Dose-seeking Study of Pembrolizumab Plus Vemurafenib and Cobimetinib Advanced Melanoma

NCT02818023 | Terminated Phase 1 DMC

• 1 other identifier: 15-131
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

The study plans to treat patients with pembrolizumab and thus blocking the PD-1/PD-L1 axis would render tumor-infiltrating lymphocytes (TILs) in the tumor parenchyma more functional as a consequence of BRAF inhibition, such that T cell activation by BRAFi would not be dampened by the PD-1/PD-L1 interaction. This combination would reverse dysfunction among T cells in the tumor parenchyma, maximizing T cell mediated immune anti-tumor efficacy. Progression free survival (PFS) with pembrolizumab in KEYNOTE-001 was 57% at 6 months, and 46.4% in the more recently reported phase III trial. PFS with vemurafenib treatment in BRIM-3 was \~50% at 6 months. Combined treatment with pembrolizumab, cobimetinib and vemurafenib for BRAF mutant melanoma is hypothesized to be safe and to improve the PFS compared to these recent historical controls. Because this combination has not yet been tested, and because the primary objective is to assess safety, the investigators are staging accrual in the first phase of the trial. The study aims to accrue up to 30 patients to the mTPI design of this study with the expectation that there will be at least 30 patients treated at RP2D. In case there are less than 30 patients on the RP2D, additional patients will be accrued. Patients will continue to receive treatment with pembrolizumab, vemurafenib and cobimetinib until disease progression or dose limiting toxicity. Patients with treatment response and no dose limiting toxicity may receive treatment with pembrolizumab for up to 24 months.

Conditions

Melanoma

Outcome Measures

Primary Outcomes (1)

• Percentage of participants that experience a dose-limiting toxicity

  determine the safety and maximum tolerated dose of vemurafenib and cobimetinib with pembrolizumab

  Up to 2 years

Secondary Outcomes (3)

• overall response rate (ORR)

  Up to 2 years

• progression free survival

  Up to 2 years

• overall survival

  up to 2 years

Other Outcomes (1)

• assessment of tumor microenvironment and immune response via biomarker level measurement

  Up to 2 years

Study Arms (1)

Pembrolizumab plus vemurafenib and Cobimetinib

EXPERIMENTAL

* Pembrolizumab will be given at a dose of 200 mg q3 weeks (this is the standard dosage, ), and vemurafenib/cobimetinib will be given at 480 mg twice daily/20 mg daily, 720 mg twice daily/40 mg daily, or 960 mg twice daily/60 mg daily. Treatment with pembrolizumab and vemurafenib will commence on the same day. * One cycle of treatment will be defined as one dose of pembrolizumab and 3 weeks of vemurafenib.

Drug: Pembrolizumab; Drug: Vemurafenib; Drug: Cobimetinib

Interventions

Pembrolizumab DRUG

Pembrolizumab will be given at a dose of 200 mg q3 weeks (this is the standard dosage, ). Treatment with pembrolizumab and vemurafenib will commence on the same day. One cycle of treatment will be defined as one dose of pembrolizumab and 3 weeks of vemurafenib.

Pembrolizumab plus vemurafenib and Cobimetinib

Vemurafenib DRUG

Vemurafenib will be given at 480 mg twice daily, 720 mg twice daily, or 960 mg twice daily. Treatment with pembrolizumab and vemurafenib will commence on the same day. One cycle of treatment will be defined as one dose of pembrolizumab and 3 weeks of vemurafenib.

Pembrolizumab plus vemurafenib and Cobimetinib

Cobimetinib DRUG

Cobimetinib will be given at 20 mg once daily, 40 mg once daily, or 60 mg once daily. Treatment with cobimetinib will commence on the same day. Cobimetinib will be given daily for 21 days, then held for 7 days.

Pembrolizumab plus vemurafenib and Cobimetinib

Eligibility Criteria

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

You may qualify if:

• Provide written informed consent obtained prior to the initiation of study procedures.
• Male and female subjects who are at least 18 years of age.
• Histologically confirmed unresectable stage III or stage IV melanoma (AJCC 7th edition classification). Cutaneous melanoma and mucosal melanoma will be eligible.
• Only patients with BRAF V600E or V600K mutated tumors will be enrolled.
• Baseline skin exam is required for all patients. Note: Cutaneous squamous cell carcinoma (SCC) lesions identified at baseline must be excised.
• Measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Baseline measurements must be obtained within 4 weeks prior to registration.
• Adequate hematologic, renal, and liver function as evidenced by the following (within 4 weeks prior to starting the study drugs):
• WBC ≥ 3,000/mm3
• ANC ≥ 1500
• Hemoglobin ≥ 9g/dL (women) or ≥ 11g/dL (men) Platelets ≥ 100,000/mm3 Serum Creatinine ≤ 1.5 x upper limit of normal (ULN)
• Serum Bilirubin ≤ 1.5 x ULN
• Serum AST and ALT ≤ 2.5 x ULN
• Note: (supportive transfusions will be allowed during screening and during treatment as deemed necessary by the treating physician)
• EKG documenting QTc interval \< 480 msec and no clinically significant arrhythmia
• Fully recovered from any effects of major surgery, and be free of significant infection.

You may not qualify if:

• Serious clinically significant illnesses, such as: cardiovascular disease (uncontrolled congestive heart failure, uncontrolled hypertension, cardiac ischemia, myocardial infarction, and severe cardiac arrhythmia), bleeding disorders, symptomatic autoimmune diseases (such as inflammatory bowel disease, autoimmune hepatitis, uncontrolled hypo or hyperthyroidism), severe obstructive or restrictive pulmonary diseases, retinopathy, active systemic infections, and inflammatory bowel disorders.
• Known HIV or AIDS-related illness, or active HBV and HCV.
• Has a known history of active TB (Bacillus Tuberculosis)
• History of grade 4 immune-related adverse events requiring treatment with prednisone, or grade 3 immune-related adverse events requiring prednisone \>10 mg/kg for \>12 weeks, if previously treated with ipilimumab.
• Prior therapy with anti-PD-1 agent(s) in the metastatic setting. Treatment with anti-PD1 in the adjuvant setting is permitted.
• Prior therapy with a BRAF and/or MEK and/or ERK inhibitors in the metastatic setting. Treatment with BRAF/MEKi in the adjuvant setting is permitted.
• Refractory nausea, vomiting, small bowel resection or any other gastrointestinal ailment that would preclude study drug absorption.
• Cardiac abnormalities
• Mean QTc interval ≥ 480 msec at screening.
• ACS/AMI -within 24 weeks prior to screening.
• PCI/PTCA -within 24 weeks prior to screening.
• Symptomatic heart failure - NYHA Class ≥ II symptoms.
• Active infection within one-week prior to study, including unexplained fever
• Systemic steroid or other immunosuppressive therapy within 4 weeks of starting the study.
• Lactating females and/or pregnant females.

Sponsors & Collaborators

• Yana Najjar: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

UPMC Cancer Center Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

pembrolizumab; Vemurafenib; cobimetinib

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)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Yana M. Najjar, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 7, 2016
• First Posted: June 29, 2016
• Study Start: July 13, 2016
• Primary Completion: June 10, 2019
• Study Completion: April 23, 2021
• Last Updated: January 3, 2022

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)