Vemurafenib Plus Cobimetinib in Advanced or Metastatic Melanoma Patients

NCT03224208 | Terminated Phase 2

• 1 other identifier: VECODUE
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged overall survival (OS) and progression-free survival (PFS) compared to dacarbazine. In the same setting, combined use of vemurafenib and cobimetinib, a selective inhibitor of MEK, yielded a significant improvement in PFS and response rate, compared to vemurafenib monotherapy, along with an advantage in OS, which did not cross the pre-specified significance bounderies (COBRIM trial). In treatment-naïve patients with mutated BRAF, both anti PD-1-based immunotherapy and BRAF-targeted agents are feasible therapeutic options, with the former and latter agents being associated with more durable and earlier responses, respectively. As suggested by National Comprehensive Cancer Network (NCCN) guidelines, the use of combined BRAF and MEK inhibitors in patients with progressive disease after immunotherapy, is also feasible, but it is not supported by category 1 evidence, in view of the lack of studies conducted in this setting. The main objective of this phase II trial is to evaluate the efficacy and safety of the combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received first-line systemic immunotherapy for inoperable locally advanced / metastatic disease.

Conditions

Melanoma; Melanoma (Skin); Melanoma Stage

Keywords

melanoma; advanced; vemurafenib; cobimetinib

Outcome Measures

Primary Outcomes (1)

• Overall Survival

  OS will be calculated from the first day of treatment until the date of death from any cause.Any patient not know to have died at the time of data analysis will be censored at the time of the last recorded date on which the patient was know to be alive.

  Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month

Secondary Outcomes (2)

• PFS

  Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month

• ORR

  Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month

Study Arms (1)

Single arm

EXPERIMENTAL

Vemurafenib will be orally adminitered at 960 mg b.i.d. on Days 1-28. Cobimetinib will be given orally at 60 mg qd on Days 1-21 of each 28-day treatment cycle until disease progression. Treatments will be continued until the development of progressive disease (as per Investigator assessment), unacceptable toxicity, consent withdrawal, death, reasons deemed by the treating physician or study termination by the Sponsor.

Drug: Vemurafenib; Drug: Cobimetinib

Interventions

Vemurafenib DRUG

Vemurafenib will be orally adminitered at 960 mg b.i.d. on Days 1-28

Single arm

Cobimetinib DRUG

Cobimetinib will be given orally at 60 mg qd on Days 1-21 of each 28-day treatment cycle

Single arm

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 confirmed, unresectable stage IIIc or stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th edition. Unresectability of stage IIIc disease must have confirmation from a surgical oncologist;
• Patients with advanced melanoma who have received one prior immunotherapy systemic regimen for advanced disease, for whom vemurafenib/cobimetinib treatment has been scheduled by the treating physician.
• Adjuvant treatment is allowed, except for anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 agents;
• Patients must be naïve to treatment for locally advanced unresectable or metastatic with BRAF/MEK inhibitors;
• Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue BRAF V600 mutation test;
• At least one measurable lesion according to disease per RECIST v1.1 criteria;
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0- 2;
• Male or female patient aged ≥ 18 years;
• Able to participate and willing to give written informed consent prior to performance of any study-related procedures and to comply with the study protocol;
• Life expectancy ≥ 12 weeks.

You may not qualify if:

• History of any prior systemic treatment for unresectable stage IIIc or stage IV melanoma (prior anti RAF or MEK agents) other than one prior first-line immunotherapy;
• Palliative radiotherapy within 14 days prior to the first dose of study treatment;
• Major surgery or traumatic injury within 14 days prior to first dose of study treatment;
• Ocular:
• History of, or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serouschorioretinopathy (CSCR), retinal vein occlusion (RVO) or neovascularmacular degeneration;
• The risk factors for RVO are listed below. Patients will be excluded if they currently have the following conditions:
• Uncontrolled glaucoma with intra-ocular pressures ≥21 mmHg;
• Serum cholesterol ≥Grade 2;
• Hypertriglyceridemia ≥ Grade 2;
• Hyperglycemia (fasting) ≥Grade 2;
• Cardiac:
• History of clinically significant cardiac dysfunction, including the following:
• Current unstable angina;
• Symptomatic congestive heart failure of New York Heart Association class 2 or higher;
• History of congenital long QT syndrome or mean (average of triplicate measurements) QTcF ≥ 450 msec at baseline or uncorrectable abnormalities inserum electrolytes (sodium, potassium, calcium, magnesium, phosphorus);

Sponsors & Collaborators

• Fondazione Melanoma Onlus: lead
• Roche Pharma AG: collaborator

Study Sites (1)

Fondazione G.Pascale

Napoli, 80131, Italy

Location

MeSH Terms

Conditions

Melanoma

Interventions

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

• Paolo Antonio Ascierto

  IRCCS Fondazione Pascale Naploli

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 19, 2017
• First Posted: July 21, 2017
• Study Start: May 17, 2018
• Primary Completion: September 12, 2020
• Study Completion: January 8, 2021
• Last Updated: April 26, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)