To Evaluate the Efficacy Beyond Progression of Vemurafenib+Cobimetinib Associated With Local Treatment Compared to Second-line Treatment in Patients With BRAFV600+ Metastatic Melanoma in Focal Progression With First-line+Vemurafenib+Cobimetinib.

NCT03514901 | Unknown Phase 2

• 1 other identifier: BeyPro2
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 14

Brief Summary

The purpose of this study is to evaluate the efficacy beyond progression of vemurafenib combined with cobimetinib associated with local treatment compared to second-line treatment in patients with BRAFV600 mutation-positive metastatic melanoma in focal progression with first-line combined vemurafenib and cobimetinib.

Conditions

Melanoma Metastatic; BRAF V600 Mutation

Outcome Measures

Primary Outcomes (1)

• Overall Survival (OS) time for patients with focal progression

  Overall survival of patients with focal progression is defined as the time, in months, from randomization to the date of death from any cause. If a patient is not known to have died, survival time will be censored at the date of last contact ("last known date alive"). Overall survival of patients with focal progression will be compared between treatment groups using a log-rank test procedure with a two-sided α =0.2 level. The OS function for each treatment group will be estimated using the Kaplan-Meier product-limit method. Median and corresponding two-sided 80% confidence intervals will be computed by treatment group. A Cox proportional hazard model for OS with treatment arm as single factor will be used to estimate the hazard ratio of vemurafenib and cobimetinib plus local treatment to Standard of Care (SOC) second-line treatment and its corresponding 80% confidence interval.

  From date of randomization until the date of death from any cause, assessed up to 24 months

Secondary Outcomes (12)

• Progression Free Survival (PFS) time for patients with focal progression

  From date of randomization until the date of death from any cause, assessed up to 24 months

• Overall Survival (OS) time for patients with non-focal progression

  From date of the last dose of vemurafenib and cobimetinib until the date of death from any cause, assessed up to 24 months

• Comparison between Overall Survival (OS) time for patients with non-focal progression and Overall Survival (OS) results of patients with focal progression

  From date of randomization or date of the last dose of vemurafenib and cobimetinib until the date of death from any cause, assessed up to 24 months

• Nature of adverse events (AE) and serious adverse events (SAE) reported throughout the study

  From baseline up to 24 months after the last treatment

• Frequency of adverse events (AE) and serious adverse events (SAE) reported throughout the study

  From baseline up to 24 months after the last treatment

Study Arms (2)

Experimental combination beyond Focal Progression

EXPERIMENTAL

Local treatment (i.e. surgery, radiotherapy) + Vemurafenib 240mg tablets (4 tabs/twice daily for 28 consecutive days) + Cobimetinib 20mg tablets (3 tabs/day for 21 consecutive days) beyond focal progression.

Other: Experimental combination beyond Focal Progression

Pembrolizumab or Nivolumab

ACTIVE COMPARATOR

Pembrolizumab daily dose 2 mg/kg milligram(s)/kilogram or Nivolumab daily dose 3 mg/kg milligram(s)/kilogram.

Drug: Pembrolizumab or Nivolumab

Interventions

Experimental combination beyond Focal Progression OTHER

Vemurafenib is taken on a 28-day cycle. Each dose consists of four 240 mg (960 mg) tablets twice daily for 28 consecutive days. The first dose should be taken in the morning and the second dose in the evening approximately 12 hours later. Each dose can be taken with or without a meal. Vemurafenib tablets should be swallowed whole with a glass of water and should not be chewed or crushed. Cobimetinib is taken on a 28-day cycle. Each dose consists of three 20 mg tablets (60 mg) and should be taken orally, once daily for 21 consecutive days, followed by a 7-day break. Each subsequent treatment cycle should start after the 7-day treatment break has elapsed. The dose should be taken in the morning. Local treatment (i.e. surgery, radiotherapy).

Experimental combination beyond Focal Progression

Pembrolizumab or Nivolumab DRUG

Pembrolizumab 2 mg/kg is administered as an intravenous infusion over 30 minutes every 3 weeks OR Nivolumab 3 mg/kg is administered intravenously over 60 minutes every 2 weeks.

Also known as: Keytruda or Opdivo

Pembrolizumab or Nivolumab

Eligibility Criteria

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

You may qualify if:

• Patients with histologically confirmed melanoma, either unresectable Stage IIIc or Stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th edition
• Patients previously untreated for metastatic melanoma
• Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue (archival or newly obtained tumor samples) by a validated mutational test
• Adequate performance status to receive vemurafenib and cobimetinib therapy as determined by treating physician
• Male or female patient aged ≥18 years
• Able to participate and willing to give written informed consent prior to any treatment-related procedures and to comply with treatment guidance
• Adequate end-organ function, defined by the following laboratory results obtained within 14 days prior to the first dose of program drug treatment:
• Bilirubin ≤ 1.5 x the upper limit of normal (ULN).
• AST, ALT, and alkaline phosphatase ≤ 3 x ULN, with the following exceptions:
• Patients with documented liver metastases: AST and/or ALT ≤ 5 x ULN.
• Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 x ULN.
• Serum creatinine ≤1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min based on measured CrCl from a 24-hour urine collection or Cockroft-Gault glomerular filtration rate estimation.
• Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use two effective forms of contraception during program therapy and for at least 6 months after completion of program therapy
• Negative serum pregnancy test prior to commencement of dosing in women of childbearing potential
• Patient should be able to swallow tablets

You may not qualify if:

• Palliative radiotherapy within 7 days prior to the first dose of program treatment
• Patients with active malignancy (other than BRAF-mutated melanoma) or a previous malignancy within the past 3 years except for patients with resected melanoma, resected BCC, resected cutaneous SCC, resected melanoma in situ, resected carcinoma in situ of the cervix, and resected carcinoma in situ of the breast
• Evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment / central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration
• Systemic risk factor for RVO including uncontrolled glaucoma, uncontrolled hypercholesterolemia, hypertriglyceridemia or hyperglycemia
• 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; presence of clinically significant ventricular or atrial dysrhythmias ≥ Grade 2.
• Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible).
• Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%, whichever is lower
• Current severe, uncontrolled systemic disease
• Major surgery or traumatic injury within 14 days prior to first dose of program treatment
• History of malabsorption or other condition that would interfere with absorption of program drugs
• Hypersensitivity to the active substance or to any of the excipients
• Pregnant or breastfeeding women

Sponsors & Collaborators

• Intergruppo Melanoma Italiano: lead

Study Sites (14)

Istituto dei Tumori "Giovanni Paolo II"

Bari, BA, 70124, Italy

Location

ASST Papa Giovanni XXIII

Bergamo, BG, 24127, Italy

Location

Policlinico Sant'Orsola Malpighi

Bologna, BO, 40138, Italy

Location

IRCCS IRST Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Meldola, FC, 47014, Italy

Location

Ospedale Policlinico San Martino

Genova, GE, 16132, Italy

Location

P.O. di Taormina - Azienda Sanitaria Provinciale di Messina

Taormina, ME, 98039, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, MI, 20133, Italy

Location

Istituto Oncologico Veneto - IRCCS

Padua, PD, 35128, Italy

Location

Ospedale S. Chiara - A.O.U. Pisana

Pisa, PI, 56125, Italy

Location

A.O.U.S. Policlinico "Le Scotte"

Siena, SI, 53100, Italy

Location

P.O. San Lazzaro - A.O.U. Città della Salute e della Scienza di Torino - Molinette

Torino, TO, 10126, Italy

Location

Istituto Europeo di Oncologia - Divisione Melanoma, Sarcoma e Tumori Rari

Milan, 20141, Italy

Location

Istituti Fisioterapici Ospitalieri - IFO - Istituto "Regina Elena"

Roma, 00144, Italy

Location

IDI Istituto Dermopatico Immacolata

Roma, 00167, Italy

Location

MeSH Terms

Interventions

pembrolizumab; Nivolumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Paola Queirolo, Dr.

  Ospedale Policlinico San Martino di Genova

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Open-label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A randomized, open-label study

Study Record Dates

• First Submitted: March 28, 2018
• First Posted: May 3, 2018
• Study Start: June 18, 2018
• Primary Completion: April 29, 2023
• Study Completion: April 29, 2023
• Last Updated: December 2, 2021

Record last verified: 2021-12

Locations

IT (14)