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.

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion 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

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT03514901
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

Intergruppo Melanoma Italiano
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Paola Queirolo, Dr.
Principal Investigator Affiliation Ospedale Policlinico San Martino di Genova
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other
Overall Status Recruiting
Countries Italy
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Melanoma Metastatic, BRAF V600 Mutation
Additional Details

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.

Arms & Interventions

Arms

Experimental: 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.

Active Comparator: Pembrolizumab or Nivolumab

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

Interventions

Other: - 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).

Drug: - 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.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

International Sites

Istituto dei Tumori "Giovanni Paolo II", Bari, BA, Italy

Status

Recruiting

Address

Istituto dei Tumori "Giovanni Paolo II"

Bari, BA, 70124

Site Contact

Michele Guida, Dr.

giuseppe.palmieri@ss.icb.cnr.it

+39 079 2841229

ASST Papa Giovanni XXIII, Bergamo, BG, Italy

Status

Not yet recruiting

Address

ASST Papa Giovanni XXIII

Bergamo, BG, 24127

Site Contact

Mario Mandalà, Dr.

giuseppe.palmieri@ss.icb.cnr.it

+39 079 2841229

Policlinico Sant'Orsola Malpighi, Bologna, BO, Italy

Status

Recruiting

Address

Policlinico Sant'Orsola Malpighi

Bologna, BO, 40138

Site Contact

Barbara Melotti, Dr.

giuseppe.palmieri@ss.icb.cnr.it

+39 079 2841229

Meldola, FC, Italy

Status

Recruiting

Address

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

Meldola, FC, 47014

Site Contact

Massimo Guidoboni, Dr.

giuseppe.palmieri@ss.icb.cnr.it

+39 079 2841229

Ospedale Policlinico San Martino, Genova, GE, Italy

Status

Recruiting

Address

Ospedale Policlinico San Martino

Genova, GE, 16132

Site Contact

Paola Queirolo, Dr.

giuseppe.palmieri@ss.icb.cnr.it

+39 079 2841229

Taormina, ME, Italy

Status

Recruiting

Address

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

Taormina, ME, 98039

Site Contact

Francesco Ferraù, Dr.

giuseppe.palmieri@ss.icb.cnr.it

+39 079 2841229

Milano, MI, Italy

Status

Recruiting

Address

Fondazione IRCCS Istituto Nazionale dei Tumori

Milano, MI, 20133

Site Contact

Michele Del Vecchio, Dr.

giuseppe.palmieri@ss.icb.cnr.it

+39 079 2841229

Istituto Oncologico Veneto - IRCCS, Padova, PD, Italy

Status

Recruiting

Address

Istituto Oncologico Veneto - IRCCS

Padova, PD, 35128

Site Contact

Vanna Chiarion Sileni, Dr.

giuseppe.palmieri@ss.icb.cnr.it

+39 079 2841229

Ospedale S. Chiara - A.O.U. Pisana, Pisa, PI, Italy

Status

Active, not recruiting

Address

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

Pisa, PI, 56125

A.O.U.S. Policlinico "Le Scotte", Siena, SI, Italy

Status

Not yet recruiting

Address

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

Siena, SI, 53100

Site Contact

Anna Maria Di Giacomo, Dr.

giuseppe.palmieri@ss.icb.cnr.it

+39 079 2841229

Torino, TO, Italy

Status

Recruiting

Address

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

Torino, TO, 10126

Site Contact

Maria Teresa Fierro, Prof.

giuseppe.palmieri@ss.icb.cnr.it

+39 079 2841229

Roma, Italy

Status

Active, not recruiting

Address

Istituti Fisioterapici Ospitalieri - IFO - Istituto "Regina Elena"

Roma, , 00144

IDI Istituto Dermopatico Immacolata, Roma, Italy

Status

Not yet recruiting

Address

IDI Istituto Dermopatico Immacolata

Roma, , 00167

Site Contact

Alessandro Scoppola, Dr.

giuseppe.palmieri@ss.icb.cnr.it

+39 079 2841229

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