RO4929097 in Combination With Cisplatin, Vinblastine, and Temozolomide in Treating Patients With Recurrent or Metastatic Melanoma

Condition(s) targeted: Melanoma (Skin)

Intervention: cisplatin (Drug); gamma-secretase/Notch signalling pathway inhibitor RO4929097 (Drug); temozolomide (Drug); vinblastine sulfate (Drug); laboratory biomarker analysis (Other); pharmacological study (Other)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Memorial Sloan-Kettering Cancer Center

Official(s) and/or principal investigator(s):
Mark A. Dickson, MD, Principal Investigator, Affiliation: Memorial Sloan-Kettering Cancer Center

RATIONALE: 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 RO4929097 together with combination chemotherapy may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of RO4929097 when given together with cisplatin, vinblastine, and temozolomide and to see how well they work in treating patients with recurrent or metastatic melanoma.

Official title: Phase Ib/II Study of the Gamma-Secretase Inhibitor (GSI) RO4929097 in Combination With Cisplatin, Vinblastine, and Temozolomide (CVT) in Patients With Metastatic Melanoma

Study design: Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Maximum-tolerated dose of gamma-secretase inhibitor RO4929097 in combination with cisplatin, vinblastine, and temozolomide (Phase IB)

Overall response rate (complete or partial response) (Phase II)

Overall survival (Phase II)

Secondary outcome:

Pharmacokinetics and pharmacodynamics of gamma-secretase inhibitor RO4929097 in combination with temozolomide (Phase IB)

Progression-free survival (Phase II)

Toxicity as assessed by NCI CTCAE v. 4.0

Detailed description: OBJECTIVES:

Primary

- To characterize the safety and tolerability of gamma-secretase inhibitor RO4929097 in

combination with cisplatin, vinblastine, and temozolomide in patients with recurrent or metastatic melanoma. (Phase IB)

- To determine the maximum-tolerated dose of this regimen in these patients. (Phase IB)

- To determine the response rate in patients treated with this regimen. (Phase II)

- To determine the overall survival of patients treated with this regimen. (Phase II)

Secondary

- To describe the pharmacokinetics and pharmacodynamics of gamma-secretase inhibitor

RO4929097 in combination with temozolomide. (Phase IB)

- To determine the progression-free survival of patients treated with this regimen.

(Phase II)

- To obtain tissue biopsy for correlative studies.

OUTLINE: This is a multicenter, phase I dose-escalation study of gamma-secretase inhibitor RO4929097 (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 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Histologically or cytologically 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

biopsies

- 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

PATIENT CHARACTERISTICS:

- 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

absorption

- 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

following:

- 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)

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- 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

inhibitor

- 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 3 months 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 nefazodone

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent anticancer agents or therapies

- No concurrent food that may interfere with gamma-secretase inhibitor RO4929097

metabolism, including ketoconazole and grapefruit juice

Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States; Recruiting
Mark A. Dickson, MD, Phone: 212-639-5218

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: August 2010
Last updated: June 3, 2011