Clinical trial NCT03514901: 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.
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.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Melanoma Metastatic
BRAF V600 Mutation
Lead sponsor: Intergruppo Melanoma Italiano
Sponsor class: OTHER
First posted: 2018-05-03
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized, open-label study
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Overall Survival (OS) time for patients with focal progression
timeFrame: From date of randomization until the date of death from any cause, assessed up to 24 months
Secondary outcomes:
measure: Progression Free Survival (PFS) time for patients with focal progression
timeFrame: From date of randomization until the date of death from any cause, assessed up to 24 months
measure: Overall Survival (OS) time for patients with non-focal progression
timeFrame: From date of the last dose of vemurafenib and cobimetinib until the date of death from any cause, assessed up to 24 months
measure: Comparison between Overall Survival (OS) time for patients with non-focal progression and Overall Survival (OS) results of patients with focal progression
timeFrame: 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
measure: Nature of adverse events (AE) and serious adverse events (SAE) reported throughout the study
timeFrame: From baseline up to 24 months after the last treatment
measure: Frequency of adverse events (AE) and serious adverse events (SAE) reported throughout the study
timeFrame: From baseline up to 24 months after the last treatment
measure: Severity of adverse events (AE) and serious adverse events (SAE) reported throughout the study
timeFrame: From baseline up to 24 months after the last treatment
measure: Timing of adverse events (AE) and serious adverse events (SAE) reported throughout the study
timeFrame: From baseline up to 24 months after the last treatment
measure: Changes in blood pressure
timeFrame: From baseline up to 24 months
measure: Changes in heart rate
timeFrame: From baseline up to 24 months
measure: Changes in temperature
timeFrame: From baseline up to 24 months
measure: Changes in respiratory rate
timeFrame: From baseline up to 24 months
measure: Changes in clinical laboratory results
timeFrame: From baseline up to 24 months
Other outcomes:
Locations:
city: Bari
country: Italy
facility: Istituto dei Tumori "Giovanni Paolo II"
state: BA
city: Bergamo
country: Italy
facility: ASST Papa Giovanni XXIII
state: BG
city: Bologna
country: Italy
facility: Policlinico Sant'Orsola Malpighi
state: BO
city: Meldola
country: Italy
facility: IRCCS IRST Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
state: FC
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino
state: GE
city: Taormina
country: Italy
facility: P.O. di Taormina - Azienda Sanitaria Provinciale di Messina
state: ME
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
state: MI
city: Padova
country: Italy
facility: Istituto Oncologico Veneto - IRCCS
state: PD
city: Pisa
country: Italy
facility: Ospedale S. Chiara - A.O.U. Pisana
state: PI
city: Siena
country: Italy
facility: A.O.U.S. Policlinico "Le Scotte"
state: SI
city: Torino
country: Italy
facility: P.O. San Lazzaro - A.O.U. Città della Salute e della Scienza di Torino - Molinette
state: TO
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia - Divisione Melanoma, Sarcoma e Tumori Rari
city: Roma
country: Italy
facility: Istituti Fisioterapici Ospitalieri - IFO - Istituto "Regina Elena"
city: Roma
country: Italy
facility: IDI Istituto Dermopatico Immacolata
Study officials:
affiliation: Ospedale Policlinico San Martino di Genova
name: Paola Queirolo, Dr.
role: PRINCIPAL_INVESTIGATOR
References: