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.

BRAF V600 Mutation Clinical Trial

Official title:

An Evaluation of 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.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03514901
• Other study ID #: BeyPro2
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 18, 2018
• Est. completion date: April 29, 2023

Study information

• Verified date: December 2021
• Source: Intergruppo Melanoma Italiano
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 120
• Est. completion date: April 29, 2023
• Est. primary completion date: April 29, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• BRAF V600 Mutation
• Disease Progression
• Melanoma
• Melanoma Metastatic

Intervention

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.

Locations

Country	Name	City	State
Italy	Istituto dei Tumori "Giovanni Paolo II"	Bari	BA
Italy	ASST Papa Giovanni XXIII	Bergamo	BG
Italy	Policlinico Sant'Orsola Malpighi	Bologna	BO
Italy	Ospedale Policlinico San Martino	Genova	GE
Italy	IRCCS IRST Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola	FC
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	MI
Italy	Istituto Europeo di Oncologia - Divisione Melanoma, Sarcoma e Tumori Rari	Milano
Italy	Istituto Oncologico Veneto - IRCCS	Padova	PD
Italy	Ospedale S. Chiara - A.O.U. Pisana	Pisa	PI
Italy	IDI Istituto Dermopatico Immacolata	Roma
Italy	Istituti Fisioterapici Ospitalieri - IFO - Istituto "Regina Elena"	Roma
Italy	A.O.U.S. Policlinico "Le Scotte"	Siena	SI
Italy	P.O. di Taormina - Azienda Sanitaria Provinciale di Messina	Taormina	ME
Italy	P.O. San Lazzaro - A.O.U. Città della Salute e della Scienza di Torino - Molinette	Torino	TO

Sponsors (1)

Lead Sponsor	Collaborator
Intergruppo Melanoma Italiano

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 a =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	Progression Free Survival (PFS) time for patients with focal progression	PFS of patients with focal progression is defined as the time, in months, from randomization to the date of the first documented tumor progression or death due to any cause, whichever comes first. Clinical deterioration will not be considered progression. For subjects who neither progress nor die, time will be censored at the date of their last tumor assessment. For subjects who start a new anti-tumor treatment, time will be censored at the start of the new treatment. For a randomized subject who does not have any post-randomization tumor assessments and who has not died, time will be censored at the randomization date. PFS will be compared between treatment groups using a log-rank test procedure with a two-sided a =0.2 level. The PFS function for each treatment group will be estimated using the Kaplan-Meier product-limit method. Median and two-sided 80% confidence intervals (CI) for median PFS will be computed by treatment group. A Cox proportional hazard model for PFS with treatment	From date of randomization until the date of death from any cause, assessed up to 24 months
Secondary	Overall Survival (OS) time for patients with non-focal progression	Overall survival of patients with non-focal progression is defined as the time, in months, from date of non-focal progression to first-line 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"). The OS function will be estimated using the Kaplan-Meier product-limit method. Median and corresponding two-sided 80% confidence intervals will be computed. Overall survival results of patients with non-focal progression will be descriptively compared with OS results of patients with focal progression (i.e. primary efficacy endpoint).	From date of the last dose of vemurafenib and cobimetinib until the date of death from any cause, assessed up to 24 months
Secondary	Comparison between Overall Survival (OS) time for patients with non-focal progression and Overall Survival (OS) results of patients with focal progression	Overall survival results of patients with non-focal progression will be descriptively compared with OS results of patients with focal progression (i.e. primary efficacy endpoint). No statistical test will be foreseen for this comparison. The overall survival results are defined as the time, in months, from the date of progression to the date of death.	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
Secondary	Nature of adverse events (AE) and serious adverse events (SAE) reported throughout the study	Nature of adverse events (AE) and serious adverse events (SAE) verified during the study. Safety analyses will be reported by actual treatment group and on the Non-focal Progression Set. AE and SAE will be assessed according to the Common Terminology Criteria for AEs (CTCAE version 4).	From baseline up to 24 months after the last treatment
Secondary	Frequency of adverse events (AE) and serious adverse events (SAE) reported throughout the study	Frequency of adverse events (AE) and serious adverse events (SAE) verified during the study. Safety analyses will be reported by actual treatment group and on the Non-focal Progression Set. AE and SAE will be assessed according to the Common Terminology Criteria for AEs (CTCAE version 4).	From baseline up to 24 months after the last treatment
Secondary	Severity of adverse events (AE) and serious adverse events (SAE) reported throughout the study	Severity of adverse events (AE) and serious adverse events (SAE) verified during the study. Safety analyses will be reported by actual treatment group and on the Non-focal Progression Set. AE and SAE will be assessed according to the Common Terminology Criteria for AEs (CTCAE version 4).	From baseline up to 24 months after the last treatment
Secondary	Timing of adverse events (AE) and serious adverse events (SAE) reported throughout the study	Timing of adverse events (AE) and serious adverse events (SAE) verified during the study. Safety analyses will be reported by actual treatment group and on the Non-focal Progression Set. AE and SAE will be assessed according to the Common Terminology Criteria for AEs (CTCAE version 4).	From baseline up to 24 months after the last treatment
Secondary	Changes in blood pressure	Changes in blood pressure during and following vemurafenib + cobimetinib administration. Blood pressure will be measured in mmHg (millimetres of mercury).	From baseline up to 24 months
Secondary	Changes in heart rate	Changes in heart rate during and following vemurafenib + cobimetinib administration. Heart rate will be measured in bpm (beats per minute).	From baseline up to 24 months
Secondary	Changes in temperature	Changes in temperature during and following vemurafenib + cobimetinib administration. Temperature will be measured in °C (degrees centigrade).	From baseline up to 24 months
Secondary	Changes in respiratory rate	Changes in respiratory rate during and following vemurafenib + cobimetinib administration. Respiratory rate will be measured in breaths per minute.	From baseline up to 24 months
Secondary	Changes in clinical laboratory results	Changes in clinical laboratory results during and following vemurafenib + cobimetinib administration. Laboratory results will be assessed according to the Common Terminology Criteria for AEs (CTCAE version 4).	From baseline up to 24 months