This phase Ib/II trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 when given together with cisplatin, vinblastine, and temozolomide and to see how well they work in treating patients with recurrent or metastatic melanoma. Gamma-secretase/Notch signalling pathway inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin, vinblastine, and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving gamma-secretase/Notch signalling pathway inhibitor RO4929097 together with combination chemotherapy may kill more tumor cells.
PRIMARY OBJECTIVES: 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/m\^2 intravenous \[IV\] daily x 3; vinblastine 1.2 mg/m\^2 IV daily x 3, and temozolomide \[TMZ\] 150 mg/m\^2 orally \[PO\] 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) SECONDARY OBJECTIVES: 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. (Phase II) OUTLINE: This is phase I dose-escalation study of gamma-secretase inhibitor RO4929097, followed by a phase II study. Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO once daily (QD) on days 1-21, cisplatin IV over 30 minutes and vinblastine IV over 30 minutes on days 1-3, and temozolomide PO QD 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 gamma-secretase/Notch signalling pathway inhibitor RO4929097 and temozolomide as above in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up for 24 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
14
Memorial Sloan-Kettering Cancer Center
New York, New York, United States
Overall Objective Response
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression
Time frame: From the time measurement criteria are met for CR or PR until the first date that recurrent or progressive disease is objectively documented, assessed up to 2 years
Maximum-tolerated Dose for Cisplatin, Vinblastine and TMZ
based on the incidence of dose-limiting toxicity as assessed the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase IB) Data is not yet available, as it's currently being analyzed.
Time frame: 21 days
Overall Survival (Phase II)
Overall response rate (complete \[CR\] or partial response \[PR\]) according to RECIST version 1.1
Time frame: Up to 2 years
Maximum Tolerated Dose for RO4929097
based on the incidence of dose-limiting toxicity as assessed the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase IB)
Time frame: 21 days
Participants' Change in Protein Levels
Participants' pre and post-treatment protein levels will be compared
Time frame: Baseline up to 2 weeks
Cycle 1 AUC/Pharmacokinetics of Gamma-secretase Inhibitor RO4929097 in Combination With Temozolomide (Phase IB)
Time frame: Days 4 and 5
Cycle 1 C Max/Pharmacokinetics of Gamma-secretase Inhibitor RO4929097 in Combination With Temozolomide (Phase IB)
Time frame: At Cycle 1
Cycle 1 Mean Day 2 Trough/Pharmacokinetics of Gamma-secretase Inhibitor RO4929097 in Combination With Temozolomide (Phase IB)
Time frame: At Day 2 of Cycle 1
Number of Participants With Presence or Absence of Markers of Notch Signalling Pathway Inhibition in Patient Tumors (Phase Ib)
The association of response or clinical benefit with the presence or absence of markers of pathway inhibition in patient tumors will be tested using Fisher's exact test.
Time frame: 2 weeks
Progression-free Survival (Phase II)
Progression-free survival curves will be generated using Kaplan-Meier methodology.
Time frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years
Participants Evaluated for Toxicity
Number of patients with AE's as assessed by NCI CTCAE v. 4.0 Please see Adverse Events section for specifics.
Time frame: Up to 30 days post-treatment
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