedule is characterised by linear kinetics up to the studied
doses, wide distribution (median[quartiles] Vss; 308(184-382 L/m2]) and moderate to high clearance (median(quartiles); 379(294-428 mL/min*m2)]. Dose
escalation continues
| 613PD I Pegylated-liposomal doxorubicin (Caelyx) plus
weekly docetaxel (Taxotere): A phase I and
pharmacokinetic study.
Evanqelos Briasoulis1, Dimitra Rammou1, Elefthena Tzamakou 1 ,
Vasilis Karavasilis1, Anatoli loannidou2, Kalliopi Soulti 2 , Nicholas Pavlidis1.
' Departmet of Medical Oncology, University of loannina, loannma, Greece;
2
Analytical Chemistry Section, European Environmental Research Institute,
loannma, Greece
Purpose: a) To characterize toxicity and define the maximum-tolerated dose
(MTD) of the combination of pegylated-liposomal doxorubicin (Caelyx) with
weekly docetaxel. b) To assess the impact of co-administration of docetaxel
on plasma kinetics of pegylated-liposomal doxorubicin.
Methods: Patients with refractory or pretreated solid tumors were enrolled.
Caelyx was administered every 4 weeks and docetaxel weekly for three consecutive weeks, followed by a 1-week rest. As dose limiting toxicity for this
study was defined a granulocytopenia grade >2 causing treatment delay of
>2 consecutive weeks, or non-haematologic toxicity grade >2. For PK analysis six consented patients were sampled twice: first, when initially received
single-agent Caelyx, and four weeks later when treated on the combination. Doxorubicin was quantified by HPLC and pharmacokinetic analysis was
performed with Win Nonlin.
Results: To date 25 patients have been treated over six dose-levels of
Caelyx/weekly-docetaxel: 30/20 mg/m2 (4 pts), 30/25 (5 pts) 30/30 (3 pts),
30/35 (4 pts), 35/30 (6 pts) and 35/35 (3 pts) Median courses given per
patient were 3 and range 1-7 MTD has not been defined as yet, but single
cases of dose-limiting granulocytopenia occurred at 35/30 (1/6) and 35/35
(1/3). Other minor toxicities observed were: grade 1-2 neutropenia (3 pts),
grade 1-2 skin toxicity (3 pts) and grade 1 alopecia (4 pts). Antitumour activity
was documented at the highest doses. Pharmacokinetic analysis showed that
weekly docetaxel did not alter plasma kinetics of liposomal doxorubicin (p=0,7
for AUC).
Conclusions: The combination of Caelyx and weekly docetaxel makes an
interesting chemotherapy regimen that merits further clinical evaluation in patients with malignancies amenable to treatment with antracychnes and taxanes.
This combination demonstrated a favorable toxicity profile and allowed optimal
dosing of both drugs, apparently due to documented lack of pharmacokinetic
interaction. Dose escalation is ongoing but doses of Caelyx/weekly-docetaxel
up to 35/35 can safely be administered
| 6 1 4 P D | Phase I and pharmacokinetic (PK) study of a new
liposome-encapsulated doxorubicin formulation in
patients with refractory solid tumors.
Carmen Munoz 1 , Marisa Munoz 2 , Carmen Balafia 3 , Jose L Ponton 1 ,
Margarita Garcia 2 , M a Angeles Llorens4, Mercedes Gimeno 4 ,
Rafael Rosell 3 , Jose R. Germa 2 , Miguel A. Izquierdo2 ' Dept. Pharmacy,
Catalan Institute of Oncology, Hospitalet de Llobregat, Spam;2 Dept.
Oncology, Catalan Institute of Oncology, Hospitalet Llobregat, Spam;3 Dept
Oncology, Hosp. German Trias Pujol, Badalona, Spam; * Tedec-Meiji Farma,
Madrid, Spain
A new formulation of liposome-encapsulated doxorubicin (LD-TM), developed
by Tedej -Meidi, incorporates an antioxidant agent in the phospholipid bilayer
that provides chemical advantages. In animals, LD-TM showed longer t1/2 and
larger AUC than free doxorubicin (FD). A phase I study of LD-TM given as a
1 hr i.v. infusion every 21 days was conducted in patients (pts) with advanced
and refractory solid tumors. From a starting dose of 30 mg/m 2 , dose was
escalated in increments of 10 mg/m2. Thus far, 29 pts have been included.
Neutropenia was the predominant hematologic toxicity (tox). At 80 mg/m2, 2/6
pts experienced DLT (neutropenic fever). Gr.3 thrombocytopenia was seen in
Anmih of Oncology, Supplement 4 to Volume 11. 2000
E 2000 Kluwer Academic Publishers, Printed in The Netherlands
Novel therapeutics and pharmacology, biological approaches
3 pts. No gr.3/4 non-hematologic toxicity was seen. The most frequent tox was
fever and chills 8-12 hrs after administration; it did not recur with pre-treatment
with acetaminophen and antihistaminics Gr 1 palmo-plantar erythrodysestasia
was seen in only 2 pts (not dose related). The 70 mg/m2 cohort was expanded
to further define tox and to study the PK profile of LD-TM. Four more pts were
treated in this cohort. To compare tox and PK between FD and LD-TM, pts
received a first course of FD 70 mg/m2 and subsequent courses of LD-TM
70 mg/m2. No DLT was seen. The hematological tox of LD-TM was lower
than FD at equal doses. PK analysis was done in courses 1 (FD) and 2
(LD-TM) on each pt. The mean AUC-LDTM (total dox) was 2.8 times larger
than AUC-FD (p<0.001). In addition, other PK parameters like MRT, Cl and
t1/2 were significantly longer for LD-TM. In conclusion, the tox of LD-TM varies
from other LD (i.e. Caelix 8 ) and shows also differences with FD. The PK
profile of LD-TM is also intermediate between FD and Caelix* Re-escalation
to LD-TM 80 mg/m2 is being performed to better charactenze tox and PK
I 615PD | Histamine dihydrochloride injections inhibit growth
rate of Leydig cell sarcoma (LTW) in the liver:
A study in rats.
Peter Naredi 3 , Magnus Rizell 1 , Per Lindner1, Kristoffer Hellstrand2
' Department of Surgery, Sahlgrenska University Hospital, Gothenburg,
Sweden;2 Department of Virology, Sahlgrenska University Hospital,
Gothenburg, Sweden; 3 Department of Surgery, Urnea University Hospital,
Umea, Sweden
Histamine dihydrochlonde protects T cells and NK cells from monocyte/
macrophage-induced apoptosis Histamine has been shown to inhibit the
growth rate of several munne carcinomas and sarcomas Clinical studies
with histamine dihydrochlonde (Maxaminea) in combination with interleukin-2
and/or interferon-a indicate similar results, especially in melanoma patients
with liver metastases. The aim of this study was to test the effect of various
routes of histamine administration on tumor growth rate of LTW (1) implanted
in the liver and (2) implanted subcutaneously (s.c.) in Wistar/FU rats.
Methods: Histamine was administered either as a bolus s c. injection (0.5
mg/kg) daily, or as a continuous infusion (2 mg/kg/24h) with an osmotic pump
(Alzet 2002), starting from the day of inoculation of 1x106 LTW cells Tumor
weight was recorded after 10 days of treatment. Normal saline was used as a
control.
Results: In animals treated with bolus injections of histamine, liver tumors
weighed 54% less (p<0 001), and subcutaneous tumors weighed 37% less
(p<0.01) compared to corresponding tumors in saline-treated animals. In both
types of tumors, administration of histamine via an osmotic pump had no
statistically significant influence on tumor weight compared to saline-treated
animals.
Conclusion: In addition to previously reported munne tumors, histamine
dihydrochloride also inhibits tumor growth rate of Leydig cell sarcoma (LTW),
especially in the liver. The effect of histamine was observed when administered
as a bolus injection, whereas a continuous infusion had no effect.
| 616 | Phase I study of docetaxel (D), Carboplatin (C) and
etoposide (E) in advanced solid tumors.
Frank Dunphy, Teresa Dunleavy, Cynthia Cantrell, John Visconti,
John Ftichart, Steven Pincus, Paul Petruska. Dept of Hematology/Oncology,
Saint Louis University Health Sciences Center, St. Louis, USA
D was added to C and E to develop a new triplet.
Eligibility: advanced cancer, performace status <2 Early Schedule (ES)
administered D i v. day 1, C i.v. day 1, and etoposide i.v. day 1, 2, 3. The
sequence of D/C administration was reversed to day 3, Late Schedule (LS),
with the subsequent course. After dose-limiting marrow suppression was
observed, the schedule was changed to C i.v. day 1, and E i. v. d1, po d2, 3.
Schedule of D was changed twice, first to a Weekly Schedule (WS) i.v day 1,
8, 15 and then to a Split Schedule (SS) i v. day 1,15 repeated q 28 days See
table.
Level
7
8
S
D
C
E
DLT
SS
45
45
5
5
70i.v./140po
75i.v./140po
0%
Anc 60%
ss
Abbreviations- S, schedule; Anc, absolute neutrophil count, i v, intravenous; po, orally; DLT,
dose-limiting toxicity.
51 patients were treated. Responses were observed in 8 of 49 evaluable:
3 small cell lung; 2 pancreatic; 2 head and neck; 1 ovarian. DLT for ES, LS,
WS was neutropenic fever observed in mean of 58% (range, 40—75). SS was
tolerated without dose-limiting toxicity until level 8 where neutropenic fever was
observed in 60%. Hematopoietic growth factor eliminated an asymptomatic
neutrophil nadir at level 7.
Conclusion: ES, LS, and WS had unacceptable hematologic toxicity. SS
had less hematologic toxicity and was safe through level 7 At level 8, DLT
was neutropenic fever. Growth factor eliminated a neutrophil nadir observed
with level 7.
Annals of Oncology, Supplement 4 to Volume 11, 2000
617P I Probucol treatment in protection against endothelial
toxicity of 5-fluorouracil.
Sara Kinhult', Maria Albertsson \ Jan Eskilsson2, Magdalena Cwikiel 1 .
' Dept of Oncology, Lund University Hospital, Lund, Sweden, 2Dept of
Cardiology, Lund University Hospital, Lund, Sweden
Introduction: Cardiotoxicity is a rather unusual but serious side effect of 5-fluorouracil treatment, with unclear pathophysiology (Robben, Cancer 1993). Clinical data suggest that coronary artery endothelium could be involved (Labianca,
Tumori 1982) Expenmental studies indicate one possible pathophysiological
mechanism behind 5-FU induced cardiotoxicity, showing a toxic effect of 5-FU
on the endothelium, with a secondary thrombus foimation (Cwikiel, Scaiiriiny
Microsc 1996;Ann Oncol 1996) This toxicity might be caused by generation
of free radicals, leading to lipid peroxidation and cell membrane damage.
Probucol, a lipid-lowering drug with strong antioxidant properties has previously been shown to provide complete protection against doxorubicin (a potent
antitumour antibiotic) cardiomyopathy without interfering with its antitumour effect (Siveski-lliscovic, Circulation 1995). In the present study we evaluated the
possible role of Probucol treatment in protection of toxic and thrombogemc
effects of 5-FU on vascular endothelium in a rabbit model.
Methods: Rabbits in three groups were treated with 1) probucol 60 mg/kg
intraperitoneally for two weeks (n=15); 2) probucol as above as pretreatment
before single dose of 5-FU 25 mg/kg mtrarterially (n=15), and 3) saline alone
(n=15). Arterial endothelium was examined with scanning electron microscopy
Damages were compared with a fourth group treated with 5-FU alone (n=15).
Results: Probucol treated animals showed only mild damage to the endothelium. The serious damage seen in 5-FU treated animals on day 3 and
7 after treatment, with intima disruption and thrombus formation, was totally
absent in the probucol pretreatment group
Conclusions: The study indicates protective effect of Probucol in prevention
of 5-FU induced endothelial injury. The findings also suggest that free radical
mediated mechanisms could be involved in the toxic effect of 5-FU on vascular
endothelium.
| 618P | Amifostene in pediatric cancers.
Prakash Chitalkar, Anil Dhar, Chandar Vipan. Medical Oncology, Command
Hospital Pune, Pune, India
Thirty three children with malignancies were entered on a chemoradiotherapy
study and amifostene support with the objective of documenting hematological
and organ toxicities. Patients were 13 months to fourteen years old, with
a median of six years. Nineteen were males and fourteen females. Their
diagnoses were: non-Hodgkin's lymphomas (7); relapsed acute lymphoblastic
leukemia (7); Ewings sarcoma (4); germ cell tumor (4), neuroblastoma (4)
embryonal rhabdomyosarcoma (3); osteosarcoma (3); hepatoblastoma (1).
The pathobiological indications were renal insufficiency at presentation (8/33),
ureteric encasement (5/33); heavy alkylator pretreatment (4/33); neuropathy
(6/33); imminent radiotherapy (3/33). Putative chemotherapy agents, prior to
which amifostene was administered were cyclophosphamide (21), cisplatin
(20) and etoposide (7). Eighty-six cycles were given, median five cycles(range
2 to 7). The amifostene dose was 740 mg per meter square per cycle in fifteen
minute infusion approximately half an hour prior to the dose of the putative
agent. Lymphoma patients (seven each) were randomized to the amifostene
supported and unsupported groups.
Side effects of amifostene were minimal with three episodes of nausea. The
neutropenic nadir was 0.7 x 109/L and the platelet nadir was 50 x 109/L without bleeding episodes. Renal insufficiency ameliorated in 6/8 (75%); ureteric
encasement diminished in 3/5 (60%) and disappeared in two (40%). The
next cycle was given on schedule in 82/86 (93%) cycles. In the unsupported
lymphoma group there were two toxic deaths with a neutropenic nadir of 0.1
x 109/L while the neuteropenic nadir in the amifostene group was 1.0 x 109/L
and platelet nadir was 70 x 109/L with a saving of US Dollars 540 per cycle
in the amifostene group. Overall 9 complete responses, 17 partial responses
and three nonresponses. occurred. Amifostene is a abroad-spectrum cytoprotectant in peditric cancers. It reduces marrow and organ toxicities and permits
dose intense chemotherapy while sparing the use of CSFs, reducing costs
significantly.
I 619P | Preliminary data on the combination of ifosfamide (Ifo)
and topotecan (Topo) in small cell lung cancer (SCLC)
and advanced ovarian cancer (AOC).
Paolo Pronzato, Alessandra Tognoni, Floriana Pensa, Franco Vaira,
Antonella Vigani, Annunziata Manna, Luigi Cadenotti, Ermanno Ghio,
Pieraldo Canessa, Leonardo Marino. Dept. Medical Oncology, Ospedale S.
Andrea, La Spezia, Italy
Most patients with SCLC or AOC show tumor progression after an initial
response to first line chemotherapy (CT). Therefore, second line CT with
a palliative intent should be developed. The alkylating agent Ifo and the
topoisomerase inhibitor Topo have been shown active as single agents, both
in SCLC and AOC. We have considered the combination of Ifo and Topo as
a second line CT for SCLC and AOC, in order to see activity and toxicity.
© 2000 Kluwer Academic Publishers, Printed in The Netherlands
135
Novel therapeutics and pharmacology, biological approaches
With these premises, two phase II trials were started Entry criteria were as
follows. For SCLC: age <76 years, performance status <3, no renal or liver
or heart failure; extended disease SCLC with measurable or evaluable lesions
in progression during or after a first line CT including a platinum compound
and etoposide. For AOC age <76 years, performance status <3, no renal or
liver or heart failure; advanced disease with measurable or evaluable lesions
in progression during or after a first line CT including a platinum compound
and paclitaxel. Treatment consisted of Ifo 1500 mg/m2 i.v. days 1 & 2, Topo
1.3 mg/m2 days 1-3. The uroprotector Uromitexan was added at the dose of
300 mg/m2 i.v before Ifo and 600 mg/m2 p o. 4 and 8 hours after Ifo days 1 &
2. So far 8 pts with AOC (median age 70, range 56-75) and 6 pts with SCLC
(median age 73; range 72-75) entered the trials; 5 AOC pts and 4 SCLC pts
have been evaluated for toxicity and response. Main toxicities observed are:
neutropenia g.3-4 in 3/9 pts; anemia g. 3-4 in 3/9 pts; mucositis g.2 in 2/9 pts;
emesis g.2 in 3/9 pts. 3/5 pts with AOC had a partial response (PR): duration
of response was 6, 9 and 10 months; 1/4 pts with SCLC had a PR lasting 6
months. Additional pts will be recruited in order to further evaluate activity and
toxicity of this new regimen.
| 620P | A phase I study of oral uracil/ftorafur (UFT) plus
leukovorin in combination with weekly paclitaxel (P) in
patients (pts) with solid tumors.
Frank Mayer'. Joachim von Pawel 2 , Joachim Beck 3 , Michael Schroeder",
Jbrg T Hartmann', Lothar Kanz 1 , Carsten Bokemeyer1. ' Dept.
Oncology/Hematology, University of Tuebmgen Medical Center, Tubingen,
Germany: 2 Asklepios Fachklimken Munchen-Gauting, Munchen-Gauting,
Germany, 3 Johannes Gutenberg University, Mainz, Germany, 4St. Johannes
Hosp.,, Duisburg, Germany
Introduction: Ftorafur is an orally available prodrug of 5-FU. Its combination
with uracil in a molar ratio of 1:4 has been shown to increase the 5-FU
concentration in tumor cells. P possesses a broad activity against solid
tumors, and an in-vitro synergism with UFT. A phase I study was performed to
determine the maximum tolerated dose (MTD) of this combination.
Study design: UFT/leukovorin were applied at a fixed dose of 300 mg/m2
and 90 mg, respectively, divided into three doses at days 1 -28, recycled on
day 36 P was applied as 1-hour infusion on days 1,8,15, and 22 at doses
increasing by 10 mg/m2-steps, starting with 50 mg/m2 up to 100 mg/m2. MTD
was defined as >2 in 3 pts or >3 in 6 pts with dose-limiting toxicity (DLT) at a
given dose level. Any non-hematological toxicities grade 3-4, granulocytopenia
grade 3 and thrombocytopenia grade 4 were considered DLT, when observed
dunng the 1 s t cycle.
Results: 37 pts with various solid tumors have been included up to the
highest dose level with 100 mg/m2 of P, 36 pts being evaluable for DLT. Two
pts did not complete the first course due to early progression. 28 pts are off
treatment. 69 cycles have been applied to these 28 pts. 6 DLT have been
observed so far (diarrhea WHO 3/4 x 4, fatigue syndrome x 1, anemea 3 x
1), no DLT occured at levels 5 or 6 Dunng subsequent courses, the following
3/4 toxicities occured: anemia x 4, thrombocytopenia x 1, leukocytopenia x 1,
diarrhea x 4, anorexia x 2, perianal mucositis x 1, infection x 1, pain x 3.
Conclusion: Due to the lack of overlapping toxicities, the combination of
UFT/leukovorin and P is well tolerated. Major side effects are attributable to
the gastrointestinal toxicity of UFT. The observed frequency is in line with
previous reports of UFT alone. In combination with UFT and leukovorin, P
can be escalated up to doses with proven single-agent activity. Accrual for the
highest dose level is ongoing. Final data will be presented.
| 621P | Vinca alkaloids toxicity in HIV-related neoplasms.
Augusta Torresin. Giovanni Cassola, Giovanni Penco, Sandra Meneghini.
Dept. Infectious Diseases, E.O. Ospedali Galliera, Genoa, Italy
Protease inhibitors (PI), the most potent compounds in highly active antiretroviral therapy (HAART) of HIV infection, induce toxic interactions with other drugs
due to simultaneous metabolism through the cytochrome P450 system (CYP
3A). Vinca alkaloids (VIN) are also cleared through this path, and therefore
more toxic when used concurrently with inhibitors of CYP 3A, i.e. itraconazole. As HIV-related lymphomas and Kaposi's sarcoma are frequently treated
with VIN-containing regimens plus HAART, caution is recommended. In our
experience the association PI+VIN led to neurotoxicity in 4 patients and VIN
had to be withdrawn. Three patients developed paresthesia and pain in both
upper and lower extremities, one pt had paralytic ileus when first treated with
vincristine and developed neuritic pain in the upper limbs upon rechallenge
with vinorelbine. Toxicity developed early and resolved sponteaneously after
VIN withdrawal in all pts but one, who had preexisting mild polyneuropathy.
As HIV positive pts are prone to develop penpheral neurotoxicity induced by
HIV per se, alcoholism, malnourishment and eventually antiretroviral drugs,
"caution" in monitonng VIN-PI co-administration may not be enough. Vinorelbine might be a better choice provided that polyneuropathy has not already
occurred otherwise VIN or Pl-spanng regimens should be devised when CT
and HAART are to be co-administered.
136
622P
Phase I clinical study of CPT-11 hepatic arterial short
infusion chemotherapy (HAIC).
Giammana Fiorentini. Ugo De Giorgi, Silvia Ricci Lucchi, Petros Giovanis,
Barbara Kopf, Giorgio Papiani, Maurizio Marangolo. City Hospital,
Department of Oncology and Haematology Ravenna, Italy
CPT-11 is a new topoisomerase-1 inhibitor with significant activity in colorectal
cancer (CRC). HAIC is a new tool to control liver metastases from CRC.
Up to now, few drugs are useful and handling in HAIC. Liver toxicity is a
limiting factor for HAIC, then new antineoplastic drugs with low liver toxicities
as hepatic (H), biliary (B), vascular (V) are urgently requested. Based on a
previous report (Van Groeningen, Proc ASCO 1997, Abs 768), we investigated
CPT-11 HAIC to determinate the maximum tolerated dose (MTD), to define
HBV and systemic toxicity (ST). We studied five pts, 3 male and 2 female,
median age 52 years (range 39-59), ECOG Performance Status (PS) of 0 (4
pts), and 2 (1 pt). Pts had liver metastases from CRC (4 pts), and soft tissue
sarcoma (1 pt), with a median liver substitution of 33% (10-55%). Pts were
given CPT-11 as a short HAIC on 30 minutes, diluted in 50 ml of normal saline,
every 3 weeks. Table shows preliminary results (° grade 2 asthenia, ' grade 2
abdominal right upper quadrant pain, § grade 2 diarrhea) One pt with SD was
observed, lasting 112 days with CEA reduction (9712 to 4001), and CA19-9
(14616 to 217).
Step
Dose
mg/m 2
No
Pts
Hep Art.conc
pg/mL(x10 9 )
Delivered
Cycles
ST/HBV
observed
Start
I
II
III
IV
V
54
66
70
87
100
128
1
3
1
2
2
1
1 6
21
26
32
38
4 1
2
3
1
4
3
1
1°/0
0/1 •
0/0
1§/0
2§/0
0/0
Conclusions: 1) in the present schedule the MTD of CPT-11 HAIC has not
been reached at 128 mg/m2 for ST and and 4 1 pg/mL for HBV, 2) diarrhea
seems the most relevant toxicity even if less than expected (probably due to
less intestinal wall exposure to CPT-11 systemic blood concentration), 3) HBV
toxicity is minimal. These preliminary results suggest that CPT-11 should be
considered a new drug suitable for HAIC programs.
| 623P | Reduction of skin toxicity of pegylated liposomal
doxorubicin (PLD) by concomitant administration of
dexamethasone and pyridoxin in patients (pts) with
anthracyclin-sensitive malignancies - A phase I/I I trial.
Christian Kollmannsberqer1, Frank Mayer1, Andreas Harstnck2,
Fnedemann Honecker', Udo Vanhbfer2, Carsten Oberhoff2, Lothar Kanz1,
Carsten Bokemeyer1. ' University of Tuebmgen Medical Center, Dept. of
Medicine II, Germany;2 Univ.of Essen Medical Center, Dept. of Medicine II,
Germany
PLD (Caelyx3) has shown activity in a variety of solid malignancies. Its doselimiting toxicities (DLT) are myelosuppression and a palmo-plantar erythema
(PPE). The severity of PPE depends on the dose and schedule of PLD. The
present study evaluated the maximum tolerable dose intensity (MTDI) of PLD
in patients with solid tumors when given dexamethasone (DEX) and pyridoxin
(PYR) in order to reduce the frequency and severity of PPE. DEX 8 mg was
administered p.o. twice daily from day -1 until day +5 of each cycle and PYR
100 mg was given continously p.o twice daily PLD was applied at doses
escalating from 40 to 50 to 60 mg/m2 given q 4 weeks. In a second step,
interval reductions at the highest 4 weekly dose from 28 to 21 to 14 days
was planned. Evaluable pts had received at least 2 cycles of therapy. 27 pts
with various solid tumors have been included to date. 8 pts received only 1
cycle (4 pts anaphylaxia, 2 pts early progression, 2 pts. refused). A total of 51
cycles were applied to the remaining 19 pts. MTDI was 60 mg/m2 every 28
days, 3/7 pts with 21 day interval developed PPE grade 3 or 4, 2 of these pts
also had mucositis grade 3. At the 28 day interval, PPE grade 3 occurred only
in 1/12 pts (during the 3 rd cycle) However, this pt discontinued DEX on day
2. Leukocytopenia 3 was observed in 4 pts and thrombocytopenia 2 in one
patient. The white blood count and thrombocyte nadirs were at days 17 and
15. No neutropenic fever was observed. Apart from alopecia, no other '3 or "4
toxicity occurred.
Conclusion: Compared to reported frequencies of up to 25%, the incidence
of PPE caused by PLD appears to decrease with concomitant DEX and PYR.
MTDI and recommended dose for future trials is PLD 60 mg/m2 every 4 weeks
accompanied by DEX and PYR.
Annals of Oncology, Supplement 4 to Volume 11, 20(H)
"l 2000 Kluwer Academic Publishers, Printed in The Netherlands
Novel therapeutics and pharmacology, biological approaches
| 624P | Clinical phase-l and pharmacokinetic study with
liposomal doxorubicin (DL-1) in patients with
advanced metastatic cancer.
Klaus Mross. Thomas Gierlich, Gerhild Ziegler-Widmer, Brigitte Haring,
Wolfgang Marz, Uwe Sauer, Hansjorg Eibl, Clemens Unger. Dept. Medical
Oncology, Tumor Biology Center, Freiburg, Germany
Introduction: DL-1 is a liposomal formulation with encapsulated doxorubicin
(DOX) within membranes consisting of distearoylphosphatidylcholine (DSPC)
and negative charged lipids distearoylphosphatidic acid (DSPA). Other liposomal formulations of DOX like TLC D-99 and Doxil differ in their membrane
composition, their charge and thus in the pharmacokinetic behaviour.
Material and methods: A total of 28 pts (15 female and 13 male) with
advanced cancer (different tumor types) were treated. Median age was 59 yrs
(37 - 73). The dose was escalated from 20 (n=3), 40 (n=4), 60 (n=11), 80 (n=7)
to 100 (n=3) mg/m2 The drug was administered as 1 hour infusion every three
weeks. 16 pts who had received two (or more) drug administrations qualified
for evaluation of tumor response (WHO) All pts except one were evaluated
for toxicity (CTC).
Results: Dose-limiting toxicities (DLT, grade 3/4) were thrombopenia, neutropenic fever, vomiting and drug-induced fever 6-9 hours after drug administration DLT has been observed in 3/3 (100%) pts at the 100 mg/m2
(thrombopenia, neutropenia, drug-induced fever, vomiting), in 1/7 (14%) pts at
the 80 mg/m2 (neutropenic fever) and in 1/11 (9%) pts at the 60 mg/m2 dose
level (drug-induced fever, neutropenic fever). 1/28 pts dropped out during,
8/28 after the 1 s t treatment cycle because of progressive disease and 4/28 pts
dropped out because of DLT. No drug-related death and no cardiotoxicity was
observed No objective tumor response has been observed in these advanced
cancer pts However 7/16 pts had SD lasting between 9 and 18 weeks
Conclusion: The spectrum of side effects differs from that of free doxorubicin
with respect to a repetitive dose-related drug-induced fever at the day of DL-1
administration Neither a significant mucositis and stomatitis was observed nor
cardiotoxicity The recommended dose for phase II trials is 80 mg/m2.
I 625P | A phase I clinical trial of cisplatin and raltitrexed in
newly diagnosed patients with metastatic carcinoma
of unknown primary (CUP).
J. Raats1, B. Rapoport2-3, R. Mahomed 3 , A. Uys 3 . ' Panorama Mediclmic,
Cape Town, South Africa;2 Dept. Medical Oncology, University of Pretoria,
Pretoria, South Africa;3 Dept. Medical Oncology, The Medical Oncology
Centre of Rosebank, Johannesburg, South Africa
Between 23 04.1999 and 29.10 99 12 newly diagnosed patients with metastatic
cancer of unknown primary (CUP) were treated with raltirexed and cisplatin in
a phase I study. There were 6 females and 6 males and their median age was
58 years. The median performance status (PS) was 1. Sites of metastases
included the gastointestinal tract, mediastinum, lung, liver, pancreas, lymph
nodes and skin. Raltitrexed was given at a fixed dose of 3 mg/m2 while the
cisplatin dose was escalated at a starting dose of 60 mg/m2. Dose escalation
of cisplatin was given as detailed in the table below in cohorts of at least 3
patients
Dose Level
Cisplatin dose (mg/m2)
Raltitrexed dose (mg/m2)
60
70
80
| 627P [ Toxicity and feasibility of paclitaxel-carboplatin (PC)
weekly combination chemotherapy in patients with
various solid tumours.
Rudolf Morant, Giannicola D'Addario, Chnstel Bdhme, Thomas Cerny.
Onkologie, Kantonsspital, St. Gallen, Switzerland
The 3-weekly combination of P 125-200 mg/m2 and C AUC 5-7 is an effective
chemotherapy in various solid tumours. In addition to the platelet sparing effect
of PC, weekly administration of taxanes seems to improve tolerability (Calvert
AH, 1997). We conducted a phase l-ll study with P 75 mg/m2 and C AUC 2-3 day
1,8,15 q4wks. Dose of C was increased from AUC 2 to 3 in all 76 non irradiated
patients (pts) without undue toxicity 95 of 98 pts are evaluable. Median age
was 59 years (20-81), 75 males, 20 females. Tumours treated were advanced
non small cell lung cancers (27 pts), esophageal carcinomas (28, including
14 neoadjuvant), head and neck (13), bladder (8), cervix (7), sarcomas (4),
mesotheliomas (2), neuroendocrine tumours (2), 1 pt with anal, thymic, gastric
carcinoma each and 1 pt with cancer of unknown origin 19 pts received
concomitant radiotherapy (RT). 45 tumours were squamous cell carcinomas,
34 adenocarcinomas, 7 transitional cell carcinomas, 5 sarcomas and 4 of
other histology. In 326 cycles (1-8 per pt, mean 3.4) we observed grade III
leucopenia in 21 cycles (6.4%) and 1 grade IV leucopenia, thrombocytopenia
grade III, IV in 1 cycle each. Further toxicities were nausea l-lll in 41 pts,
diarrhea in 13 pts (2 grade IV). Thromboembohc events were seen in 7 pts,
esophagitis ll-lll during RT in 10 pts, mild neurologic symptoms in 8 pts. 3
cutaneous allergic reactions and 34 infections were seen (no hospitalizations).
ORR was 57%, 50 pts PR, 4 CR (3 pCR). Median time to response was 2
months.
Conclusions: Weekly PC is safe, feasible and well tolerated in outpatient
use even with concomitant RT. It allows high dose intensity and yields rapid
responses ORR in solid tumours is high. This regimen should further be
explored in palliative and neoadjuvant settings.
| 628P | Pharmacokinetic evaluation of the oral form of
Navelbine® all along its clinical development.
At dose level 3,2 patients died due to febrile neutropenia. Febrile neutropenia
was the dose limiting toxicity at the cisplatin dose of 80 mg/m2. A decrease
in renal function was documented in 3 patients. Other significant side effects
included nausea and vomiting ranging from grade I to III, grade III neutropenia,
oesophagitis, stomatitis, colitis and septicaemia. Anaphylaxis was documented
in one patient following cisplatin administration. Two complete responses (CR)
and 1 partial response (PR) were documented.
The recommended doses for a phase II study with this combination in
patients with CUP is raltirexed at a dose' of 3 mg/m2 and cisplatin at a dose of
70 mg/m'.
This treatment is fairly well tolerated and shows efficacy in some patients
with CUP. A phase II study has been initiated.
6 2 6 P | Phase I study of paclitaxel, UFT and leucovorin
calcium in patients with metastatic solid tumors.
Katherine H. Tkaczuk'- 2 . L. Austin Doyle 1 2 , Nancy Tait1-2,
Catherine Quinn 1 , Elizabeth Duckham 12 , Frances Buadi1-2, Timothy Chen 1 ,
Martin Edelman1'2. ' Greenebaum Cancer Center, University of Maryland,
Baltimore, USA;2 Veterans Administration Medical Center, Baltimore, USA
Paclitaxel (Tax) and UFT have demonstrated antitumor activity in a variety of
solid tumor malignancies as single agents. We conducted a phase I study of
Tax, UFT and leucovorin calcium (LC) in patients (pts) with solid tumors to
assess toxicities, and the maximum tolerated dose (MTD) of the combination.
Annals of Oncology, Supplement 4 to Volume 11, 2000
Standard phase I eligibility criteria were used. Tax was administered in a
fixed dose of 80 mg/m2 intravenously as 1-hour infusion on days 1, 8, 15
and 22 of each 6-week cycle. UFT was escalated and administered orally
twice daily(bid) with LC also administered orally in a fixed dose of 30 mg
bid before UFT on days 1,2, 3, 4 and 5 of each week for 4 out of 6 weeks.
Patient profile: 3 females, 3 males, median age 54 (range 38-70), median
ECOG performance status 0 (range 0-2). Three pts had breast carcinoma
(Ca), 2 pts esophageal Ca, 1 pt non-small cell lung Ca. G-CSF use was
not permitted. Six pts were treated, 3 in cohort I with total daily dose (TDD)
of UFT of 400 mg, with no dose limiting toxicity observed. Three pts were
treated in cohort II with TDD of UFT of 500 mg. Fifty-six weekly cycles
were administered, and 2 weie held foi 1 week due to myelosuppression or
upper respiratory infection. One pt in cohort II developed grade IV diarrhea,
the doses of UFT and Tax were reduced and he was able to continue on
treatment. Hematologic toxicities were mild with median WBC 4.55 x 103
/mcl, (range 2.3-14.2), median ANC 2.546 x 103/mcl (range 0.988-10,220),
median hemoglobin 11.5 g/dl (range 9.5-14.2), median platelet count, 229 x
103/mcl (range 103-442). Grade l/ll non-hematologic toxicities include fatigue,
supraventricular tachycardia, dizziness, nausea, alopecia, mucositis, sinusitis,
facial flushing and hypokalemia. MTD was not reached and the study continues
to accrue pts.
Antoine Adenis 1 , Jacques Bonneterre1, Michel Marty 2 , Paul Henri Cottu 2 ,
Roland Bugat3, Philippe Variol4, Christian Puozzo 4 . ' Institut Oscar Lambret,
Lille, France;2IGR, Villejuif, France; 3 Institut Claudius Regaud, Toulouse,
France; 4 Dept. Clinical Pharmacokinetics, Pierre Fabre Medicament, Castres,
France
An oral form of Navelbines(vinorelbine) has been developed to propose
to patients a convenient alternative to the IV treatment Since oral forms are
suspected of presenting a different pharmacokinetic pattern from the IV, several
clinical studies were completed to assess this hypothesis. During the oral
dose escalation phase I study, dose proportional increase of blood exposure
was established from 60 to 100 mg/m2 as previously demonstrated with IV
Navelbine®. The absolute bioavailability of the soft gelatine capsule evaluated
at the recommended dose (80 mg/m2) in 24 patients was 43 ± 14%. Moreover,
the inter-patient variability on blood exposure was the same for the IV and
the oral administrations (CV = 37-38%). Since protein binding of vinorelbine is
low (14%) and non saturable, this factor is unlikely to impact the bioavailability
whatever the oral dose. Neutropenia, the dose limiting toxicity of Navelbine®,
was demonstrated to be correlated with blood exposure, independently of
the administration route. Food effect assessed in a cross-over design in 12
patients had no relevant influence on the pharmacokinetics of oral Navelbine®.
In conclusion, these phase I studies demonstrated large similarities on the
pharmacokinetic behaviour between the oral and the IV forms of Navelbine9
and an equivalent blood exposure for a 80 mg/m2 oral and a 30 mg/m2 IV
doses (as for 60 mg/m2 and 25 mg/m2 respectively). Pharmacokinetic data
collected during phase II trials supported those conclusions.
© 2000 Kluwer Academic Publishers, Printed in The Netherlands
137
Novel therapeutics and pharmacology, biological approaches
629P
A phase I pharmacokinetic study of declopramide in
combination with cisplatin in patients with advanced
cancer.
Scot Remick, A. Dowlati, K. Robertson, C. Buchter, S. Ingalls, C. Hoppel,
T Spiro, V. Makkar, B. Overmoyer, S Gerson. Developmental Therapeutics
Program, Ireland Cancer Center at University Hospitals of Cleveland and
Case Western Reserve University and Louis B. Stokes VA Medical Center,
Cleveland, OH, USA
Declopramide (3-chloro-procainamide), is a newly synthesized N-substituted
benzamide. It has been shown to decrease tumor-doubling time with cisplatin
in mouse xenograft models. We completed a phase I trial to determine the
maximum tolerated dose (MTD) of declopramide when given with cisplatin and
to study the pharmacokinetics (PK) Twenty-six patients (pts) with advanced
prior treated solid tumors were enrolled and given an escalated dose of
declopramide orally over a dose range of 400-1600 mg once daily for 3
consecutive days. On day 2 a fixed dose of cisplatin (75 mg/m2) was given
intravenously. Cycles were repeated q28 days. A total of 58 cycles were
given. There was little toxicity over the entire dose escalation and there were
no apparent cumulative side effects. Myelosuppression was negligible No
renal toxicity was observed. Prolongation of QTc interval was dose-limiting
(declopramide alone), symptomatic at 1600 mg (0.54 msec). A transient
increase of ~10% in QTc has been observed across the dose escalation
with no further consequences. Peak plasma concentration correlated with the
time of maximum QTc prolongation. At the 400 mg dose mean peak plasma
concentration was 3150 ng/ml (± 791). The time elapsed to peak measured
declopramide concentration after dose administration increased with dose (1
hr. at dose of 400 mg, 2 hrs. at dose of 800 mg). Mean trapezoidal AUC from
0-48 hr at the dose of 400 mg is 20348 (±2036). N-acetyl-declopramide is
a minor metabolite (<2% of parent drug), which is different than prechnical
munne studies. A pt with melanoma had a PR; 3 SD (6,6,8 mos.). The
recommended phase II dose of declopramide is 600 mg in combination with
cisplatin on this schedule (Study sponsored by OXiGENE, Inc., Boston, MA )
| 630P | 4'-epidoxorubicin-loaded polybutyl-2-cyanoacrylate
nanoparticles (PBCN): In vitro and in vivo antitumor
activity.
Margarita Antcheva 1 , Margarita Simeonova2, Maria Hadjikirova' ' National
Oncological Centre, Sofia, Bulgaria;2 Speciality Polymers Ltd, Sofia, Bulgaria
Drug earners, including biodegradable polyalkylcyanoacrylate nanoparticles,
have been used for overcoming the side effects of antracychne cytostatics and
for increasing their therapeutic index The aim of the present study was to
investigate the ability of PBCN to modify antitumor effect of 4'-epidoxorubicin
(farmorubicin, FR) in experimental conditions: in vitro on the growth of cells of
human monocyte like tumor celle line U-937 and in vivo on growth of Lewis
lung carcinoma (LLC) in mice. We have compared cytotoxic activity of free
FR, FR entrapped in polymer matrix of nanoparticles dunng polymerization
(FR/PBCN), FR adsorbed on previously prepared PBCN (FR-ads), physical
mixture of FR+PBCN, prepared ex tempore, unloaded PBCN and saline
solution. In in vitro conditions polymer bounded forms of FR induced stronger
cytotoxic effects on U-937 tumor cells, which were dependent in their degree
of expression on modes of association with carrier, enhanced by adsorbed FR,
across phys. mixtures and most strongly expressed by FP/PBCN. The effect
was time- and dose-dependent. Free FR suppressed synthesis of DNA, while
polymer bounded one stimulated DNA synthesis, but blocked the division of
cells. In in vivo expenments on mice bearing LLC, the treatment with tested
compounds on days 1, 4, 8 and 11 after transplantation induced inhibition of
tumor growth (ITG). Percents of ITG, evaluated 96 h after the last injection
have demonstrated that polymer bounded forms had higher antitumor efficacy
than free FR. The mixtures were more toxic than FR/PBCN and FR-ads. It
is interesting that unloaded PBCN induced some ITG However the median
survival of treated tumor-beanng mice was not prolonged. In conclusion, our
results of the present study demonstrated that polymer carrier is able to modify
the therapeutic efficacy of FR. Partially supported by the National Science Fund
of the Bulgarian Ministry of Education and Science under grant N. X-618/1996.
631P | Feasibility and myeloprotective effect of high-dose
amifostine combined with high-dose
cyclophosphamide.
Michele Ghielmini', Sabine Van der Bosch 1 , Manuela Bosshard',
Sandra Pampallona 2 , Luca Gabutti 3 , Hans-Peter Egger4, Markus Kiess 4 ,
Franco Cavalli 1 , Cristiana Sessa 1 . ' Dept. of Oncology, Oncology Institute of
Southern Switzerland, Bellinzona, Switzerland; 2 ForMed, Statistics for
Medicine, Evolene, Switzerland; 3 Department of Nephrology, Lugano,
Switzerland; * Essex Chemie AG, Luzern, CH, Switzerland
patients previously treated with the same HD-CTX regimen served as control.
The dose of amifostine was escalated in cohorts of 3 patients each from 4 x
570 mg/m2 to 4 x 910 mg/m2 without severe toxic effects. Further patients
were treated at the highest dose level Side effects included fall of blood pressure (always less than 20% of baseline value), asymptomatic hypocalcemia
(from a median value of 2.4 to 1.7 mmol/L) and a decrease of creatinine
clearance (from a median value of 102 to 85 ml/mm). Patients treated in the
study experienced significantly longer hospital stays (median 12.5 vs 8.5 days)
and thrombocytopenia (median 5 days vs 2 days with platelets < 20 x 109/L)
than controls PBSC mobilisation was comparable in the 2 groups
Conclusion: Amifostine can be given safely in one day at the dose of 4 x
910 mg/m2; its use in combination with HD-CTX is not recommended because
it has no myeloprotective effect.
[ 632P | Dose-intensity (Dl) based escalation phase I study of
MG1114 (Irofulven) exploring 3 different i.v. schedules
in advanced solid tumors.
Jerome Alexandre1. Eric Raymond2, Etienne Brain 3 , Mahmoud Ould Kaci 4 ,
Shen Smith5, Jean-Louis Misset1. ' FSMIST, Hopital Paul Brousse, Villejuif,
France;2 Inst Gustave-Roussy, Villejuif, France, 3 Cntre Rene Huguenin,
St-Cloud, France; 4 CAC, Kremlm-Bicetre, France;5 MGI Pharma,
Minneapolis, USA
Irofulven, an illudin derivative active in preclinical solid tumor (ST) models,
is currently in phase l/ll development Initial phase I studies were performed
using a dailyx5 q4 week(w) schedule (Sch), with a recommended dose (RD)
of 11 mg/m2/dx5d in a 5' infusion Delayed thrombocytopenia (T) was the
principal dose limiting toxicity (DLT), and grade (G) 2/3 acute/subacute emesis
and asthenia/anorexia were also observed, leading to frequent treatment
delays/discontinuations. To circumvent these toxicities, a new phase I trial
exploring 3 different intermittent dosing Sch is ongoing, with traditional acute
DLT definitions, but including compliance with planned Dl over 2 cycles in
DLT/MTD criteria (non-administration of scheduled D8/D15 with delay >1w or
a cycle delay >2w for toxicity is considered DLT). Sch. A: D1,8,15 q4w, Sch.
B D1,8q3w, Sch C:D1,15q4w Starting Dl being 75% of the daily x 5 RD (10
mg/m2/w), planned Dl was increased by 2 mg/m2/w at successive dose levels
(DL) if <50% of <6 patients (pts)/DL experienced DLT. Steroids+anti-5HT3,
and hydration before and after each dosing, were systematically given. As of
4/2000, 15 pts with advanced ST were treated (M/F 8/7), median age: 55
(25-71). 10 pts were treated with Sch. A, DL 1(13.3 mg/m2/d) and DL 2 (16
mg/m2/d): 5 pts each, 9 pts evaluable for safety. Treatment delays due to T or
neutropenia (N) are the only DLTs: 1/4 pt (T G3) at DL 1, 2/5 pts (T G2, N G3)
at DL 2 No other G3/4 toxicities were observed. A 50% PSA decrease was
observed in 1 prostate cancer pt.
MGI 114 weekly Sch A, has a better clinical safety profile than the daily x
5 q4w Sch While the preliminary MTD of Sch A appears 16 mg/m2/d (DL 2),
Sch B and C exploration is ongoing. Updated results will be presented.
633P Docetaxel (Txt) in the chemotherapy of elderly cancer
patients (pts).
Natalia Besova, Nadezda Orel, Vera Gorbounova. Department of
Chemotherapy, Cancer Research Center of Russia, Moscow, Russian
Federation
11 elderly pts, median age 71,2y (range 67-77y) were treated with Txt. Pts
had different malignancies breast cancer (BC)-2 pts, ovarian cancer (OC)-2
pts, gastric cancer (GC)-3 pts, non-small cell lung cancer (NSCLC)-1 pt, smal
cell lung cancer (SCLC)-2 pts, carcinoid (CRN)-1 pt. Age of 7/11 pts was
>70 y, 6/11 pts had >3 concomitant diseases. ECOG pretreatment PS was
0 - 2 pts, 1 - 4 pts, 2 - 3 pts, 3 -2pts. 2 pts were treated with Txt alone at
a dose 100mg/m2/21d (1BC as a second line CT + 1CRN), 1 pt (BC)-with
Txt 80mg/m2 + adnamycin 40mg/m2 every 21 d, 5 pts-with Txt 75mg/m2 +
CDDP75 mg/m2 every 21 d, 3 pts-with Txt 65-70mg/m2 d2 + CDDP 65mg/m2
d2 + 5FU 320mg/m2 1-3d, every 28d All pts received 77 treatment cycles
(els) (range 2-10). The main toxicities were hematological and gastrointestinal:
neutropenia-50% of els (gr lll+IV-28,3%), anemia-16,7% of els (gr IV-5%),
stomatitis-11,6% of els (gr 111-1,6%), diarrhea-8,2% of els (gr lll+IV-4,8%).
We recorded 3 episodes of non-fatal febnle neutropenia in 3 pts. The dose
reduction of Txt was performed in 4 pts due to: febrile neutropenia+diarrea gr
IV—1 pt, febrile neutropenia+stomatitis gr 111-1 pt, febrile neutropenia-1 pt, poor
performance status-1 pt. Neurotoxicity was noted in 3 pts: gr l-2pts, gr 11-1
pt. The results were: BC-2/2 PR (37 and 23 weeks), OC - 1/2PR (42 weeks)+
1/2SD (33 weeks), NSCLC - 1/1PR (18 weeks), SCLC - 2/2PR (21 and 39+
weeks), GC - 1/3PR (9+ weeks) +1SD+1PD, CRN - 1 SD (44 weeks). 5/11 pts
showed improvement of their PS.
Conclusion: Txt is well tolerated and effective drug for the treatment of
elderly cancer pts not only as a singe agent but in combined chemotherapy
To determine whether escalating doses of amifostine could decrease the myelotoxicity and improve the mobilisation of blood progenitors (PBSC) caused by
high doses (HD) of cyclophosphamide (CTX), sixteen patients with diagnoses
of lymphoma were treated with HD-CTX, given a total dose of 7 g/m2 subdivided into 4 doses, each preceded by amifostine. A group of 12 lymphoma
138
Annals of Oncology, Supplement 4 to Volume 11, 2000
© 2000 Kluwer Academic Publishers, Primed in The Netherlands
Novel therapeutics and pharmacology, biological approaches
I 634P I Apoptosis in human prostate cancer cells shows
enhanced sensitivity to taxol in the presence of
exisulind.
William J. Thompson, Li Liu, Marti Lloyd, Gary A. Piazza, Rif Pamukcu. Cell
Pathways, Inc, Horsham, PA, USA
Exisulind (EXI), a selective apoptotic anti-neoplastic drug (SAAND), and taxol
(TX), a taxane, are pro-apoptotic agents with different mechanisms of action
EXI in advanced clinical trials for prevention and regression of colon polyps in
familial adenomatous polyposis, has shown PSA stabilization in a clinical trial
on patients with rising PSA levels post-prostatectomy. In colon cancer cells
(CC), data on EXI support a mechanism involving cGMP phosphodiesterase
inhibition leading to cGMP-dependent protein kinase activation. We have
tested in prostate CC if at a fixed time post-drug application, whether EXI
would more effectively induce apoptosis in the presence of a drug like TX
with a different mechanism of action, in this case microtubule stabilization
Conversely, we determined if TX would be more effective in the presence of
EXI. Hormone dependent-LNCaP and hormone independent-PC3 CC were
plated at 10000 cells/well in 96 well plates for 24 hr before simultaneous drug
applications. Apoptosis was determined after 48 hr of drug treatment using
DNA-fragmentation measured with ELISA to provide quantitative apoptosis
values. EXI induced apoptosis in LNCaP and PC3 CC with EC50's of 600 and
740 /iM, respectively. TX alone induced apoptosis in LNCaP, but not in PC3,
showing an EC50 = 7 nM. In LNCaP EXI caused a dramatic left shift in the
TX dose-response curve. Maximal effect occurred at 4 nM, thus indicating
a synergistic response. In LNCaP EXI dose-response also showed a 2 fold
increase in apoptosis sensitivity with 5 nM TX. In PC3 EXI dose-response
showed a left-shift with TX at 10 nM. The data provide pre-clinical rationale for
clinical trials designed to determine the combined actions of these two classes
of drugs with differing mechanisms of action in prostate cancer patients
I 635P I ZD9331 plus topotecan in patients with refractory solid
malignancies: A phase I dose-escalation study.
Al B. Benson III 1 , Elizabeth Poplin 2 , Edwin Douglass3. ' Division of
Hematology/Oncology, Robert H Lune Comprehensive Cancer Center of
Northwestern University, Chicago, IL, USA, 2 Cancer Institute of New Jersey,
New Brunswick, NJ, USA;3 AstraZeneca, Wilmington, DE, USA
ZD9331, a novel folate analogue, is an inhibitor of thymidylate synthase (TS).
Unlike other TS inhibitors, it is not polyglutamated and may, therefore, show
good activity in tumour cells with low folylpolyglutamate synthetase activity. A
phase I study has shown that ZD9331 has activity against a range of solid
tumours, including ovarian cancer. The dose schedule for phase II studies
was determined as 130 mg/m2 given on days 1 and 8 of a 3-week cycle. A
combination of ZD9331 and topotecan, a topoisomerase I inhibitor approved
for use in recurrent ovarian cancer, may improve the outcome for patients with
tumours refractory to current therapy The aim of this study is to determine the
maximum tolerated dose of ZD9331 administered on days 1 and 8 (30-min
iv infusion) in combination with topotecan administered on days 1-5 (30-min
iv infusion) of a 3-week cycle On day 1, ZD9331 is administered first, with a
30-min break before topotecan administration Up to 20 patients with refractory
solid malignancies will be recruited. ZD9331 will be administered at 65 mg/m2
at dose levels 1-5, increasing to 97 and 130 mg/m2 at dose levels 6 and 7,
respectively The initial dose of topotecan will be 0 5 mg/m2 with increments of
0 25 mg/m2 to 1 5 mg/m2 at dose levels 5, 6 and 7. A total of 15 patients have
been enrolled to date: 8 at dose level 1 and 7 at dose level 2. Patient accrual
is ongoing and detailed results will be presented.
636P
A phase I and pharmacokinetic study of declopramide
as a single agent and in combination with IV
5-FU/leucovorin in patients with advanced cancer.
John Randall Eckardt, Ann Schmidt, Alexander Denes, Burton Needles
Medical Oncology, St. John's Mercy Medical Center, St. Louis, USA
Declopramide (3-chloro-procainamide) is a newly synthesized N-substituted
benzamide currently being studied for its DNA repair inhibitory effects and its
ability to induce apoptosis in conjunction with current standard chemotherapy.
Twenty-two patients with advanced solid tumors (18 colorectal; 3 head & neck;
1 hepatoma) received escalating doses of declopramide orally (400-900 mg
daily for five days) followed, after a 2-day rest, with declopramide + 5-FU
325-425 mg/m2 + LV 20 mg/m2 for 5 days every 28 days. Standard phase I
eligibility criteria used.
Results: At 900 mg/m2, two patients were observed with asymptomatic
QTc prolongation (25% increase in QTc that normalized in 24 hours). This
was considered a dose limiting toxicity. Therefore, the MTD for declopramide
was established at 800 mg/m2. No other significant toxicities were attributed
to declopramide. Two of two patients at the 425 mg/m2 dose level of 5-FU
developed dose limiting gastrointestinal toxicity with grade 3/4 diarrhea and
mucositis. Other grade 1/2 toxicities included fatigue, diarmea, nausea and
vomiting. Therefore, the recommended dose for phase II trials with this regimen
is declopramide 800 mg orally for 5 days followed in 30 minutes by 5-FU 375
mg/m2 + LV 20 mg/m2 for 5 days. Activity: One patient with advanced colon
Annals of Oncology, Supplement 4 to Volume 11, 2000
cancer achieved a CR which has been maintained for > 2 years. Two patients
achieved a minor response and maintained for 2-7 months (mean = 4.5
months). Seven patients had stable disease for 2-14 months (mean = 5.2
months). One patient with hepatocellular carcinoma maintained stable disease
for a total of 17 cycles (14 months). The last patient enrolled with head and
neck cancer had an unconfirmed partial response after cycle 2. All patients
excluding the CR and unconfirmed PR have developed progressive disease
after 2-17 cycles. PK analysis is ongoing. Plans for phase II trial evaluation
are underway. Supported by a grant from OXiGENE, Inc.
I 637P I Drug interaction of capecitabine and phenytoin in the
therapy of cerebral and visceral metastatic breast
cancer.
Gerhard Schaller, Andreas Ebert, Andrea Kuhle, Nikola Bangemann.
Gynecology and Obstetrics, Medical Center Benjamin Franklin, Berlin,
Germany
Brain metastases have a 10-15% incidence in breast cancer patients and may
require permanent anticonvulsive therapy. Phenytoin (Zentropil8) is particularly
well suited because of its negligible sedative and hypnotic side effects. In the
systemic cytostatic therapy of metastatic breast cancer, however, it is necessary
to consider possible interactions that can lead to signs of phenytoin intoxication.
Two breast cancer patients with brain and liver metastases were treated with
a combination of capecitabine (Xeloda®) and trastuzumab (Herceptin®) Six to
eight weeks after the initiation of capecitabine therapy, both patients developed
cerebellar symptoms indicative of phenytoin intoxication. After excluding other
interactions, pharmacological examinations showed that this was attributable
to a hitherto unknown interaction with capecitabine. The mechanism of this
interaction has not yet been fully clarified. Investigations thus far point to a
downregulation of the isoenzyme P4502C9 by capecitabine. This enzyme plays
a major role in the hepatic degradation of phenytoin In view of the probable
drug interaction, frequent monitoring of the phenytoin level is imperative in
conjunction with capecitabine therapy if phenytoin cannot be replaced by
alternative anticonvulsants
638PJ Incidence of thrombocytopenia (T) induced by
gemcitabine (G)-based therapy: Influence of schedule.
Luis Cirera 1 , Catherine A. Smith 2 , Patrick Peterson2, Baojin Zhu 3 , Debasish
F. Roychowdhury2 r Hospital Mutua de Terrasa, Terrasa - Barcelona, Spam;
2
Lilly Research Laboratories, Indianapolis, USA;3IUPUI, Indianapolis, USA
T has been noted with G (Gemzar®)-based therapy, but significance of T and
influence of schedule have not been evaluated In this report, phase ll/lll trials
were identified from the G clinical trial database.
Objectives: To determine incidence, assess clinical sequelae of T, evaluate important clinical factors influencing T. Previously treated or chemonaive
patients were included. Data were divided into single-agent (S) G (61) or combination (C)(31) trials. Patients (pts) with WHO/CTC grade 3/4 T (<50,000//zl)
or hemorrhage (H) were identified. T and H incidence was estimated and influence of dose/schedule analyzed using chi-square test. Platelet transfusions
(PLT) were recorded In the S group, 7% (177/2609) of pts had grade 3/4 T
(73% grade 3, 27% grade 4). 1 pt had grade 3 H No pts had grade 4 H. 35
(1%) pts received 37 PLT. In the C group (including all drug combinations),
40% (726/1804) of pts had grade 3/4 T (55% grade 3, 45% grade 4). 9 (0.5%)
pts had grade 3/4 H (10 episodes of grade 3 and 1 episode of grade 4). 111
(6%) pts received 156 PLT. In the C group, 1518 and 278 pts were on a 28(D 1,8,15 Q28d) and 21- (D 1,8 Q21d) day schedule, respectively. Incidence
of grade 3/4 T on the 28-day schedule was 43% (648/1518) of pts vs 28%
(78/278) of pts on a 21-day schedule (p<0.001). Further analysis limited to
pts treated with G + cisplatin (<75 mg/m2) showed that grade 3/4 T was less
common on a 21- vs 28-day schedule (30% vs 49%) (p=0 001). However, this
effect of schedule was not seen with higher doses of cisplatin (100 mg/m2).
Conclusion: G-based therapy produces T, but clinical sequelae (H and
PLT) were minimal. Combination therapy produces more T than single-agent
therapy. A 21-day schedule produces less T.
639P
Management of unresectable hepatocellular carcinoma
(HCC) with cisplatin/epinephrine (CDDP/epi) injectable
gel administered percutaneously: Radiologic and
histologic evidence of tumor ablation.
Philip Johnson', T.W.T Leung', T.J. vogl 2 , G. Gores 3 , M. Giovannini 4 ,
J. O'Grady5, L. Anthony6, A. Ill Benson7, P.J. Thuluvath 8 . ' Dept. of Clinical
Oncology, Prince of Wales Hospital, Shatin, N.T., Hong Kong, China, and The
Clinical Trials Group; 2Johann Wolfgang Goethe University, Frankfurt,
Germany; 3Mayo Clinic, Rochester, USA;4 Institut Paoli-Calmettes,
Marseilles, France;5 Kings College Hospital, London, UK;6LSU Medical
Center, New Orleans; 7 Northwestern University Medical School, Chicago;
8
Johns Hopkins University Medical Center, Baltimore, USA
We assessed the efficacy and safety of a novel percutaneous treatment
for unresectable HCC using CDDP/epi injectable gel (IntraDose®), designed
© 2000 Kluwer Academic Publishers, Printed in The Netherlands
139
Novel therapeutics and pharmacology, biological approaches
to achieve uniform intratumoral CDDP concentrations for extended periods
This ongoing phase II trial is evaluating treatment-naive, or previously resected/relapsed patients with unresectable primary HCC; tumor response and
survival are endpoints. Eligibility measurable disease (<3 tumors, max. dia.
<7 cm, total vol. <200 cm3), no extrahepatic or major vascular involvement
Treatment: 510 ml of CDDP/epi gel (1 ml contains 4 mg CDDP, 0 1 mg epi; 20
mg gel), administered by percutaneous intratumoral injection under ultrasound
or CT guidance, once a week for 4 treatments; 4 more at investigator discretion. Tumor response was assessed using 3-phase CT to estimate percent
decrease in viable tumor volume (CR or PR, both sustained >28 days). Fortyfour patients have been evaluated for safety, 38 for response. Mean age: 64
yr (37-81); median total tumor vol.: 36 cm 3 (2-329 cm 3 ); median treatments:
4 (1-8). CDDP/epi gel produced reductions in viable tumor in 21/38 patients
(55%), 9 CR and 12 PR, only 4 of these patients developed new tumors in
other untreated hepatic sites. When survival of the first 29 patients from this
group was compared with a contemporary group of 29 patients with matching
liver disease and liver tumors that underwent surgical resection, the survival
curves are similar. Orthotopic liver transplantation was performed in 3 patients
(6 lesions: median vol. 4.3 cm 3 , range 1.1-70 cm3) within 2-6 months after
completing a median of 4 treatments Histologic analyses of the explanted
livers confirmed the tumor necrosis classified as complete by CT. In a fourth
patient, who died after receiving 3 treatments, the autopsy showed ~75%
necrosis of treated lesions. Drug administration was convenient and safe with
moderate and manageable side effects. Intratumoral CDDP/epi gel may provide an effective treatment for patients with unresectable HCC measuring <7
cm, and can be used to control tumor growth in patients with HCC awaiting
liver transplantation.
| 640P | Exisulind enhances the growth inhibitory effects of
gemcitabine and vinorelbine on human lung cancer
cell lines.
Joan Schiller. Gerard Bittner Dept of Medicine, Medical Oncology, University
of Wisconsin, Madison, Wl, USA
Exisulind is a selective apoptotic anti-neoplastic drug (SAAND) that inhibits
NNK induced mouse lung tumor formation (Carcinogenesis 19(8) 1353-1356,
1998) and shows growth inhibitory activity in vitro against non-small cell
(NSCLC) and small cell lung cancer cell lines alone and in combination with
paclitaxel and cisplatin (Cancer Res 59:6178-6184, 1999) The current study
evaluated growth inhibitory activity of exisulind alone and in combination
with chemotherapeutic agents in the NSCLC cell line, Calu-6. Cancer cells
were plated in culture for 24 hours and gemcitabine or vinorelbine in varying
concentrations were added to the wells for one hour. The cells were washed
with media, treated with varying concentrations of exisulind for four days,
dissociated, and counted. Data below show the mean percent of control
cell growth calculated from triplicate determinations. Individually, exisulind,
gemcitabine, and vinorelbine all showed dose-dependent inhibition of tumor
growth. The combination of exisulind with gemcitabine or vinorelbine resulted
in additional growth inhibitory effects. Similar additive effects were seen in the
large cell carcinoma cell line H460.
Exisulind
(Mg/ml)
0
10
20
40
Gemcitabine (ng/ml)
Vinorelbine (ng/ml)
0
5
10
20
0
1.25
2.5
5
100
74
49
29
83
65
46
29
56
42
33
17
44
36
27
15
100
78
51
35
61
46
26
17
42
31
33
17
31
27
15
11
Values are percent of control cell growth.
These results provide rationale for clinical studies being planned in NSCLC
utilizing combinations of exisulind and vinorelbine or gemcitabine in an effort
to attain better clinical outcomes than with single agent treatments.
641P
Phase I trial of pemetrexed disodium and vinorelbine
(VNB) in patients with advanced malignancy.
Stephen Clarke 1 . Michael Millward1, Philip Beale 1 , James Bishop 1 ,
Annabel Childs 1 , Michael Boyer 1 , Paul De Souza 2 . ' Sydney Cancer Centre,
Sydney, Australia;2 Eli Lilly, Sydney, Australia
Pemetrexed disodium (ALIMTA, LY231514) is a novel folate based anti-cancer
drug which inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR)
and glycinamide nbonucleotide formyltransferase (GARFT), has multiple tumor
activity that includes non-small cell lung (NSCLC), mesothelioma, breast, and
colon cancers. As it would be particularly helpful to define active non-platinum
based regimens for NSCLC, this study was initiated to define the maximally
tolerated doses and toxicities of the combination of pemetrexed (given as a
10 minute infusion day (d) 1) and VNB (d 1 and 8) administered on a 21 d
cycle. Standard phase I inclusion/exclusion criteria were applied and the dose
escalation plan is shown below.
From mid 1999 to date, 14 pts (5 females and 9 males), median age 52
years, received 35 cycles of therapy (median 2, range 1-6). Following dose
140
Dose Level
1
2
3
4
5
6
ALIMTA (mg/m2)
Vinorelbine (mg/m2)
Patient No
DLT
300
400
400
500
500
600
15
15
23
23
30
30
3
6
3
2
0
1
0
0
level 2, vitamin B12 and folic acid were given to all pts because they had been
shown to reduce toxicity from ALIMTA. The median PS was 1 and pts with a
variety of malignancies have been enrolled including renal cell - 2, melanoma
- 2, lung cancer - 3, adenocarcinoma unknown primary - 2 and 1 each of
colon, ovarian, pancreas, squamous cell cancers (SCC) and mesothelioma
Grade 3/4 toxicities encountered so far have included neutropenia, rash and
diarrhoea, each in 1 pt One pt with SCC penis has obtained a partial response
in pulmonary metastases. Currently dose level 4 is being completed.
642P A phase I study of the combination of gemcitabine (G),
vinorelbine (V) and cisplatin (P) in patients (pts) with
solid tumors.
Dirk Schnivers, Joke Dyck, Jan Van den Brande, Pascal Wilmes,
Annehes Korst, Filip Lardon, Jan Vermorken Dept Medical Oncology,
University Hospital Antwerp, Edegem, Belgium
A phase I study was performed to determine the maximum tolerated dose, the
safety (DLT) and the doses for phase II of GVP in different schedules
Starting doses were P 75 mg/m2/d on day 1, G 800 mg/m2/d and V 25
mg/m2/d Three schedules were tested: A: G 4 hours before P and V with V/G
on day 8 and 15; B: G 24 hours after P and V, C: V and G 24 hours after P,
both in B and C followed by V/G on day 9 and day 16. Cycle interval was 4
weeks.
Six patients were treated in each schedule with 22 cycles in A, 21 in B and
23 in C Hematologic toxicity prevented the planned administration in 39 cycles
on day 15/16
Grade 3-4 neutropenia and thrombocytopenia were seen in 77% and 36%
of cycles in A, 7 1 % and 48% in B and 83% and 43% in C, respectively Grade
3-4 vomiting was observed in 3 cycles and fatigue in 2 cycles in A and fatigue
and stomatitis in 1 cycle in C Neutropenic fever occurred in 1 patient in A and
3 patients in C. Platelets were given to 2 patients in B and 1 patient in C. One
complete and 1 partial response were observed
Conclusion: none of the schedules could be given in the proposed doses.
DLT's were seen in A (neutropenic fever: 1/6 patients), B (grade 4 thrombocytopenia 2/6 patients) and C (neutropenic fever 3/6 patients, grade 4
thrombocytopenia' 1/6 patients).
| 643P | Ifosfamide (IF) pharmacokinetics (PK): Continuous
infusion (Cl) versus 3H infusion (IV3H) in advanced
tumours.
Etienne G.C. Brain 1 , Benjamin Besse', Joelle Santoni', Sophie Weill 1 ,
Alain Goupil1, Bernard Gourmel 2 , FrangoisTurpin1, Francois Lokiec1.
' Medical Oncology, Rene Huguenin Cancer Centre, Saint-Cloud, France;
2
Biochemistry, Saint-Louis Hospital, Pans, France
The bifunctional oxazaphosphorine alkylating agent IF requires in vivo activation by liver P450 enzymes to exert its cytotoxic activity, after release in
tumour cells of the mustard from 4-OH-IF, producing ultimately adducts and 2
strands cross-links of DNA. The other main metabolic pathway relies also on
hepatic microsomes and yields chloroacetaldehyde, 2 and 3-dechloroethyl-IF
(2 and 3-DC) which are believed to be inactive and/or to contnbute to IF side
effects. Thus the ratio of production of 4-OH-IF (transport form for IF mustard)/2DC+3-DC+4-OH-IF, using AUC as comparison parameter, may illustrate
the real contribution of IF to its therapeutic action.
In order to explore the impact of different schedules of administration on IF
therapeutic effect, we designed a randomized PK trial with intra-patient (pt)
cross over in advanced tumours Pts received successively 2 cycles of IF 3
g/m2/day (d) x 3 d q4w by Cl then IV 3 H (or the reverse sequence), and were
monitored for IF PK (IF, 4-OH-IF, 2 and 3-DC) and toxicity. We looked also at
the production of adducts in leucocytes (eg 8-OH-G).
As of April 2000, in 4 evaluable pts who received both cycles (Cl and IV3H),
we found a low ratio of IF "activationTtoxification" based on AUC values
(1-3%), without different impact of either bolus or Cl. In case of IV3H, there
was a clear induction of IF metabolism over 3 d (increased clearance 3.2 d1
vs 5.9 L/h/m2 d3 and decreased t , ^ 6.2 d1 vs 3.3 h d3]. Detection of adducts
in DNA is in progress.
Conclusion: These preliminary data do not seem to favour either schedule
in term of PK parameters, but information on adducts formation and toxicity
are still necessary to draw final conclusions on IF "best way of administration".
Annah of Oncology, Supplement 4 to Volume 11. 2000
© 2000 Kluwer Academic Publishers, Printed in The Netherlands
Novel therapeutics and pharmacology, biological approaches
I 644P | Validation of intra-patient dose escalation
methodology for dose-ranging studies in combination
chemotherapy.
Christopher Poole. Sarah Jordan, Venice Archer, Neil Steven CRC Institute
for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
Introduction: Use of cytoxic chemotherapy doses close to the maximum
tolerated (MTD) is an established tenet of conventional practice, and its determination remains the primary objective of early phase clinical evaluation.
Inter-patient dose escalation, based on successive 3-patient cohorts receiving
treatment at increasing dose levels, affords the best opportunity of distinguishing acute from cumulative dose-limiting toxicities, but the MTD reflects
few toxic events. Drugs which show single agent activity near this dose are
typically further investigated within combination regimens Decisions about
doses used in combination regimens are conventionally made either arbitranly
(risky), or through further inter-patient dose escalation designs (time consuming). With so many new drugs in development, there is an urgent need for
a streamlined but safe dose-ranging methodology for combination regimens.
With increasing evidence of the generality of sigmoid dose response curves,
the notion of 'adequate treatment' is assuming greater importance, and there
may be a need for more systematically-acquired information about the range
and distribution of MTD's in radical treatments. Intra-patient dose escalation
dose-ranging methodology may resolve these problems We present here data
validating this approach
Methods: Retrospective; model treatment regimen carboplatin minimum
dose AUC6 and paclitaxel 175 mg/m2/3hr infusion, (research arm of the
MRC ICON-3 protocol) for patients with previously untreated ovarian cancer.
Carboplatin doses were escalated by 10% each cycle to provide a target
neutrophil count 1.0-1 5, or a platelet count 100-115x109/l
Results: n=36 pts, 27/36 achieved MTD as defined and 'censored' data from
n= 9 patients who failed to achieve target counts, despite escalations. Median
age, 58 3yrs (36 4-75.6), median GFR at entry, 73mls/min (36-122) and at
MTD, 73mls/min (36-140); median MTD ('censored' values, n=9), AUC7.4
(6.1-9.4), median MTD (n=27), AUC8.0 (5.7-9 0)
Conclusion: These MTD's are comparable with data from conventional
dose escalation strategies, and justify prospective intra-patient dose escalation
studies in novel combinations, eg gemcitabine, carboplatin & paclitaxel.
645P Phase I trial of weekly irinotecan plus docetaxel in
patients with advanced solid tumors.
Albert Font. Jose Miguel Sanchez, Monica Guillot, Albert Abad, Miquel Taron,
Mireia Margeli, Agusti Barnadas, Rafael Rosell. Hospital Germans Trias i
Pujol, Badalona, Barcelona, Spain
Innotecan (CPT-11) and docetaxel (DOC) have broad antitumor activities as
single agents Preclinical synergistic cytotoxicity with sequential topoisomerase
I inhibitors and docetaxel has been demonstrated (Taron M et al Ann Oncol
1998;9[Suppl 4] 135). Diarrhoea and leukopenia are the main toxicities for
CPT-11 and DOC, respectively. We designed a weekly schedule of CPT-11
and DOC in an attempt to alter the toxicity profile and improve the therapeutic
index The goals of this study were to determine the maximum-tolerated dose
(MTD) and the recommended doses for subsequent phase II studies Patients
(p) with advanced solid tumors received CPT-11 (90 minute iv) followed by
DOC (30 minute iv) on days 1, 8 and 15 every 28 days Separate cohorts of 3
p each were treated at each level. Doses (mg/m2) of CPT-11 and DOC were
level I: 60/20; level II: 60/25; level III: 70/25; level IV: 70/30. All p had received
prior chemotherapy Twenty-four p were enrolled, 18 are evaluable for toxicity
(level I: 6 p, level II: 3 p; level III: 3 p; level IV 6 p). Patient characteristics- 15
male/3 female; median age 56 years (range 32-74), median Karnofsky index
70%. Previous chemotherapy regimens: 1 (11p), 2 (5 p), 3 (1 p) and 5 (1 p).
Forty-seven courses have been administered. Mean number of courses 2.6
(range 1-5). Non-hematologic toxicity included: Grade 3 mucositis, 1 p (level
I); grade 2 and 3 asthenia, 2 p (1 level-ll, 1 level-IV), 1 p (level II), respectively;
grade 3 diarrhoea, 1 p (level II). Grade 3 and 4 hematologic toxicity grade 4
leukopenia, 2 p (level IV); febrile neutropenia: 1 p (level IV). A partial response
was observed in one non-small-cell lung cancer patient at level III.
Conclusions: MTD was reached at dose level IV due to dose-limiting
leukopenia. Based on these results, we have undertaken a phase II study in
NSCLC at the recommended dose of CPT-11/DOC 70/25 mg/m2.
6 4 6 P | Results of the phase l-ll study of gemcitabine (GEM) in
combination with oxaliplatin (OX) in patients (pts) with
advanced non-small-cell lung cancer (NSCLC) and
ovarian cancer (OC).
dose limiting toxicity (DLT), the recommended dose (RD), the pharmacokinetics
profile and to evaluate the antitumor activity of this combination in pts with
advanced NSCLC and OC. GEM was administered over 30 minutes followed
by OX infused over 2 hours on d1 and d14 of each 4 week (wk)-cycle (cy).
Thirty-four pts (25 NSCLC and 9 OC pts) received a total of 115 cycles. There
were 19 males and 15 females, median age was 54 (37-75), and 7 1 % of
pts had PS 0. All OC and 5 NSCLC pts were pretreated with cisplatin or
carboplatin-based regimens.
Results: 34 pts are evaluable for acute and 29 pts for chronic toxicity. There
was no acute DLT after cy 1. Hematological toxicity was < Gr 3 except for 4
episodes of Gr 3 non febnle neutropenia in 3 pts, and 3 episodes of Gr 3-4
thrombocytopenia in 3 pts. Other toxicities were mild to moderate except for
2.5% of cy associated with Gr 3 transient asthenia. Six pts (1 chemonaive,
5 pretreated) expenenced Gr 3 OX-related neurotoxicity, requiring treatment
discontinuation for 3 pts at the 5th cy. Among 28 evaluable pts, 10/21 NSCLC
and 2/7 OC pts showed an objective response (1 CR, 11 PR)
Dose level
(DL)
1
2
3
4
5
6
GEMOX
(mg/m2 D1, 14)
Pts
Cy
800/70
1000/70
1000/85
1200/85
1200/100
1500/85
3
3
3
10
3
12
11
15
15
38+
12
24+
Delays/
Dose reduction
_
_
3*
3*
2*
2* + ongoing
Withdrawals
for toxicity
_
2"
2"
ongoing
*Gr 2 thrombocytopenia and Gr 3 asthenia from cy 2-3, **Gr 3 asthenia from cy 3 and Gr
3 neurosensory from cy 5
Conclusion: GEMOX combination could be safely administered on a D1
and D14 schedule, without acute toxicity. Because of cumulative toxicity,
follow-up is necessary to establish the RD. This regimen is well-tolerated and
achieves promising antitumor activity in NSCLC and platinum-pretreated OC
pts. Pharmacokinetic results will be presented during the meeting.
I 647P I Gemcitabine and carboplatin combination in advanced
solid tumors: A phase I trial.
Davide Tassinan. Giuseppe Pasini, Valentina Arcangeli, Maria Panzini,
Giuliana Drudi, Lorenzo Gianni, Giovanni Oliveno, Sergio Sarton,
Francesca Fochessati, Alberto Ravaioli. Dept of Oncology, City Hospital,
Rimini, Italy
Introduction: To evaluate the maximum tolerated dose (MTD) and the dose
limiting toxicity (DLT) of gemcitabine (G) and carboplatin (C) combination, a
phase I trial was performed in our department.
Methods: All the patients were treated with C on day 1° and G on day
1°-8°-15° every 28 days. C and G starting doses were respectively 3.5
mg/ml/min and 600 mg/m2, and they were alternatively increased to 4, 4 5
and 5 mg/ml/min, and 800 and 960 mg/m2. Toxicity was evaluated weekly,
response every two courses of chemotherapy The identification of the MTD
and DLT were considered the primary end-points of the trial, response rate
and time to progression the secondary ones.
Results: 32 patients with advanced solid tumors were enrolled into the trial;
all the patients were pre-treated with chemotherapy, and presented a progression of disease before entering into the trial. DLT was haematological, and the
MTDs were 4.5 mg/ml/min and 800 mg/m2 for C and G respectively. Haematological toxicity, and thrombocytopenia in particular caused the omission of
the 15-day G administration in 74 out of 114 performed courses (64.9%),
even if neutrophil and platelet counts rapidly recovered after few days without
requiring any supportive treatment No febrile episodes or platelet trasfusions
were required during the trial. Response rate was encouraging with 3 (9.4%)
complete regression, 4 (12.5%) partial regression, 4 (12.5%) stabilization of
disease and a median time to progression of 30 weeks. Grade III-IV haematological toxicity occurred in 8 (25%) patients, while non-haematological toxicity
was mild, with no grade IV toxicity, and grade III mucositis in 1 (3.1%) patient.
Conclusions: Our data seem to suggest a 21 day schedule with C
4.5mg/ml/min on day 1°, and G 800 mg/m2 on day 1° and 8° for further
phase II trials, (supported by Istituto Oncologico Romagnolo).
I 648P | Preliminary analysis of chemotherapy-induced
cardiotoxicity in breast cancer patients treated with
amifostine.
S. Faivre', E. Raymond1, F. Lokiec2, C. Monnerat', J. Vicente-Azevedo',
P. Pautier'.C. Lhomme1, L Kayitalire1, J.P. Armand 1 , T. Le Chevalier1.
1
Dept. of Medicine, Institut Gustave-Roussy, Villejuif, France;2 Centre
Rene-Huguenin, St. Cloud, France
Alfredo Marinelli1, Carmela Romano 1 , Salvatore Di Somma 2 ,
Giuseppe Cudemo2, Giuseppe Caputo 2 , Gaetano Salvatore2,
Alberto Cuocolo3, Francesca Ciani 4 , Ferdinando Russo 4 , A.
Raff aele Bianco'. ' Dip. Oncologia Endocrinologia Clinica, 2 Dip. Medicina
Climca Spenmentale, 3 Dip. Scienze Biomorfologiche Funzionali, " Dip.
Strutture Funzioni Tecnologie Biologiche, Universita degli Studi "Federico II",
Napoli, Italy
Single agents GEM and OX have clinical antitumor activity in NSCLC and
their combination has in vitro synergy (Faivre, 1999). We designed a phase l-ll
outpatient study in order to establish the maximal tolerated dose (MTD), the
Several antineoplastic drags have been reported to cause cardiac side effects
including cardiomyopathy, ischemias, arrhitmias and myocardial necrosis and
cardiotoxicity is an important chronic cumulative dose-limiting toxicity of many
Annuls of Oncology, Supplement 4 to Volume 11, 2000
© 2000 Kluwer Academic Publishers, Printed in The Netherlands
141
Novel therapeutics and pharmacology, biological approaches
therapeutic antineoplastic regimen. We analysed cardiac funcion in 13 advanced breast cancer patients, 6 treated whit 6 cycles of FEC (5-fluorouracil
600 mg/m 2 ; epirubicin 90 mg/m 2 ; cyclophosphamide 600 mg/m2) and 7 treated
with 6 cycles of AFEC (FEC plus amifostine 740 mg/m2). Amifostme is an
organic thiophosphate derivative that selectively protects normal tissues from
treatment-related toxicity without any demonstrated diminution of antitumor
efficacy. Our patients were monitored, before (I) and after (II) chemotherapy,
by clinical evaluation, ECG, EcoCG, miocardial scintigraphy (SPECT) and
endomiocardial biopsy (EMCB) in the same ventricular region evaluated by
SPECT.
Actin (%)
FEC
AFEC
I
II
93 3
91 4
65
86
Desmm ( %)
I
II
90
84 4
80
85
Vimentin (%)
I
II
43.3
28 6
60
25
Cardiac monitoring in both groups did not reveal significant changes in
clinical, ECG, EcoCG and scintigraphic parameters while after treatment, we
found, in patients who had received FEC, a cytoskeleton damage with a
loss of contractile filaments (Actin 93 3% vs 65%) and an increase of fibrosis
(Vimentin 43.3% vs 60%), initial markers of irreversible myocardial impairment.
No alterations were found in patients receiving AFEC before and aftertreatment
(Actin 91 4% vs 86%, Vimentin 28 6% vs 25%).
| 649P [ Protective effect of human recombinant interleukin-1/3
(betaleukin) on leukopoiesis in patients receiving
anticancer chemotherapy.
Michael L Gershanovich', Larisa Filatova1, Sergey Kethnsky2,
Andrey Simbirtzev2. ' Dept. of Medical Oncology, N.N. Petrov Research
Institute of Oncology, St. Petersburg, Russian Federation; 2 State Institute of
High-Pure Medicals, St. Petersburg, Russian Federation
In our phase II studies, a novel preparation of human recombinant mterleukin-1 p
- betaleukin (B.) demonstrated significant activity as a leukopoiesis stimulator
in toxic grade III-IV leukopenia caused by combination cancer chemotherapy
(Problems in oncology 1998; 44 181-186). The purpose of this study was to
determine whether B. (in contrast to GM-CSF or G-CSF) also has a protective
effect on leukopoiesis when combined anticancer chemotherapy has to be
given without interruption in spite of toxic grade ll-lll leukopenia In a group
of 36 patients with malignant lymphomas and leukopenia after the previous
standard chemotherapy (nadir 1.1x109/L) the same chemotherapy regimen
was given along with intravenous infusion of B at a single dose of 15-20
ng/kg/day on days 1 to 5. As a result of this treatment the absolute number of
WBC on day 7 ± 1 made up 4.8 ± 0 4, i.e. returned to its normal range, and
the absolute amount of granulocytes had increased by 187% by the same day
Another group of 16 pts with malignant lymphomas (13) and advanced breast
cancer (3) having grade II toxic leukopenia and granulocytopenia were given
B. at a dose of 4.5 ng/kg/day subcutaneously from day 1 to 10 along with
the same chemotherapy regimen as group 1. WBC and granulocytes count
made on day 9 0 ± 1.0 demonstrated the levels of 5 5 ± 0.5 x 109/L and 3 7 ±
0.4x10 9 /L, correspondingly.
Conclusion: B. has significant protective effect on leukopoiesis suppressed
by cytostatics. Further studies of this preparation of rhlL-1,8 are needed.
650P
Suppression of tumor growth in mice by vaccination
of MUC1 cDNA.
Keuchi Kontani. Satoru Sawai, Yoshitomo Ozaki, Jun Hanaoka, Shuhei Inoue,
Shozo Fujino Second Department of Surgery, Shiga University of Medical
Science, Otsu, Japan
DNA vaccines have been reported to be beneficial for maintaining high levels
of the tumor antigen expression and for eliciting a strong anti-tumor immunity
in vivo. In this study, we attempted to induce anti-MUC1 immunity and to
suppress tumor growth in mice by vaccination of DNA encoding MUC1 mucin.
This glycoprotein is highly expressed in many human cancer cells and can
be recognized by cytotoxic T lymphocytes in humans as well as in murines.
To assess the ability of DNA vaccination to induce MUC1-specific immunity
in vivo, BALB/c mice were vaccinated with expression vectors containing
MUC1 cDNA. In 8 of the 11 mice immunized with MUC1 cDNA, their sera
showed reactivity to MUC1 core peptides by ELISA. In contrast, all of the mice
vaccinated with the control vector did not acquire anti-MUC1 humoral immunity.
To determine whether MUC1-specific immunity elicited in the immunized mice
can suppress tumor growth, P815 parental cells or their MUC1-transfectants
were inoculated in mice vaccinated with MUC1 cDNA. Although the parental
cells grew in the mice, the MUC1-transduced cells did not grow and were
rejected. This mouse model is useful for the development of a DNA vaccine
targeting MUC1 for anti-cancer immunotherapy.
142
651P
Induction of differentiation and apoptosis in human
promyelocytic leukaemia cell line HL60 by ionizing
radiation.
Dalia Irena Adomaitiene1, Ceslava Aleksandraviciene1, Jurate Savickiene2,
Paulius Breivis1. ' Lithuanian Oncology Center, Vilnius, Lithuania; 2 Institute
of Biochemistry, Vilnius, Lithuania
Differentiation therapy aims to induce malignant cells to stop proliferating
and to express characteristics of normal cells. The study was undertaken to
investigate the effect of gamma-irradiation (0 5, 2 and 10 Gy) applied either
singly or followed by all-trans retinoic acid (RA) for differentiation induction in
human promyelocytic leukaemia cell culture HL60 Immunocytochemical study
of leukocyte CD antigens expression showed that ionizing radiation was able
to induce myeloid cell terminal granulocytic and monocytic differentiation in
HL60 culture. Expression of granulocytic differentiation was more prominent.
Investigation of irradiated HL-60 cell cultures revealed that after differentiation
induction by irradiation, a part of cell population retains the ability to respond to
RA. Cell populations induced for differentiation were shown to display a lower
expression of proliferating cell nuclear antigen PCNA. However, during the
first day of cultivation, the augmentation in PCNA expression after irradiation
was observed Differentiation induced irradiated HL-60 cell cultures underwent
inhibition of immunocytochemical expression of c-Myc and Bcl-2 proteins.
Analysis of cell death in irradiated HL-60 cultures performed morphologically
and by using TUNEL assay demonstrated that apoptotic cells represented
a minority among dead cells, while cell lysis was predominant. Cell lysis
prevalence among dead cells was observed also in RA-induced HL-60 cell
cultures.
Conclusion: this study indicates that ionizing radiation could be used as an
effective inducer of myeloid cell differentiation and in combination with other
chemotherapic agents may have implication for the differentiation therapy
optimization
[ 652P | Her-2 overexpression, p53 accumulation, tumor
angiogenesis and proliferation index (Ki-67) in
high-risk breast cancer (HRBC) patients treated with
high-dose chemotherapy (HDC) and autologous stem
cell rescue (ASCR).
Silvia Gil Calle 1 . Dolores Bautista2, Manuel Cobo 1 , Ana Jimenez 2 ,
Sebastian Luna 2 , Juana Narbona2, Ester Villar1, Francisco Carabantes1,
Carlos Juarez1, Manuel Benavides1 ' Medical Oncology, Hospital Carlos
Haya, Malaga, Spain;2 Pathology Department, Hospital Carlos Haya, Malaga,
Spain
Introduction: Genetic changes (HER-2 amplification and p53 mutations),
Tumor neoangiogenesis and High proliferation index are often associated
with worse prognosis in breast cancer patients (pts). However, little has been
reported about the role of these factors in the outcome of pts with HRBC
treated with HDC and ASCR.
Purpose: To asses the relationship between these factors and relapse-free
survival (RFS) and overall survival (OS).
Patients & methods: We retrospectively analyzed 47 pts with HRBC treated
with HDC and ASCR. Analyses were performed by mmunohistochemistry
using monoclonal antibodies against the membrane domain of HER-2 protein
(CB11, Novocastra), p53 human protein (DO7,Dako) and endothelial cells
(CD31 ,Dako). A polyclonal antibody was used to react with a nuclear antigen
present in proliferating cells (Ki67,Dako). All these factors were correlated with
pts outcome Differences in RFS and OS were compared using the log-rank
test.
Results: The median follow-up is 40,5 months (14-81). 43 pts (91%) are
alive and 18 (38%) had relapsed. HER-2 overexpression and p53 accumulation
were detected in 28% and 30% of pts respectively. Mean microvessel density
was 72/mm2 and median Ki67 was 22% (1-85). Univariate analyses for RFS
and OS failed to show prognostic value for HER-2, p53, angiogenesis, Ki-67,
ER/PR status, number of positive nodes and histologic grade. No statistical
differences were seen either when risk subgroups were compared (HER-2/p53;
positive vs negative).
Conclusions: We have not found any significant correlation between genetic
markers (HER-2 and p53), tumor angiogenesis and Ki67 index with RFS and
OS in this small group of HRBC pts treated with HDC and ASCR. The absence
of significant differences may reflect a relative benefit of HDC in the poor
prognosis subgroup (HER-2+, p53+, High Ki67 index and High MVD) as they
did the same as the better prognosis subgroup (HER-2-, p53-, Low Ki67, Low
MVD).
Supported in part by a Grant SDC#4400 of Whyeth-Lederle.
Annals of Oncology. Supplement 4 to Volume 11. 2000
© 2000 Kluuer Academic Publishers, Printed in The Netherlands
Novel therapeutics and pharmacology, biological approaches
| 653P I Capecitabine combined with trastuzumab in the
therapy of intensively pretreated
HER2-overexpressing metastatic breast cancer (MBC).
Nikola Banqemann. Andrea Kuhle, Andreas Ebert, Helmut Buhler,
Gerhard Schaller. Gynecology and Obstetrics, Med. Center Benjamin
Franklin, Berlin, Germany
The problematic therapy of MBC patients intensively pretreated with taxans
and anthracyclines is further complicated by HER2 overexpression, which is
associated with resistance to chemotherapy. Capecitabine (Xeloda s ) is an
oral antitumor agent with demonstrated chemotherapeutic effectiveness. It
is well tolerated and has hardly any myelotoxic effect. Its combination with
trastuzumab (Herceptin1-), the first humanized antibody against HER2, significantly improves the effectiveness of chemotherapy in cases of HER2-positive
cancer.
As a special case therapy, trastuzumab (2 mg/kgBW/wk) and capecitabine
were administered to 18 HER2-overexpressing MBC patients extensively pretreated with taxans and anthracyclines. Thirteen patients have been evaluated
thus far. Eight partial (47%) and 2 minor (15%) responses were demonstrated
for a mean treatment period of 5.4 ( 2 - 1 0 ) months, a capecitabine dose
of 2250 mg/m2/d for 14 days q3 and an observation penod of 9-17 months.
The median response duration was 315 (210 - 510) days Side effects were
minimal.
The combination of capecitabine and trastuzumab is an effective and well tolerated therapy for intensively pretreated HER2-overexpressing MBC. Prospective studies are needed for a final evaluation.
| 654P | Detection of the 17-1A antigen mRNA in peripheral
blood and the efficacy of the monoclonal antibody
enderocolomab in patients with hormone-refractory
prostate cancer. (Preliminary results).
Eleflhenos Georqakopoulos1, Chnstos Chnstodoulou2, George Klouvas2,
Eleni Efstathiou2, Sofia Georgakopoulou', Nikos Gonis 4, George Vogiatzis3,
Dimosthenis Skarlos2. ' Department of Molecular and Cellular Biology,
Athens Medical Centre, Athens, Greece;2 Department of Ongology, Athens
Medical Centre, Athens, Greece; 3Glaxo Wellcome Hellas A.E.B.E., Athens,
Greece, * 1 st Department of Medicine, University of Athens, Athens, Greece
The expression of 17-1A surface cancer antigen, an adhesion molecule, is
a prerequisite for the action of the monoclonal antibody enderocolomab. The
effect of enderocolomab was tested in hormone-refractory prostate cancer
patients, who were found to be positive for the presence of 17-1A mRNA
and PSA mRNA in the peripheral blood, detected by RT-and nested RT-PCR.
Dose-levels of enderocolomab: 1) 500 mg do, 100 mg dn,28,56.84 2) 200 mg
every other day 3) 500 mg every other day. Blood samples: before, immediately
after, 24 and 48 hours following infusion. In the first dose-level 17-1A mRNA
and PSA mRNA were reduced 24 hours after the infusion of 500 mg but
not of 100 mg and re-increased 48 hours later. At all time-points examined
in the second level the 17-1A mRNA and PSA mRNA were detected in low
concentrations following the infusions. No clinical response was observed in
these two groups of patients. The results obtained from a patient participating
in the third level showed a decrease of 17-1A mRNA (90% by densitometric
analysis), PSA mRNA, serum PSA, alkaline phosphatase. No serious adverse
events were reported so far.
Conclusions: The detection of 17-1A mRNA is feasible in the peripheral
blood of patients with prostate cancer, who express this antigen. The infusion
of 500 mg enderocolomab seems to have the major efficacy in the elimination
of 17-1A antigen and PSA.
| 655P | Results of a 28 day toxicity study with a potent,
non-toxic antiangiogenic agent, recombinant human
angiostatin.
B.K.L. Sim, A.H. Fortier, W.E. Fogler, E. Kough, A. Ruiz. EntreMed Inc.,
Rockville, USA
Soluble, recombinant human (rhu) angiostatin protein, a potent antiangiogenic
was assessed for safety following i.v. injection to Cynomolgus monkeys for 28
days. Doses of rhu angiostatin protein were derived from pharmacodynamic
assessments in preclinical murine tumor models, and bridging pharmacokinetics and dose-range finding studies in Cynomolgus monkeys. Male and
female monkeys were assigned to treatment groups comprised of control,
saline, or rhu angiostatin protein, expressed in Pichia pastoris, at 4.5, 150, or
300 mg/m2/day. All doses were administered in an equivalent volume at an
infusion rate of 2 mL/min. Physical examinations were performed once weekly
and blood samples were collected for hematology, chemistry, and serum drug
and antibody determinations prior to study initiation and on study days 2, 15,
and 28. There were no mortalities or unscheduled sacrifices during the course
of the study. In addition, there were no adverse clinical observations that were
related to the administration of rhu angiostatin protein. No rhu angiostatin
protein-related effects were noted on any of hematology or blood chemistry
parameters. Anatomic pathology was unremarkable in all monkeys treated
with rhu angiostatin protein. Circulating levels of rhu angiostatin protein were
Annals of Oncology, Supplemenl 4 to Volume 11, 2000
dose-dependent with mean values on day 28 of 4 5, 257, and 487 g
20-min post injection of 4.5, 150, and 300 mg/m2/day, respectively. Serum
trough level determinations of circulating rhu angiostatin protein during the
course of the study revealed drug accumulation. These studies are currently
being extended out to 90 consecutive days of i.v. and 28 days of s.c. dosing
with rhu angiostatin protein in additional cohorts of Cynomolgus monkeys.
These data indicate that rhu angiostatin protein administered intravenously
daily for 28 days to Cynomolgus monkeys is without toxicological effects and
has supported the initiation of phase I clinical trials in April, 2000.
| 656P I Regulation of cell development by xenogenlc
immunoglobulins.
Victor Ruqal, Vladimir Gonchar. Leukemia Research Group, Institute of
Hematology, St. Petersburg, Russian Federation
The aim of the work was to develop and to study a new preparation endolin regulating the development of stem cells. The method which was used
for obtaining the preparation included a repeated immunization of animals
with an antigemc material containing the human hemopoietic tissue including
hemopoietic stem cells and mesenchymal stem cells. From the antimyeloid
serum obtained, immunoglobulins of the directed action were separated. In
vitro culture studies showed that the preparation produced a stimulating effect
on the proliferation and differentiation of cells precursors of granulomonocytopoiesis. The influence of preparation on hemopoietic cell development
is confirmed by experimental studies. In experimental animals with hemoimmunosuppression caused by cytostatic and immunosuppressive preparations,
hematologic and immune values normalized two-times earlier than in the
control group of animals injected with immunoglobulins from the non-immune
serum. Immunofluorescent studies of trephine biopsies from the iliac bone
of blood and bone marrow donors have shown that the immunoglobulins the
preparation contains react specifically with both the hemopoietic cells and cells
of the microenvironment. These data are evidence of the regulatory effects
which endolin can have on the hemopoietic function of bone marrow through
a direct influence on hemopoietic precursors and mesenchymal stem cells.
Conclusion: Endolin can be used in the treatment of myelotoxic syndromes
in cancer patients. The most active fractions of endolin can be separated and
used as regulators development different cells lineages.
1 657P [ Phase I dose-finding and pharmacokinetics (PK) study
of BNP7787 (dimesna) as a possible protector of
cisplatin-induced side-effects.
Epie Boven', Miranda Verschraagen1, Ivon Zegers 1 , Frederick
H. Hausheer2, Herbert M. Pinedo1, Wim J.F. Van der Vijgh 1 . ' Medical
Oncology, Vnje Universiteit Medical Centre, Amsterdam, Netherlands;
2
Bionumerik Pharmaceuticals, Inc, San Antonio, TX, USA
BNP7787 shows protection against nephrotoxicity from cisplatin in preclinical
tumor models while the antitumor activity is retained. At the site of the kidneys
BNP7787 will be rapidly converted into mesna, where the toxic monohydrated
species of cisplatin can be inactivated. BNP7787 was studied in pts with
advanced solid tumors in 7 dosing steps from 4.1 g/m2 - 41 g/m2 (cohorts of 3
pts, highest dose 6 pts) as a 15-min infusion preceding cisplatin in a fixed dose
of 75 mg/m2 as a 1 -h infusion every 3 weeks. Pts had not been treated with
cisplatin before and creatinine clearance was > 60 ml/mm Side-effects from
BNP7787 consisting of irritation at the site of injection were less severe upon
addition of NaHCO3 to the solution. Only at the 41 g/m2 dose pts complained
of a warm feeling and dizziness during the 15-min infusion period. In 9 pts
treated with > 5 cycles one pt showed a decrease in creatinine clearance
of 91 to 57 ml/min and 3 pts had neuropathy grade 1 (all in the lower dose
range of BNP7787) Of 25 pts PR was observed in 3 pts and SD in 10 pts.
PK revealed that BNP7787 in the high dose range did not influence Cmax
and t 1/2 of hydrated cisplatin, total platinum and unbound platinum. The mean
normalized AUC-values of BNP7787 without or with cisplatin were 200(±48)
10' 3 .h'm 2 /l and 217(±38) 10'3 h*m2/l, and for mesna these values were
16 3(±7.3) 10'3.h*m2/l and 15.6(±6.8) 10'3.h*m2/l, respectively. In conclusion,
1) BNP7787 appears to be relatively non-toxic at dose levels up to 41 g/m2;
2) objective responses are observed with cisplatin preceded by BNP7787; 3)
BNP7787 at high doses does not interfere with the PK of cisplatin; 4) cisplatin
does not interfere with the PK of (di)mesna.
658P Rationale for a phase III clinical trial with /E-941
(Neovastat®) in metastatic renal cell carcinoma
patients refractory to immunotherapy.
Bernard Escudier1, Francois Patenaude2, Ronald Bukowski 3 ,
Pierre Champagne4, Pierre Falardeau4, Enc Dupont 4 . 'unite
Immunotherapie, Institut Gustave Roussy, Villejuif Cedex, France;2 Oncology,
Jewish General Hospital, Montreal, Canada;3 Cleveland Clinic center,
Cleveland, USA;" Aeterna Laboratories, Quebec, Canada
Renal cell carcinoma (RCC) is a malignancy with a poor response to multiple therapeutic agents. Immunotherapy was the most promising approach.
© 2000 Kluwer Academic Publishers, Printed in The Netherlands
143
Novel therapeutics and pharmacology, biological approaches
However, the low response rate and high toxicity of immunotherapy regimens
emphasized the need to develop new therapeutic modalities Treatment with
antiangiogenic agent such as Neovastat is a good alternative since RCC are
well vascularized tumors Neovastat is a multifunctional antiangiogenic agent
that blocks the vascular endothehal growth factor receptor signaling pathway
and inhibits specific matrix metalloproteinase (MMP-2, 9 and 12) activities.
Antimetastic activity of Neovastat was also shown in the Lewis Lung Carcinoma (LLC) model. Four clinical studies have been conducted to establish
the safety of Neovastat administered orally. In oncology, 482 patients have
received Neovastat of which 146 patients with solid tumors were exposed
for more than 6 months An exploratory retrospective survival analysis in a
subgroup of 47 patients with unresectable non-small-cell lung cancer indicated
a significant increase of survival time (median: 6 15 vs 4 17 months, p=0.017)
and approximately 2.5 fold decrease risk of death (p=0.02) in patients who received more than 2.63 mL/kg/day. In a multicenter open-label study, Neovastat
was administered in patients (n=144) with solid tumors refractory to standard
therapies. From this study, several cases outlining the therapeutic benefit of
Neovastat were reported in patients with RCC. Planned to start in Q2 2000 in
Canada, USA and Europe, a phase III randomized, double-blind placebo-controlled study will evaluate Neovastat as monotherapy in 280 metastatic RCC
patients who have progressed following a first-line of immunotherapy.
| 659P | DICEP high dose chemotherapy with or without
peripheral blood stem cell support as consolidation
treatment in young adults with high risk Ewing's
sarcoma and family of tumors.
Antonio Casado 1 . Isabel Mannque 1 , Miguel Martin 1 , Itziar Garcia
Carbonero 1 , Jose Angel Garcia-Saenz1, Mauro Omezabal 1 , Luis Flores 1 ,
Juan Carlos Camara 1 , Ramiro Carreno 2 , Eduardo Diaz Rubio1 ' Oncologia
Medica, H. Clinico San Carlos, Madrid, Spain, 2 Gastroenterologia, H. Doce
de Octubre, Madrid, Spain
Purpose: To analyze tolerance, toxicity, and impact on disease free (DFS) and
overall survival (OS) of consolidation treatment with HD-DICEP in patients (pt)
with high risk Ewing family of tumors.
Methods: Nineteen pt were included between May 1992 and January
2000 All of them received standard induction chemotherapy, 10 underwent
surgery, and 13 received radiotherapy previously to consolidation treatment
HD-DICEP scheme was applied as follows- cisplatin 75mg/m2/d on days 1
and 5, etoposide 300mg/m2/d on days 1-3, ciclophosphamyde 2250mg/m2/d
on days 4-5 Eight pt with previous extensive chemotherapy and/or pelvic
radiotherapy received haematopoietic stem cell support on day 7. All pt
received G-CSF from day 6 until haematological recovery. A second course
was given within 3-8 weeks provided complete haematological and clinical
recovery was achieved. Pt characteristics: Sex M/F 15/4; median age 25
(17-37); median PS 90. Histology: Askin 2; PNET 5; ES 11; desmoplastic small
round cell tumor: 1. Metastatic sites: bone, bone marrow, lung and liver. 5 pt
had disseminated disease and 14 locally advanced disease when entering the
DICEP program.
Results: All pt but one received 2 courses of DICEP (37 courses in total);
the remaining pt did not receive the 2nd course due to disease progression. No
grade IV clinical toxicity was observed (Bearman's scale). Bleeding occurred
in 16 courses; epigastric pain in 10 The median duration of neutropenia G IV
was 8 days. Fever occurred in 26 courses. No toxic deaths occurred. Median
OS and DFS were 30.3 and 14.2 months, with a median follow up of 55
months.
Conclusion: Although the number of pt is small these results suggest that
both OS and DFS might be improved by the DICEP consolidation treatment.
Moderate organ and haematological toxicity were observed in this series of pt
I 660P | Transcatheter arterial oily chemoembolization (TAOCE)
in the treatment of pancreatic cancer: First experience.
Alexei Polikarpov. Alexander Pavlovski, Pavel Tarazov, Vitaly Pruchansky.
Research Institute of Roentgenology and Radiation Therapy, St. Petersburg,
Russian Federation
Purpose: To analyze the first clinical experience of new treatment for locally
advanced unresectable pancreatic cancer.
Material and methods: After experimental study, we performed 21 TAOCE
in 10 pts with histologically proven adenocarcinoma of the pancreatic head
(T3-4 N 0-2 M0). We used redistribution technique as follows: Selective
catheterization and distal embolization of the gastroduodenal artery (GDA) was
performed with steel coils. Then TAOCE of proximal branches of GDA suplying
tumor was made using bolus injection of 200 - 400mg/sq.m. Gemcitabine,
emulsified in 3-5ml Lipidiol Ultrafluid. Subcutaneous injections of Octreotide
0, 1 mg x 3 was used during four days as a prophylaxe of pancreatitis. The
follow-up included clinical observation, ultrasound examination and computer
tomography or magnetic resonance imaging. TAOCEs were repeated with 1-2
month interval.
Results: There were no treatment-related complications The post-embolization syndrome included upper abdominal pains and nausea. These symptoms
disappeared within 2 days of symptomatic therapy. Now, four pts showed
144
decrease of tumors size and improvement of general condition during 2-12
mo after the beginning of treatment, and five pts showed stabilization of tumor
growth for 3 to 6 mo. However, one patient died from tumor progressions in 6
mo
Conclusion: Transcatheter arterial oily chemoembolization is a well-tolerated procedure and can cause partial tumor response in some patients with
locally advanced unresectable pancreatic head carcinoma
I 661PI CP-461 is active alone and in combination with
gemcitabine, vinorelbine, or irinotecan in non-small
cell lung cancer cell lines.
Joan Schiller1, Joseph Purvis2, Gerard Bittner1. ' University of Wisconsin,
Madison, USA;2 Cell Pathways, Inc., Horsham, USA
CP-461 is the second agent of a new class of drugs termed selective apoptotic
anti-neoplastic drugs (SAANDs). These drugs induce apoptosis in a broad
range of cancerous and precancerous cells including lung via inhibition of cyclic
GMP phosphodiesterase (cG PDE) and activation of PKG. The current study
evaluated the growth inhibitory activity of CP-461 alone and in combination
with cytotoxic agents Calu-6 cells were plated for 24 hours and incubated
for one hour with 3 different cytotoxic agents at varying concentrations. The
cells were washed and CP-461 added to the growth medium for 96 hr The
cells were dissociated, counted and the mean percent control cell growth
was calculated from triplicate determinations. Calu-6 cells exposed to CP-461
for 4 days showed tumor cell growth inhibition in a dose-dependent manner
CP-461 in combination with gemcitabine, vinorelbine or irinotecan showed
more effective growth inhibition than with each agent alone Similar additive
effects were seen in the large cell carcinoma cell line H460.
CP-461
(uglml)
0
01
02
03
Gemcitabine (ng/ml)
0
5
10
20
100
78
53
22
77
65
43
15
52
38
26
14
40
36
23
10
0
Vinorelbine (ng/ml)
5
1 25 2 5
100
84
59
34
68
52
35
20
55
48
30
21
43
31
28
13
0
Irinotecan (/zg/ml)
1 25
5
10
100
84
59
26
76
65
50
19
52
52
30
14
43
31
21
11
Values are percent of control eel! growth
These results support efficacy studies using CP-461 in combination with
these cytotoxic drugs for the treatment of human lung cancer.
NCIC CTG OV12: An international multicentre phase
I study of BAY 12-9566 (BAY) versus placebo in
patients (pts) with advanced ovarian cancer (OVCA)
responsive to primary surgery/paclitaxel + platinum
containing chemotherapy (CT).
H. Hirte1, I. Vergote1, J. Jeffrey1, R. Gnmshaw1, G. Stuart1, C. Mendiola1,
D Vorobiof\M Carey1, S Coppieters2, B. Schwartz2, D. T u \ A. Sadura1,
L Seymour1. ' NCIC Clinical Trials Group, Kingston, Canada;2 Bayer Inc.
BAY is a biphenyl MMP inhibitor selectively active against MMP-2 and MMP-9.
It has anti-angiogenic and anti-metastatic properties in vivo. In phase I studies
a dose of 800 mg BID orally was well tolerated; several pts demonstrated
prolonged disease stabilization. The present trial randomised pts with stage
3 or 4 OVCA to placebo or BAY 800 mg PO bid daily. All patients had
received 6-9 cycles of platinum/ pachtaxel containing CT, with a response
of NED, or complete or partial response; residual disease was <2cm. The
primary endpoint was progression free survival (PFS), secondary endpoints
were quality of life (QoL), toxicity, response (objective and CA125) and overall
survival (OS). The total planned sample size was 780, with 2 planned interim
analyses (IA) The study began in April 1998 and closed in September 1999
after 243 pts had been randomised, because of negative results from other
phase III trials in pancreatic and small cell lung cancer. The final analysis was
performed in August 2000 after the requisite number of events for the first
planned interim analysis had occurred. Patient characteristics: performance
status was ECOG 0/1/2 in 65/33/2%; median age 57 yrs; 80% of pts were FIGO
stage III and 20% stage IV; 60% were optimally debulked; 76% had serous
histology while 66% of pts had > grade 3 histology. Toxicity was generally
grade 1 or 2 in severity, and only nausea (20%), fatigue (18%), diarrhea
(13%) and rash (10%) occurred in more than 10% of pts. Hematologic toxicity
was mild with 2% of pts experiencing > grade 3 thrombocytopenia. The final
efficacy results will be presented.
Annals ofOncolog}. Supplement 4 to Volume 11 2000
© 2000 Kluwer Academic Publishers. Printed in The Netherlands