Download Developmental Therapeutics.Tolcher.2502

A phase I study of RO4929097, a novel
γ-secretase inhibitor, in patients with
advanced solid tumors
Anthony W. Tolcher,1 Stanislaw Mikulski,2 Wells A.
Messersmith,3 Eunice L. Kwak,4 Darlene Gibbon,5 John F.
Boylan,2 Zhi X. Xu,2 Mark DeMario,2 Jennifer J. Wheler6
1START
(South Texas Accelerated Research Therapeutics), San Antonio, TX;
La Roche, Inc., Nutley, NJ; 3University of Colorado Cancer Center
Aurora, CO; 4Massachusetts General Hospital, Boston, MA; 5The Cancer Institute
of New Jersey, New Brunswick, NJ; 6UT M.D. Anderson Cancer Center, Houston
TX, USA
2Hoffmann-
Background
• The Notch signaling pathway is involved in cell fate
decisions during normal development, and has a prooncogenic function in several solid tumors1
• γ-secretase is a large intramembrane protease complex
which is a key mediator in the Notch signaling pathway2
• By preventing Notch activation, it is anticipated that
γ-secretase inhibitors may inhibit tumor growth
• RO4929097 is a potent, selective, small molecule
γ-secretase inhibitor3
•
A phase I study was performed to evaluate the safety,
pharmacokinetics and activity of RO4929097 in patients
with refractory, advanced solid tumors
1. Koch U, Radtke F. Cell Mol Life Sci 2007;64:2746-62
2. Huppert et al. Nature 2000;405:966-70
3. Luistro L, et al. Cancer Res 2009;69:7672-80
RO4929097: in vitro activity
• RO4929097 IC50 for γ-secretase is 4 nmol/L, with >100-fold
selectivity in panel of 75 other proteins
• After RO4929097 exposure, the phenotype of NSCLC A549
tumor cells becomes more differentiated, similar to primary
bronchial epithelial cells
DMSO control
100nM
500nM
Primary bronchial
epithelial cells
Luistro, L et al. Cancer Res 2009;69:7672-80
RO4929097: in vivo activity
Tumor Type
Tumor growth inhibition (%)
LOVO (colon)
83
BxPC3 (pancreatic)
82
HCT-116 (colon)
76
A549 (NSCLC)
70
AsPC-1 (pancreatic)
58
MiaPaCa-2 (pancreatic)
53
Calu-6 (NSCLC)
42
H460a (NSCLC)
8
•
Activity in 7 of 8 human tumor xenografts (10 mg/kg qd dosing)
•
Sustained inhibitory activity after 7 or 14 days dosing supports
intermittent dosing regimens in the clinic
Luistro, L et al. Cancer Res 2009;69:7672-80
Study objectives
Primary objectives
•Determine maximum tolerated doses (MTD) for two schedules
•Recommend phase II doses
•Characterize safety and tolerability profile
Secondary objectives
•Pharmacokinetics
•Pharmacodynamics
̶
molecular biomarkers in plasma, tumor, surrogate tissues
•Anti-tumor activity
Study design
• Phase I, non-randomized, 2-arm, open-label, multicenter study
• RO4929097 given orally in two different schedules:
Day
1
8
Schedule A
15
29
36
43
50
Continuous
starting week 7
Schedule B
Schedule A: 3 days on/4 days off wks 1 & 2, q3 wks (1st 2 cycles)
then continuous administration
Schedule B: days 1-7 q3 wks
Assessments
•
Standard safety assessments (NCI-CTC)
•
PK samples cycle 1 (1st and last dosing days) and cycle 2 (day 1)
•
CYP3A4 induction (midazolam DDI substudy)
•
Effects of γ-secretase inhibition on:
– Aβ-40 (plasma)
– Hes-1 and MYC expression (hair follicles)
– Hes-1, MYC, ICN-1 and additional biomarkers (tumor tissue)
– Soluble markers angiogenesis/cytokines
•
Tumor assessments (RECIST) every 6 weeks by CT or MRI
•
PET-CT evaluation at baseline, cycles 1 and 2
Patient demographics
N=94*
Age, median (range), years
60 (26-87)
Sex (male/female), %
46/54
ECOG (0/1/2), %
28/70/2
Tumor type, %
Melanoma
Colorectal
Sarcoma
Ovarian
Neuroendocrine
Hormone-refractory prostate
Other
Median no. prior regimens (range)
20
13
11
10
7
7
32
3 (0-12)
*Schedule A (n=47); Schedule B (n=47)
Dose-limiting toxicities
•
DLTs observed in 4 patients:
– Hypophosphatemia (transient grade 3): schedule B 27 mg (n=2)
– Asthenia (transient grade 3): schedule A 80 mg (n=1)
– Pruritus (grade 3): schedule B 60 mg (n=1)
•
DLTs have not precluded dose escalation on either schedule
•
RO4929097 dose range used to date:
‒ Schedule A: 3-270 mg
‒ Schedule B: 3-135 mg
•
Maximum tolerated doses:
– Schedule A: not reached (PK-related stopping of dose escalation)
– Schedule B: not reached (PK-related stopping of dose escalation)
Safety summary
• RO4929097 is well tolerated
• Skin and gastrointestinal events and fatigue are the
most common treatment-related toxicities
• Most (95%) treatment-related events are grade 1/2
severity
• No grade 4 events have been reported
• Discontinuations for related events occur rarely (2%)
• Dose adjustments in any cycle are also uncommon
(11%)
Common treatment-related AEs (≥10%)
Incidence [no. patients (%)]
By NCI CTC grade
By schedule
3
Schedule A
(n=47)
Schedule B
(n=47)
6
0
11 (23)
14 (30)
14
5
3
5 (11)
17 (36)
17 (18)
5
12
0
9 (19)
8 (17)
Diarrhea
15 (16)
10
4
1
6 (12)
9 (19)
Hypophosphatemia
14 (15)
0
9
5
3 (6)
11 (23)
Emesis
11 (12)
7
4
0
3 (6)
8 (17)
Event
Overall
(n=94)
1
2
Nausea
25 (27)
19
Skin (rash,
eczema, pruritus)
22 (24)
Fatigue
Pharmacokinetics
Schedule A
Schedule B
45000
70000
40000
AUC0-24 (ng*hr/mL)
AUC0-24 (ng*hr/mL)
C1D1
80000
60000
50000
40000
30000
20000
25000
20000
15000
0
12
24
36
54
80 120 180 270
30mg/kg nude mouse
efficacy exposure
(~5200 ng*hr/mL)
10000
0
Dose (mg)
•
30000
5000
6
C2D1
35000
10000
3
C1D7
3
6
12
18
27
40
60
90
135
10mg/kg nude mouse
efficacy exposure
(~1700 ng*hr/mL)
Dose (mg)
Exposure increased with dose in both schedules
• Exposure reaches/exceeds effective levels in xenograft model at
doses ≥6 mg
P4503A4: auto-induction potential
•
Exposure increases with dose on day 1 of both schedules
•
At high doses, exposure decreases after repeated dosing
•
After ‘drug holidays’ in both schedules, exposure returns to
day 1 levels generally on day 1 of cycle 2 in most patients
•
Auto-induction of P4503A4 is considered the most likely
reason for decreased exposure after repeated dosing
•
Preclinical study indicated that RO4929097 is 3A4 substrate
and inducer
•
Importantly, exposure reaches/exceeds effective levels
estimated from xenograft model at doses ≥6 mg, including
dose cohorts that demonstrated auto-induction
Pharmacodynamics: plasma Aβ40
Schedule A
Schedule B
ABeta % change from BL, Sch A
ABeta % change from BL, Sch B
Dose (mg)
3
60
Dose (mg)
100
12
18
80
36
54
20
0
270
180
-20
% change from BL
% change from BL
12
24
6
40
60
3
27
40
6
20
40
60
0
-20
90
80
120
0
5
10
15
Time (hour)
20
135
0
5
10
15
20
Time (hour)
• Increase in Aß40 levels 0-4 hrs postdose, followed by decrease towards baseline by 24 hrs
• At higher doses, decrease below baseline is durable up to 24 hrs postdose
• Data consistent with dose-dependent modulation of γ-secretase proteolytic activity
Activity: clinical benefit summary
No. of patients (%)
Schedule A
(n=47)
Schedule B
(n=47)
Total
(n=94)
≥4 cycles (3 months)
12 (25)
14 (30)
26 (28)
≥8 cycles (6 months)
3 (6)
4 (9)
7 (7)
Duration of therapy
• Tumor types most commonly among clinical benefit population
– Melanoma (6 of 19 patients)
– Sarcoma (3 of 10 patients)
– Ovarian (3 of 9 patients)
– 11 patients (12%) had FDG-PET response (EORTC criteria) in
cycle 1 or 2
Antitumor Activity: patient details
Patient / tumor / disease
burden
25F, epithelial sarcoma,
soft tissue and pulm mets
Schedule
Dose
Best Response
B
6 mg
Mixed response, overall –12%
RECIST; 6 cycles total
69F, melanoma, in transit mets
B
18 mg
Near 100% PET response,
Clinical flattening of in transit
lesions; 16 cycles total
39M, melanoma,
widespread cutaneous mets
B
27 mg
-27% (RECIST), measurable
disease; 6 cycles total
76F, neuroendocrine colon
peritoneal and nodal disease
B
40 mg
RECIST PR; 10 cycles total
51F, sarcoma
cervical paraspinal
B
60 mg
Prolonged SD, 10 cycles
PD, 2 mo. on last prestudy Rx
80 mg
Prolonged SD (10 cycles total) +
C2 PET – 31%,
PD < 3mo. on last prestudy Rx
54M, chondrosarcoma,
peritoneal & soft tissue mets
A
Case study: PET scans
May 5 2008
Pretreatment
June 11 2008
Post C2
Case study: CT scans
Jan 6 2009
May 19 2009
Conclusions
• RO4929097 is safe and well tolerated with prolonged
administration on two intermittent dosing schedules
• Day 1 drug exposures increase with dose for both
schedules, but decreases at later time-points with
repeated dosing at higher dose levels consistent with
auto-induction
• Aβ40 data suggest RO4929097 modulates γ-secretase
activity at all doses
• Encouraging signs of anti-tumor activity (RECIST
responses and prolonged SD), including melanoma
and sarcoma
Next steps
• In the present study, cohort expansions and paired
tumor biopsies are currently ongoing to define phase II
doses
• Phase II study in 2nd/3rd line NSCLC initiated
• A collaboration with CTEP, US NCI is ongoing; over 30
clinical studies are currently planned
Acknowledgements
START
Cancer Institute of New Jersey
Amita Patnaik
Cecilia Thomas
Kyri Papadopoulos
MD Anderson
Jacalyn Neceskas
Univ. Colorado
Rozelle Kurzrock
Sarah Eppers
Chetna Wathood
Stacy Grolnic
Massachusetts General Hospital
Geoffrey Shapiro
Donald Lawrence
Trial sponsored by Hoffmann La-Roche
Stacey Ukrainskyj
Karen Wang
Our Patients and their families
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