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. Wheler 6 1 START (South Texas Accelerated Research Therapeutics), San Antonio, TX; 2 Hoffmann- La Roche, Inc., Nutley, NJ; 3 University of Colorado Cancer Center Aurora, CO; 4 Massachusetts General Hospital, Boston, MA; 5 The Cancer Institute of New Jersey, New Brunswick, NJ; 6 UT M.D. Anderson Cancer Center, Houston TX, USA A phase I study of RO4929097, a novel γ-secretase inhibitor, in patients with advanced solid tumors
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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.
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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; 2Hoffmann- La Roche, Inc., Nutley, NJ; 3University of Colorado Cancer CenterAurora, CO; 4Massachusetts General Hospital, Boston, MA; 5The Cancer Institute of New Jersey, New Brunswick, NJ; 6UT M.D. Anderson Cancer Center, HoustonTX, USA
A phase I study of RO4929097, a novel γ-secretase inhibitor, in patients with advanced solid tumors
Background
• The Notch signaling pathway is involved in cell fate decisions during normal development, and has a pro-oncogenic 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;405:966-703. 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
User
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RO4929097: in vivo activity
• 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
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
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:
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
1Day 8 15
Schedule A
Schedule B
29 36 43
Continuous starting week 7
50
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
• 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
• 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
0 5 10 15 20
-20
60
40
20
0
Schedule A%
ch
an
ge
fro
m B
L
ABeta % change from BL, Sch A
3
12
246
270
180
80120
5436
Time (hour)
Dose (mg)
0 5 10 15 20
-20
60
40
20
0
80
100
Schedule B
% c
ha
ng
e f
rom
BL
ABeta % change from BL, Sch B
18
12
3
40
60
90
135
6
27
Time (hour)
Dose (mg)
Activity: clinical benefit summary
• 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
No. of patients (%)
Duration of therapy
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)
Patient / tumor / disease burden
Schedule
Dose Best Response
25F, epithelial sarcoma, soft tissue and pulm mets
B 6 mgMixed 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
• 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 JerseyAmita Patnaik Cecilia Thomas
Kyri Papadopoulos Jacalyn Neceskas
MD Anderson Univ. ColoradoRozelle Kurzrock Sarah Eppers
Chetna Wathood Stacy Grolnic
Massachusetts General HospitalGeoffrey Shapiro
Donald Lawrence
Trial sponsored by Hoffmann La-RocheStacey Ukrainskyj