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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

Phase 1/Phase 2
18 Years
Open (Enrolling)
Recurrent Melanoma, Stage IV Melanoma

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Trial Information

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.
(Phase II)

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.

Inclusion Criteria:

- Patients must have histologically or cytologically MSKCC confirmed recurrent or
metastatic melanoma

- Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1
dimension (longest diameter to be recorded), meeting 1 of the following criteria:

- Lesion > 10 mm by CT scan, MRI, or caliper measurement by clinical exam

- Lymph nodes > 15 mm in short axis by CT scan or MRI

- Lesion > 20 mm by chest X-ray

- Patient with accessible tumor must agree to undergo pre- and post-treatment tumor

- No known brain metastases

- Patients with resected or successfully treated brain metastases with
stereotactic radiosurgery and who have been free from recurrence or progression
for ≥ 3 months allowed

- Life expectancy > 3 months

- ECOG performance status 0-2 (Karnofsky 60-100%)

- WBC ≥ 3,000/mm³

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 9 g/dL

- Total bilirubin normal

- AST and ALT ≤ 3 times upper limit of normal

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- Fertile patients must use 2 forms of effective contraception ≥ 4 weeks before,
during, and for ≥ 12 months after completion of study treatment

- Negative pregnancy test

- Not pregnant or nursing

- Able to swallow tablets

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to gamma-secretase inhibitor RO4929097 or other agents used in
this study

- No malabsorption syndrome or other condition that would interfere with intestinal

- Not serologically positive for hepatitis A, B, or C and have an active infection, a
history of liver disease, or other forms of hepatitis or cirrhosis

- No uncontrolled electrolyte abnormalities including hypocalcemia, hypomagnesemia,
hyponatremia, hypophosphatemia, or hypokalemia, defined as less than the lower limit
of normal for the institution, despite adequate electrolyte supplementation

- No uncontrolled intercurrent illness including, but not limited to, any of the

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- A history of torsades de pointes or other significant cardiac arrhythmias other
than chronic, stable atrial fibrillation that require antiarrhythmics or other
medications known to prolong QTc

- No psychiatric illness and/or social situations that would limit compliance with
study requirements

- Patients who have had another cancer allowed provided there is convincing evidence
that melanoma is the disease requiring therapeutic intervention

- No QTcF > 450 msec (male) or > 470 msec (female)

- No concurrent food that may interfere with gamma-secretase inhibitor RO4929097
metabolism, including ketoconazole and grapefruit juice

- Recovered from prior therapy to < grade 2 toxicities as assessed by NCI CTCAE

- One prior systemic therapy for recurrent or metastatic disease allowed

- No prior cisplatin, vinblastine, temozolomide, dacarbazine, or a gamma-secretase

- At least 3 weeks since prior systemic therapy (6 weeks for carmustine, nitrosoureas,
or mitomycin C)

- At least 5 half-lives since prior small molecule-targeted therapy

- At least 6 weeks since prior anti-CTLA4 antibody

- No other concurrent investigational agents

- No concurrent medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)

- No concurrent strong inducers/inhibitors or substrates of CYP3A4, including
indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, and

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent anticancer agents or therapies

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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)

Outcome Time Frame:

21 days

Safety Issue:


Principal Investigator

Mark Dickson

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

August 2010

Completion Date:

Related Keywords:

  • Recurrent Melanoma
  • Stage IV Melanoma
  • Melanoma



Memorial Sloan Kettering Cancer CenterNew York, New York  10021