Phase Ib/II Study of the Gamma-Secretase Inhibitor (GSI) RO4929097 (IND #109291) in Combination With Cisplatin, Vinblastine, and Temozolomide (CVT) in Patients With Metastatic Melanoma
I. To characterize the safety and tolerability of daily RO4929097 (gamma-secretase/Notch
signalling pathway inhibitor RO4929097) administered orally daily in combination with CVT
(starting dose: cisplatin 25 mg/m2 IV daily x 3; vinblastine 1.2 mg/m2 IV daily x 3, and TMZ
150 mg/m2 PO daily x 5) administered on an every 21 day schedule. (Phase Ib) II. To
determine the maximum-tolerated dose (MTD) of RO4929097 with CVT in patients with metastatic
melanoma with correlative biomarkers for Notch pathway signaling and gamma secretase enzyme
activity. (Phase Ib) III. Based on the MTD from the phase Ib study, to conduct a phase II
trial and to determine the response rate and overall survival. (Phase II)
I. To describe the pharmacokinetics and pharmacodynamics of the combination of RO4929097 and
temozolomide. (Phase Ib) II. To obtain tissue biopsy for correlative studies before the
initiation of therapy and one week after treatment with RO4929097 and CVT. (Phase Ib and II)
III. To determine the progression-free survival of patients treated at the phase II dose.
OUTLINE: This is a multicenter, phase I dose-escalation study of gamma-secretase inhibitor
RO4929097, followed by a phase II study.
Patients receive RO4929097 orally (PO) once daily on days 1-21, cisplatin IV over 30 minutes
and vinblastine IV over 30 minutes on days 1-3, and temozolomide PO once daily on days 1-5.
Treatment repeats every 21 days for 6 courses in the absence of disease progression or
unacceptable toxicity. Patients without progressive disease continue to receive RO4929097
and temozolomide as above in the absence of disease progression or unacceptable toxicity.
Patients undergo blood sample collection at baseline and periodically during courses 1 and 2
for pharmacokinetics studies. Patients with accessible tumor may undergo tumor tissue
collection at baseline and during week 2 of course 1 for correlative studies.
After completion of study therapy, patients are followed up for 24 months.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum-tolerated dose based on the incidence of dose-limiting toxicity (DLT) as assessed the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase IB)
Memorial Sloan-Kettering Cancer Center
United States: Food and Drug Administration
|Memorial Sloan Kettering Cancer Center||New York, New York 10021|