Gamma-secretase/Notch Signalling Pathway Inhibitor RO4929097 in Combination With Cisplatin, Vinblastine, and Temozolomide in Treating Patients With Recurrent or Metastatic Melanoma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01196416
First received: September 4, 2010
Last updated: December 6, 2013
Last verified: December 2013
  Purpose

This phase I/II trial is studying 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.


Condition Intervention Phase
Recurrent Melanoma
Stage IV Melanoma
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Drug: vinblastine sulfate
Other: pharmacological study
Drug: cisplatin
Drug: temozolomide
Other: laboratory biomarker analysis
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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) [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
  • Overall response rate (complete [CR]or partial response [PR]) according to RECIST version 1.1 (Phase II) [ 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 ] [ Designated as safety issue: No ]
    Simon two-stage design will be employed. Calculated along with a 95% confidence interval.

  • Overall survival (Phase II) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change in protein levels by immunohistochemistry (IHC) (Phase Ib) [ Time Frame: From baseline to 2 weeks ] [ Designated as safety issue: No ]
    Pre and post-treatment protein levels will be compared by Wilcoxon signed-rank test (for paired samples).

  • Association of response or clinical benefit with the presence or absence of markers of pathway inhibition in patient tumors (Phase Ib) [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    Tested using Fisher's exact test.

  • Pharmacokinetics of gamma-secretase inhibitor RO4929097 in combination with temozolomide (Phase IB) [ Time Frame: At baseline, and at days 1, 2, and 3 of courses 1 and 2 ] [ Designated as safety issue: No ]
  • Progression-free survival (Phase II) [ Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years ] [ Designated as safety issue: No ]
    Progression-free survival curves will be generated using Kaplan-Meier methodology.

  • Toxicity as assessed by NCI CTCAE v. 4.0 [ Time Frame: Up to 30 days post-treatment ] [ Designated as safety issue: Yes ]
    Reported by type, frequency and severity.


Estimated Enrollment: 86
Study Start Date: August 2010
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (RO4929097, cisplatin, vinblastine, temozolomide)
Patients receive RO4929097 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.
Drug: gamma-secretase/Notch signalling pathway inhibitor RO4929097
Given PO
Other Names:
  • R4733
  • RO4929097
Drug: vinblastine sulfate
Given IV
Other Names:
  • 29060-LE
  • Exal
  • Velban
  • Velbe
  • Velsar
Other: pharmacological study
Other Name: pharmacological studies
Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Drug: temozolomide
Given PO
Other Names:
  • SCH 52365
  • Temodal
  • Temodar
  • TMZ
Other: laboratory biomarker analysis
Correlatives studies

Detailed Description:

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/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)

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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 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
  • 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)
  • 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 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 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 nefazodone
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  • No other concurrent anticancer agents or therapies
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01196416

Locations
United States, New York
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Sponsors and Collaborators
Investigators
Principal Investigator: Mark Dickson Memorial Sloan-Kettering Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01196416     History of Changes
Other Study ID Numbers: NCI-2011-02524, NCI-2011-02524, CDR0000684220, 10-085, 10-085, 8491, U01CA069856, N01CM62206
Study First Received: September 4, 2010
Last Updated: December 6, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Temozolomide
Cisplatin
Vinblastine
Dacarbazine
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents

ClinicalTrials.gov processed this record on April 15, 2014