Download Improved safety profile of a macromolecular taxane: integrated

Presented at the European Society for Medical Oncology (ESMO), October 29 – November 2, 2004, Vienna, Austria
Improved safety profile of a macromolecular taxane:
an integrated safety summary of XYOTAX™ (paclitaxel
poliglumex; CT-2103) phase 1-2 and phase 2 trials
Paola Barbieri,1 Fred Oldham,2 Joan Holman,2 Anna M. Liberati3
Cell Therapeutics, Inc., Bresso MI, Italy; 2Cell Therapeutics, Inc., Seattle, Washington, USA;
3
Policlinico Monteluce, Istituto di Medicina Interna e Scienze Oncologiche, Perugia, Italy
1
Table 2. Drug-Related Hematologic Adverse Events (N = 125)
ABSTRACT
No. (%) of patients
XYOTAX™ (paclitaxel poliglumex; CT-2103) is an innovative taxane that has been designed to improve on the
Grade 1
Grade 2
Grade 3
Grade 4 or 5
Total
0 (0)
9 (7)
10 (8)
5 (4)
24 (19)
therapeutic index of conventional taxanes by providing prolonged tumor exposure to active drug while minimizing
systemic exposure. A macromolecule conjugate of paclitaxel and poly-L-glutamate, XYOTAX™ takes advantage
Neutropenia
of the greater permeability of tumor vasculature and lack of lymphatic drainage to accumulate in tumor tissues.
Anemia
The mechanism by which XYOTAX™ interacts with tumor cells is being elucidated and likely involves endocytosis of
Thrombocytopenia
the polymer conjugate followed by intracellular release of active paclitaxel by lysosomal enzymes (eg, cathepsin B).
Preclinical studies suggest that XYOTAX™ may be more efficacious and safer than paclitaxel. Safety was evaluated
by analyzing preliminary data on the adverse events in 125 patients with lung and ovarian cancers treated in
7 (6)
10 (8)
5 (4)
0 (0)
22 (18)
11 (9)
6 (5)
0 (0)
0 (0)
17 (14)
Leukopenia
7 (6)
2 (2)
7 (6)
0 (0)
16 (13)
Febrile neutropenia
0 (0)
0 (0)
0 (0)
1 (1)
1 (1)
phase 1-2 and phase 2 clinical trials with XYOTAX™ 175 mg/m2 q3wk; 60 patients had been treated with 3 or more
prior therapies. Responses were observed in both tumor types, and the serious adverse events were mostly disease-
Table 3. Drug-Related Hepatic- and Renal-Related Adverse Events (N = 125)
related. The frequently reported drug-related adverse events were neuropathy (43%), fatigue (34%), nausea
No. (%) of patients
(26%), neutropenia (19%), anemia (18%), and thrombocytopenia (14%). The grade 3 or 4 drug-related adverse
events that occurred in 5% or more of patients were neutropenia (12%), neuropathy (14%), and fatigue (6%).
No grade 4 neuropathy was observed. Prior taxane treatment and a greater number of cycles of treatment with
Elevated aspartate
XYOTAX™ were associated with a greater risk for neuropathy. Alopecia was infrequent, and complete hair loss
aminotransferase level
was not reported. This analysis suggests that the safety profile of XYOTAX™ is similar to that of paclitaxel, except
Elevated alanine
that the severity of events is less than that with paclitaxel. These results are consistent with preclinical data that
aminotransferase level
suggest that XYOTAX™ is more tolerable than conventional taxanes. XYOTAX™ is currently undergoing further
clinical evaluation in 4 large phase 3 trials in patients with advanced non–small cell lung cancer and ovarian cancer.
Elevated alkaline
Grade 2
Grade 3
Grade 4 or 5
Total
7 (6)
1 (1)
0 (0)
0 (0)
8 (6)
3 (2)
2 (2)
0 (0)
0 (0)
5 (4)
1 (1)
0 (0)
0 (0)
0 (0)
1 (1)
1 (1)
0 (0)
0 (0)
0 (0)
1 (1)
phosphatase level
Elevated bilirubin level
INTRODUCTION
Grade 1
Cytotoxic agents in the form of polymeric drug conjugates may have a number of advantages over standard
drug preparations, including preferential distribution to and accumulation in tumor tissue,1 evasion of multidrug-
25
resistance efflux pumps in tumor cells that would normally be drug-resistant,2,3 and a lower volume of distribution
and longer distribution and elimination phases that prolong the exposure of tumor cells to active drug.1,4
XYOTAX™ is an innovative taxane that has been designed to take advantage of the benefits of polymeric drug
20
18
conjugation by linking paclitaxel to a biodegradable poly-L-glutamate backbone.4
Binding paclitaxel to a polymeric carrier renders XYOTAX™ inactive in the plasma, thereby reducing its exposure
to normal tissue. As a result, a lower incidence of adverse events related to the exposure of normal tissue to
cytotoxic drug would be expected.2 In addition, XYOTAX™ is a water-soluble molecule by virtue of its poly-L-
Grade 1
Grade 2
Grade 3
21
Patients
(%)
15
10
10
glutamate backbone, making shorter infusion times possible and eliminating the need for solubilizing agents
6
such as polyoxyethylated castor oil (Cremophor EL). This property prevents hypersensitivity reactions that can
5
result from the infusion of solubilizing agents and eliminates the need for routine premedications such as
4
5
2
histamine blockers and glucocorticoids.5,6
0
Preclinical studies suggest that XYOTAX™ may be more efficacious and safer than paclitaxel, having in vivo
antitumor activity in paclitaxel-resistant tumors, synergy with other chemotherapy agents and radiotherapy, and
a maximum tolerated dose approximately twice that of paclitaxel.
1,4
0
Alopecia
1
Fatigue
Nausea
The data presented here detail the adverse
events that occurred in patients with solid tumors treated with XYOTAX™ in 2 phase 1-2 and phase 2 studies.
PATIENTS AND METHODS
Figure 1. Drug-related alopecia, fatigue, and nausea in patients treated with XYOTAX™.
DISCUSSION AND CONCLUSIONS
CTI 1071: Phase 1-2 trial of XYOTAX™ in patients with recurrent epithelial ovarian, fallopian tube, or primary
The administration of standard paclitaxel is associated with a variety of adverse events, depending on the patient
peritoneal carcinoma
population. A recent randomized study of paclitaxel given once a week or every 3 weeks in patients with recurrent
The objectives of this multicenter open-label study were to determine the response rate and time to progression
disease reported grade 3 or 4 neutropenia in 45% of 101 patients, grade 2 neuropathy in 29%, alopecia in 79%,
in a heterogeneous population of patients treated with XYOTAX™ for epithelial ovarian, fallopian tube, or
and arthralgia in 8%.7 XYOTAX™ was designed to have the therapeutic effects of paclitaxel with less systemic
primary peritoneal carcinoma that was either sensitive or resistant to taxanes and platinum compounds, and
exposure to the active drug for greater safety and tolerability. In preclinical studies XYOTAX™ was generally well
to determine the tolerability and safety of XYOTAX™ in this patient population. Ninety-seven patients have been
tolerated and had transient effects on hematology and clinical pathology measures, including dose-related
treated with a dose of XYOTAX™ 175 mg/m2 as a 10-minute intravenous infusion every 21 days, and enrollment
decreases in platelet counts and levels of hepatic enzymes.1,4
is complete.
Grade 3 and 4 neutropenia was the most common severe adverse event, but it was not associated with febrile
CTI 1069: Phase 2 trial of XYOTAX™ as first-line chemotherapy in patients with non–small cell lung cancer aged
neutropenia or temporally related to infectious events. There were 5 reported instances of grade 4 neutropenia,
70 years or older or with a performance status of 2
with the neutrophil nadir occurring between days 7 and 15 of treatment. Febrile neutropenia developed within
The objectives of this multicenter open-label study were to evaluate the efficacy and tolerability of XYOTAX™
3 days in 1 patient. Platelet counts decreased slightly with increasing number of treatment cycles, but all cases
in patients with non–small cell lung cancer aged 70 years or older or aged 18 to 69 years with an Eastern
of grade 3 thrombocytopenia were transient and were not associated with bleeding.
Cooperative Oncology Group performance status of 2. Twenty-eight patients were given XYOTAX™ 175 mg/m2
as a 10-minute intravenous infusion every 21 days.
In the present studies of XYOTAX™ in the treatment of heavily pretreated patients with ovarian cancer and highrisk patients with non–small cell lung cancer peripheral neuropathy appears to be dose-limiting after repeated
cycles, but no grade 4 neuropathy was reported. Prior taxane use and a greater number of cycles of treatment
RESULTS
are associated with a greater risk of neuropathy.8 The incidence of neuropathy was higher in the ovarian cancer
Because a variety of terms were used to report neuropathic adverse events, the following terms were evaluated
study and is probably related to prior exposure to neurotoxic agents.
in aggregate as the grouped term “neuropathy”: peripheral neuropathy (not otherwise specified), hypoesthesia,
Hypersensitivity reactions were uncommon. It is not known whether there are any predisposing factors (such
neuropathy (not otherwise specified), paresthesia, peripheral sensory neuropathy, neuropathic pain, peripheral
as prior exposure to taxanes or prior hypersensitivity reactions to taxanes) that could predict these events. The
motor neuropathy, oral paresthesia, and sensory loss. Using this aggregate term, neuropathy developed during
frequency and severity of hypersensitivity reactions to paclitaxel have been well characterized.5,6 The majority of
treatment with XYOTAX™ in 43% of patients. The most common form of neuropathy reported was peripheral
these reactions have been thought to be due to a nonimmunologically mediated response to the polyoxyethylated
neuropathy. No grade 4 neuropathy was reported (Table 1).
castor oil base, which is not used with XYOTAX™, possibly explaining the lower incidence of hypersensitivity
Neutropenia was the most frequent hematologic adverse event, occurring in 19% of patients, including grade 4
in 4% of patients. No grade 4 anemia, leukopenia, or thrombocytopenia was reported (Table 2).
There were no elevations in hepatic or renal enzyme levels of higher than grade 2. No adverse events related to
hepatic or renal markers occurred in more than 6% of patients (Table 3).
reactions without the use of routine premedications.5 Furthermore, the shorter infusion times required with
XYOTAX™ may have also contributed to the lower incidence of hypersensitivity reactions.6
These data indicate that XYOTAX™ is generally well tolerated and has a safety profile similar to that of paclitaxel,
except that the severity of adverse events is less than that with paclitaxel. These results are consistent with
preclinical data that suggest that XYOTAX™ is more tolerable than conventional taxanes and support the concept
Hypersensitivity reactions were observed infrequently and were usually mild to moderate reactions that were easily
that XYOTAX™ remains inactive in the plasma, thus reducing the exposure of normal tissue to cytotoxic paclitaxel.
controlled with routine medications. Five patients discontinued treatment because of hypersensitivity reactions.
XYOTAX™ is currently undergoing further clinical evaluation in 4 large phase 3 trials in patients with advanced
Eight percent of patients had hypersensitivity reactions, 2 of which were grade 3 and none of which were grade 4.
non–small cell lung cancer and ovarian cancer.
Patients did not routinely receive prophylaxis for hypersensitivity.
Alopecia occurred in only 6% of patients, and never at a severity greater than grade 2. Complete hair loss was not
reported. Nausea was reported in 26% of patients and was primarily grade 1, with only 1 patient having grade 3
nausea. Fatigue was reported in 34% of patients, most often grade 1 or 2 (Figure 1).
poly(L-glutamic acid)-paclitaxel conjugate. Cancer Res. 1998;58:2404-2409.
3. McCormick-Thomson LA, Duncan R. Poly(amino acid) copolymers as a potential soluble drug delivery system, I:
No. (%) of patients
Peripheral neuropathy
Grade 2
Grade 3
Grade 4 or 5
Total
12 (10)
9 (7)
11 (9)
0 (0)
32 (26)
Neuropathy, not otherwise specified
3 (2)
4 (3)
2 (2)
0 (0)
9 (7)
Hypoesthesia
4 (3)
1 (1)
1 (1)
0 (0)
6 (5)
Paresthesia
4 (3)
1 (1)
0 (0)
0 (0)
5 (4)
Peripheral sensory neuropathy
2 (2)
2 (2)
1 (1)
0 (0)
5 (4)
Neuropathic pain
0 (0)
1 (1)
1 (1)
0 (0)
2 (2)
Paresthesia, oral
1 (1)
0 (0)
0 (0)
0 (0)
1 (1)
Peripheral motor neuropathy
0 (0)
0 (0)
1 (1)
0 (0)
1 (1)
Peripheral sensorimotor neuropathy
0 (0)
0 (0)
1. Li C, Yu DF, Newman RA, et al. Complete regression of well-established tumors using a novel water-soluble
2. Duncan R. Drug-polymer conjugates: potential for improved chemotherapy. Anticancer Drugs. 1992;3:175-210.
Table 1. Drug-Related Neuropathic Adverse Events (N = 125)
Grade 1
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