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.

NCT ID: NCT03514901

Last Updated: 2021-12-02

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 120 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-06-18
• Study Completion Date: 2023-04-29

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.

Detailed Description

Melanoma is a heterogeneous skin tumor, characterized by mutations of different oncogenes. Almost half of patients with advanced melanoma have a gene mutation of BRAF serine-threonine kinase. Over the past 5 years, two BRAF inhibitors targeting these mutations, vemurafenib and dabrafenib, have shown high rates of rapid response in phase II and III studies. However, the duration of responses is limited in most patients due to the development of acquired resistance. Mechanisms of resistance to BRAF inhibitor therapy are diverse and include the reactivation of the mitogen-activated protein kinase (MAPK) pathway in over two-thirds of tumors, along with promotion of parallel signaling networks.

Recently, the combination of drugs was superior in terms of responses, Progression Free Survival (PFS) and Overall Survival (OS) compared to monotherapy.

The data from recent studies confirm the clinical benefit of the combination of Vemurafenib with cobimetinib and support the use of the combination as a standard first-line approach to improve survival in patients.

The aim of this randomized, open-label, phase II study is to evaluate the efficacy, in terms of overall survival, of vemurafenib combined with cobimetinib associated with local treatment compared with second-line therapy, in patients with BRAFV600 mutation-positive metastatic melanoma in focal progression with first-line combined vemurafenib and cobimetinib.

Conditions

Melanoma Metastatic; BRAF V600 Mutation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Experimental combination beyond Focal Progression

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.

Group Type: EXPERIMENTAL

Experimental combination beyond Focal Progression

Intervention Type: 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).

Pembrolizumab or Nivolumab

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

Group Type: ACTIVE_COMPARATOR

Pembrolizumab or Nivolumab

Intervention Type: 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.

Interventions

Experimental combination beyond Focal Progression

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).

Intervention Type: OTHER

Pembrolizumab or Nivolumab

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.

Intervention Type: DRUG

Other Intervention Names

Keytruda or Opdivo

Eligibility Criteria

Inclusion Criteria

• 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:

1. Bilirubin ≤ 1.5 x the upper limit of normal (ULN).

2. 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.

3. 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
• Absence of any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the treatment regimen
• Patient does not currently participate in other clinical trials

Exclusion Criteria

• 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:

1. Current unstable angina.

2. Symptomatic congestive heart failure of New York Heart Association class 2 or higher.

3. 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.

4. Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension controlled with anti-hypertensives to ≤ Grade 1 are eligible).

5. 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Intergruppo Melanoma Italiano

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Paola Queirolo, Dr.

Role: PRINCIPAL_INVESTIGATOR

Ospedale Policlinico San Martino di Genova

Locations

Istituto dei Tumori "Giovanni Paolo II"

Bari, BA, Italy

ASST Papa Giovanni XXIII

Bergamo, BG, Italy

Policlinico Sant'Orsola Malpighi

Bologna, BO, Italy

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

Meldola, FC, Italy

Ospedale Policlinico San Martino

Genova, GE, Italy

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

Taormina, ME, Italy

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, MI, Italy

Istituto Oncologico Veneto - IRCCS

Padua, PD, Italy

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

Pisa, PI, Italy

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

Siena, SI, Italy

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

Torino, TO, Italy

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

Milan, , Italy

Istituti Fisioterapici Ospitalieri - IFO - Istituto "Regina Elena"

Roma, , Italy

IDI Istituto Dermopatico Immacolata

Roma, , Italy

Countries

Italy

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

BeyPro2

Identifier Type: -

Identifier Source: org_study_id