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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. Wheler 6

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  1. 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; 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

  2. 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;405:966-70 3. Luistro L, et al. Cancer Res 2009;69:7672-80

  3. 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

  4. RO4929097: in vivo activity Activity in 7 of 8 human tumor xenografts (10 mg/kg qd dosing) Sustained inhibitoryactivity after 7 or 14 days dosing supports intermittent dosing regimens in the clinic Luistro, L et al. Cancer Res 2009;69:7672-80

  5. 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

  6. Study design Day 1 8 15 29 36 43 50 Schedule A Continuous starting week 7 Schedule B • 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

  7. 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

  8. Patient demographics *Schedule A (n=47); Schedule B (n=47)

  9. 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)

  10. 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%)

  11. Common treatment-related AEs (≥10%)

  12. Pharmacokinetics Schedule A Schedule B C1D1 C1D7 C2D1 45000 80000 40000 70000 35000 60000 30000 50000 25000 AUC0-24 (ng*hr/mL) AUC0-24 (ng*hr/mL) 40000 20000 30000 15000 30mg/kg nude mouse efficacy exposure (~5200 ng*hr/mL) 20000 10000 10000 5000 10mg/kg nude mouse efficacy exposure (~1700 ng*hr/mL) 0 0 3 6 12 18 27 40 60 135 90 3 6 12 24 36 54 80 120 270 180 Dose (mg) Dose (mg) • Exposure increased with dose in both schedules • Exposure reaches/exceeds effective levels in xenograft model at doses ≥6 mg

  13. 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

  14. Pharmacodynamics: plasma Aβ40 Schedule A Schedule B ABeta % change from BL, Sch A ABeta % change from BL, Sch B Dose (mg) Dose (mg) 100 3 60 12 18 80 12 24 40 60 6 3 27 36 40 20 54 % change from BL % change from BL 6 20 40 0 270 60 0 180 -20 -20 90 80 120 135 0 5 10 15 20 0 5 10 15 20 Time (hour) 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

  15. 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

  16. Antitumor Activity: patient details

  17. Case study: PET scans May 5 2008 Pretreatment June 11 2008 Post C2

  18. Case study: CT scans Jan 6 2009 May 19 2009

  19. 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

  20. 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

  21. Acknowledgements START Cancer Institute of New Jersey Amita Patnaik Cecilia Thomas Kyri Papadopoulos Jacalyn Neceskas MD Anderson 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 OurPatients and their families “

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