A phase I study of RO4929097, a novel gamma secretase inhibitor, in patients with advanced solid tumors.

Abstract

2502 Background: Aberrant Notch signaling is implicated in many human cancers. RO4929097 (R) is a potent, selective oral inhibitor of gamma-secretase, a key enzyme in Notch activation. Preclinically, R has shown tumor differentiation to a less transformed phenotype and efficacy in multiple xenografts. This phase I study explored R safety, PK and PD endpoints. Methods: Dosing regimens were days 1-3, 8-10 Q 3 wks (schedule A, “A”) and days 1-7 Q 3 wks (schedule B, “B”). PK sampling in cycles 1-2. PD: AB-40, angiogenic markers (including IL-6, Il-8), Notch targets (HES1) in surrogates and tumors (RPTD), and cycle 1+2 FDG- PET. Response (RECIST) was assessed Q 6 wks. Results: 89 pts have received R; A=42 (10 cohorts, 3-270 mg/d), B= 47 (10 cohorts, 3-135 mg/d fasted + 12-18 mg/d fed). Overall, R is well-tolerated. Common (>10%) related AEs were reversible fatigue, nausea, emesis, diarrhea, hypophosphatemia, pruritus, and rash; 92% were grade 1/2 with no grade 4. Only 2 pts discontinued R due to related AEs. PK: In both A and B, R exposures increased with dose for all cohorts tested. AUCs exceeded xenograft MECs at doses >= 12 mg/d in both A and B. Average T1/2 was > 20 hrs. Food had no effect on PK. At higher dose levels, reversible, time-dependent PK were observed. PD: For both A + B, serum AB-40 levels increased between 0-4 hrs post R, then decreased towards pretreatment levels by 24 hrs. Antitumor activity included neuroendocrine CA (PR, 10 cycles) and melanoma (-27%, 6 cycles). Eleven pts had FDG-PET responses (EORTC), including a PET CR in a melanoma pt. Others with prolonged therapy (5-10 cycles) included 4 sarcoma and 3 ovarian CA pts. Preliminary data (n=25) suggest lower relative predose serum IL-6 + IL-8 among responding and prolonged SD pts. Conclusions: R therapy is feasible and well-tolerated on both schedules. R T1/2 supports QD dosing. Low dose, prolonged administration may optimize R exposure and minimize time-dependent PK. A continuous dosing schedule is planned. Encouraging signs of antitumor activity (RECIST) and prolonged stable disease were observed in pts with melanoma, neuroendocrine, sarcoma, and ovarian cancers. Validation of pretreatment IL-6 and IL-8 as response predictive markers will be explored in phase I/II R trials. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Genentech/OSI (not directly with Roche) Roche Chemotherapy Foundation Roche