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

NCT01196416 | Completed Phase 1 Results

• 7 other identifiers: NCI-2011-02524CDR000068422010-0858491N01CM62206P30CA008748U01CA069856
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Recurrent Melanoma; Stage IV Skin Melanoma

Outcome Measures

Primary Outcomes (4)

• 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

  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.

  21 days

• Overall Survival (Phase II)

  Overall response rate (complete \[CR\] or partial response \[PR\]) according to RECIST version 1.1

  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)

  21 days

Secondary Outcomes (7)

• Participants' Change in Protein Levels

  Baseline up to 2 weeks

• Cycle 1 AUC/Pharmacokinetics of Gamma-secretase Inhibitor RO4929097 in Combination With Temozolomide (Phase IB)

  Days 4 and 5

• Cycle 1 C Max/Pharmacokinetics of Gamma-secretase Inhibitor RO4929097 in Combination With Temozolomide (Phase IB)

  At Cycle 1

• Cycle 1 Mean Day 2 Trough/Pharmacokinetics of Gamma-secretase Inhibitor RO4929097 in Combination With Temozolomide (Phase IB)

  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)

  2 weeks

Study Arms (1)

Treatment (RO4929097, cisplatin, vinblastine, temozolomide)

EXPERIMENTAL

Patients receive gamma-secretase/Notch signalling pathway inhibitor RO4929097 PO 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.

Drug: Cisplatin; Drug: Gamma-Secretase Inhibitor RO4929097; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Temozolomide; Drug: Vinblastine Sulfate

Interventions

Cisplatin DRUG

Given IV

Also known as: Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin

Treatment (RO4929097, cisplatin, vinblastine, temozolomide)

Gamma-Secretase Inhibitor RO4929097 DRUG

Given PO

Also known as: RO4929097

Treatment (RO4929097, cisplatin, vinblastine, temozolomide)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (RO4929097, cisplatin, vinblastine, temozolomide)

Pharmacological Study OTHER

Correlative studies

Treatment (RO4929097, cisplatin, vinblastine, temozolomide)

Temozolomide DRUG

Given PO

Also known as: CCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temodal, Temodar

Treatment (RO4929097, cisplatin, vinblastine, temozolomide)

Vinblastine Sulfate DRUG

Given IV

Also known as: 29060 LE, 29060-LE, Exal, Velban, Velbe, Velsar, VINCALEUKOBLASTINE

Treatment (RO4929097, cisplatin, vinblastine, temozolomide)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or cytologically Memorial Sloan Kettering Cancer Center (MSKCC) confirmed recurrent or metastatic melanoma
• All Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be \> 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or \> 20 mm when measured by chest x-ray; lymph nodes must be \> 15 mm in short axis when measured by CT or MRI
• Patients may have had up to one prior systemic therapy for recurrent or metastatic disease, but cannot have previously been treated with cisplatin, vinblastine, temozolomide, dacarbazine, or a gamma-secretase inhibitor; at least 3 weeks must have elapsed since the last dose of systemic therapy; for small molecule targeted therapy, at least 5 half-lives must have elapsed; at least 6 weeks must have elapsed if the last regimen included carmustine (BCNU) or mitomycin C or an anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody
• Life expectancy of greater than 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
• Hemoglobin \>= 9 g/dL
• Leukocytes \>= 3,000/mcL
• Absolute neutrophil count \>= 1,500/mcL
• Platelets \>= 100,000/mcL
• Total bilirubin =\< institutional upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 X institutional upper limit of normal
• Creatinine within normal institutional limits OR creatinine clearance \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
• Women of childbearing potential and men must use two forms of contraception (i.e., barrier contraception and one other method of contraception) at least 4 weeks prior to study entry, for the duration of study participation, and for at least 12 months post-treatment; should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study and for 12 months after study participation, the patient should inform the treating physician immediately
• Women of childbearing potential are required to have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days and within 24 hours prior to the first dose of RO4929097 (serum or urine); a pregnancy test (serum or urine) will be administered every 4 weeks if their menstrual cycles are regular or every 2 weeks if their cycles are irregular while on study within the 24-hour period prior to the administration of RO4929097; a positive urine test must be confirmed by a serum pregnancy test; prior to dispensing RO4929097, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of RO4929097
• Female patients of childbearing potential are defined as follows:

You may not qualify if:

• Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier
• Patients may not be receiving any other investigational agents
• Patients with known brain metastases are excluded unless brain metastases have been resected or successfully treated with stereotactic radiosurgery and the patient has been free from central nervous system (CNS) recurrence or progression for 3 months
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to RO4929097 or other agents used in the study
• Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible
• Preclinical studies indicate that RO4929097 is a substrate of CYP3A4 and inducer of CYP3A4 enzyme activity; caution should be exercised when dosing RO4929097 concurrently with CYP3A4 substrates, inducers, and/or inhibitors; furthermore, patients who are taking concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4 should be switched to alternative medications to minimize any potential risk; the following medications with strong potential for interaction are not allowed: indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone
• Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption
• Patients must be able to swallow tablets
• Patients who are serologically positive for hepatitis A, B or C, and have an active infection, or have a history of liver disease, other forms of hepatitis or cirrhosis are ineligible
• Patients with 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 are excluded from this study
• Uncontrolled intercurrent illness including, but not limited to, 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 corrected QT interval (QTc); psychiatric illness/social situations that would limit compliance with study requirements; patients may have had another cancer but there must be convincing clinical evidence that the melanoma is the disease requiring therapeutic intervention
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with RO4929097; these potential risks may also apply to other agents used in this study
• HIV-positive patients on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
• Cardiovascular: baseline QTc \> 450 msec (male) or QTc \> 470 msec (female)
• Patients who have not recovered to \< Common Terminology Criteria for Adverse Events (CTCAE) grade 2 toxicities related to prior therapy are not eligible to participate in this study

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

Cisplatin; 1,2-diaminocyclohexaneplatinum II citrate; Platinum; 2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; Temozolomide; Vinblastine

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Metals, Heavy; Elements; Transition Elements; Metals; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Results Point of Contact

• Title: Dr. Mark Dickson
• Organization: Memorial Sloan Kettering Cancer Center

DicksonM@mskcc.org

646-888-4164

Study Officials

• Mark Dickson

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 4, 2010
• First Posted: September 8, 2010
• Study Start: August 1, 2010
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: November 18, 2019
• Results First Posted: October 18, 2017

Record last verified: 2019-10

Locations

US (1)