Clinical Trial to Evaluate the Efficacy of Vemurafenib in Combination With Cobimetinib (Continuous and Intermittent) in BRAFV600-mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma
NCT ID: NCT02583516
Last Updated: 2020-02-17
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE2
Total Enrollment
70 participants
Study Classification
INTERVENTIONAL
Study Start Date
2015-06-30
Study Completion Date
2019-09-30
Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of two different schedules of administration of vemurafenib in combination with cobimetinib (continuous and intermittent) in previously untreated BRAFV600- mutation positive patients with unresectable locally advanced or metastatic melanoma.
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Detailed Description
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Conditions
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Melanoma
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Study Groups
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A - Continuous Administration
960 mg of vemurafenib po, bid, days 1 to 28 and 60 mg of cobimetinib po, od, days 1 to 21, for each 28-days' cycle.
Group Type
EXPERIMENTAL
vemurafenib and cobimetinib
Intervention Type
DRUG
Comparison between different treatment regimens
B - Intermittent Administration
960 mg of vemurafenib po, bid, days 1 to 28 and 60 mg of cobimetinib po, od, days 1 to 21, for each 28-days' cycle, during 12 weeks. After that period, patients will be treated with both drugs at the same doses indicated previously, but with an intermittent pattern: vemurafenib days 1 to 28 followed by 14 days off (4 weeks on and 2 weeks off) and cobimetinib days 1 to 21 followed by 21 days off (3 weeks on and 3 weeks off)
Group Type
EXPERIMENTAL
vemurafenib and cobimetinib
Intervention Type
DRUG
Comparison between different treatment regimens
Interventions
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vemurafenib and cobimetinib
Comparison between different treatment regimens
Intervention Type
DRUG
Eligibility Criteria
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Inclusion Criteria
1. Patients with histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma.
2. Patients must be naïve to treatment for locally advanced unresectable or metastatic disease.
3. Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue.
4. Measurable disease per RECIST v1.1.
5. ECOG performance status of 0 or 1.
6. Additionally, patients to be included in the biomarker sub- study should meet the following criteria:
* Consent to provide archival tissue for biomarker analyses.
* Consent to undergo tumor biopsies.
7. Male or female patient aged major or equal 18 years.
8. Able to participate and willing to give written informed.
9. Life expectancy mayor o igual 12 weeks.
10. Adequate hematologic and end organ function, within 14 days prior to first dose of study drug treatment:
* ANC major or equal 1.5 × 109/L.
* Platelet count major or equal 100 × 109/L.
* Hemoglobin major or equal 9 g/dL.
* Albumin major or equal 2.5 g/dL.
* Bilirubin minor or equal 1.5 × the upper limit of normal (ULN).
* AST, ALT, and alkaline phosphatase minor or equal 3 × ULN, with the following exceptions:
* Patients with documented liver metastases: AST and/or ALT minor or equal 5 × ULN.
* Patients with documented liver or bone metastases alkaline phosphatase minor o equal 5 × ULN.
* Serum creatinine minor o equal 1.5 × ULN or CrCl major or equal 40 mL/min on the basis of measured CrCl from a 24- hour urine collection.
11. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use 2 effective forms of contraception during the course of this study and for at least 6 months after completion of study therapy.
12. Negative serum pregnancy test within 10 days prior to commencement of dosing in women of childbearing potential.
13. Absence of any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol and follow-up after treatment discontinuation schedule.
2. Patients must be naïve to treatment for locally advanced unresectable or metastatic disease.
3. Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue.
4. Measurable disease per RECIST v1.1.
5. ECOG performance status of 0 or 1.
6. Additionally, patients to be included in the biomarker sub- study should meet the following criteria:
* Consent to provide archival tissue for biomarker analyses.
* Consent to undergo tumor biopsies.
7. Male or female patient aged major or equal 18 years.
8. Able to participate and willing to give written informed.
9. Life expectancy mayor o igual 12 weeks.
10. Adequate hematologic and end organ function, within 14 days prior to first dose of study drug treatment:
* ANC major or equal 1.5 × 109/L.
* Platelet count major or equal 100 × 109/L.
* Hemoglobin major or equal 9 g/dL.
* Albumin major or equal 2.5 g/dL.
* Bilirubin minor or equal 1.5 × the upper limit of normal (ULN).
* AST, ALT, and alkaline phosphatase minor or equal 3 × ULN, with the following exceptions:
* Patients with documented liver metastases: AST and/or ALT minor or equal 5 × ULN.
* Patients with documented liver or bone metastases alkaline phosphatase minor o equal 5 × ULN.
* Serum creatinine minor o equal 1.5 × ULN or CrCl major or equal 40 mL/min on the basis of measured CrCl from a 24- hour urine collection.
11. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use 2 effective forms of contraception during the course of this study and for at least 6 months after completion of study therapy.
12. Negative serum pregnancy test within 10 days prior to commencement of dosing in women of childbearing potential.
13. Absence of any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol and follow-up after treatment discontinuation schedule.
Exclusion Criteria
1. History of prior RAF or MEK pathway inhibitor treatment.
2. Palliative radiotherapy within 14 days prior to the first dose of study treatment.
3. Major surgery or traumatic injury within 14 days prior to first dose of study treatment.
4. Active malignancy other than melanoma that could potentially interfere with the interpretation of efficacy measures. Patients with a previous malignancy within the past 3 years are excluded except for patients with resected BCC or SCC of the skin, melanoma in-situ, carcinoma in-situ of the cervix, and carcinoma in-situ of the breast. History of isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer is allowed.
5. History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration.
The risk factors for RVO are listed below. Patients will be excluded if they have the following conditions:
* Uncontrolled glaucoma with intra-ocular pressures \> 21 mmHg.
* Serum cholesterol major or equal Grade 2.
* Hypertriglyceridemia major or equal Grade 2.
* Hyperglycemia (fasting) major or equal Grade 2.
6. 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 or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus). If not automated, calculation of QTcF must be done through the following formula: QTcF = (QT interval in ms) / \[(60 / heart rate in bpm) )\^(1/3)\]
* Uncontrolled hypertension major or equal Grade 2 (patients with a history hypertension controlled with anti-hypertensives to minor or equal Grade 1 are eligible).
* Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%.
7. Patients with active CNS lesions (including melanomatous meningitis) are excluded. However, patients are eligible if:
* All known CNS lesions have been treated with stereotactic therapy or surgery, AND
* There has been no evidence of clinical and radiographic disease progression in the CNS for major or equal 3 weeks after radiotherapy or surgery.
Whole brain radiotherapy is not allowed, with the exception of patients who have had definitive resection or stereotactic therapy of all radiologically detectable parenchymal brain lesions.
8. Current severe, uncontrolled systemic disease.
9. History of malabsorption or other condition that would interfere with absorption of study drugs.
10. Pregnant or lactating.
11. Unwillingness or inability to comply with study and follow- up procedures.
12. The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:
* St. Johns wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer).
* Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor).
2. Palliative radiotherapy within 14 days prior to the first dose of study treatment.
3. Major surgery or traumatic injury within 14 days prior to first dose of study treatment.
4. Active malignancy other than melanoma that could potentially interfere with the interpretation of efficacy measures. Patients with a previous malignancy within the past 3 years are excluded except for patients with resected BCC or SCC of the skin, melanoma in-situ, carcinoma in-situ of the cervix, and carcinoma in-situ of the breast. History of isolated elevation in prostate-specific antigen in the absence of radiographic evidence of metastatic prostate cancer is allowed.
5. History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration.
The risk factors for RVO are listed below. Patients will be excluded if they have the following conditions:
* Uncontrolled glaucoma with intra-ocular pressures \> 21 mmHg.
* Serum cholesterol major or equal Grade 2.
* Hypertriglyceridemia major or equal Grade 2.
* Hyperglycemia (fasting) major or equal Grade 2.
6. 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 or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus). If not automated, calculation of QTcF must be done through the following formula: QTcF = (QT interval in ms) / \[(60 / heart rate in bpm) )\^(1/3)\]
* Uncontrolled hypertension major or equal Grade 2 (patients with a history hypertension controlled with anti-hypertensives to minor or equal Grade 1 are eligible).
* Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%.
7. Patients with active CNS lesions (including melanomatous meningitis) are excluded. However, patients are eligible if:
* All known CNS lesions have been treated with stereotactic therapy or surgery, AND
* There has been no evidence of clinical and radiographic disease progression in the CNS for major or equal 3 weeks after radiotherapy or surgery.
Whole brain radiotherapy is not allowed, with the exception of patients who have had definitive resection or stereotactic therapy of all radiologically detectable parenchymal brain lesions.
8. Current severe, uncontrolled systemic disease.
9. History of malabsorption or other condition that would interfere with absorption of study drugs.
10. Pregnant or lactating.
11. Unwillingness or inability to comply with study and follow- up procedures.
12. The following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment:
* St. Johns wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer).
* Grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor).
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Roche Farma, S.A
INDUSTRY
Sponsor Role
collaborator
Pivotal S.L.
INDUSTRY
Sponsor Role
collaborator
Grupo Español Multidisciplinar de Melanoma
OTHER
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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José Antonio López-Martín, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Hospital Universitario 12 de Octubre
Alfonso Berrocal, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Hospital General Universitario de Valencia
Locations
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Hospital Universitario Donostia
Donostia / San Sebastian, Guipuzcoa, Spain
Site Status
Hospital General Universitario Santa Lucía
Cartagena, Murcia, Spain
Site Status
Hospital Clínic de Barcelona
Barcelona, , Spain
Site Status
Hospital del Mar
Barcelona, , Spain
Site Status
Hospital Universitario Vall d'Hebron
Barcelona, , Spain
Site Status
Hospital Insular de Gran Canaria
Las Palmas de Gran Canaria, , Spain
Site Status
Hospital Universitario Lucus Augusti
Lugo, , Spain
Site Status
Hospital Universitario 12 de Octubre
Madrid, , Spain
Site Status
Hospital Universitario La Paz
Madrid, , Spain
Site Status
Hospital Regional Universitario de Málaga
Málaga, , Spain
Site Status
Hospital Clínico Universitario de Salamanca
Salamanca, , Spain
Site Status
Hospital Universitario de Canarias
Santa Cruz de Tenerife, , Spain
Site Status
Hospital Universitario Virgen Macarena
Seville, , Spain
Site Status
Hospital General Universitario de Valencia
Valencia, , Spain
Site Status
Hospital Universitario Doctor Peset
Valencia, , Spain
Site Status
Hospital Universitario y Politécnico La Fe
Valencia, , Spain
Site Status
Hospital Álvaro Cunqueiro (Complejo Hospitalario Universitario de Vigo)
Vigo, , Spain
Site Status
Hospital Universitario Miguel Servet
Zaragoza, , Spain
Site Status
Countries
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Spain
References
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Paraiso KH, Fedorenko IV, Cantini LP, Munko AC, Hall M, Sondak VK, Messina JL, Flaherty KT, Smalley KS. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer. 2010 Jun 8;102(12):1724-30. doi: 10.1038/sj.bjc.6605714.
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BACKGROUND
Ribas A, Gonzalez R, Pavlick A, Hamid O, Gajewski TF, Daud A, Flaherty L, Logan T, Chmielowski B, Lewis K, Kee D, Boasberg P, Yin M, Chan I, Musib L, Choong N, Puzanov I, McArthur GA. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a phase 1b study. Lancet Oncol. 2014 Aug;15(9):954-65. doi: 10.1016/S1470-2045(14)70301-8. Epub 2014 Jul 15.
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BACKGROUND
Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, Mandala M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Sovak MA, Chang I, Choong N, Hack SP, McArthur GA, Ribas A. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014 Nov 13;371(20):1867-76. doi: 10.1056/NEJMoa1408868. Epub 2014 Sep 29.
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BACKGROUND
Das Thakur M, Stuart DD. The evolution of melanoma resistance reveals therapeutic opportunities. Cancer Res. 2013 Oct 15;73(20):6106-10. doi: 10.1158/0008-5472.CAN-13-1633. Epub 2013 Oct 4.
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BACKGROUND
Callahan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T, Wolchok JD, Solit DB, Rosen N, Abdel-Wahab O, Levine RL, Chapman PB. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med. 2012 Dec 13;367(24):2316-21. doi: 10.1056/NEJMoa1208958. Epub 2012 Nov 7.
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BACKGROUND
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-55. No abstract available.
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BACKGROUND
Gonzalez-Cao M, Mayo de Las Casas C, Oramas J, Berciano-Guerrero MA, de la Cruz L, Cerezuela P, Arance A, Munoz-Couselo E, Espinosa E, Puertolas T, Diaz Beveridge R, Ochenduszko S, Villanueva MJ, Basterretxea L, Bellido L, Rodriguez D, Campos B, Montagut C, Drozdowskyj A, Molina MA, Lopez-Martin JA, Berrocal A. Intermittent BRAF inhibition in advanced BRAF mutated melanoma results of a phase II randomized trial. Nat Commun. 2021 Dec 1;12(1):7008. doi: 10.1038/s41467-021-26572-6.
Reference Type
DERIVED
Related Links
Access external resources that provide additional context or updates about the study.
http://www.groupgem.org/
Spanish Multidisciplinary Melanoma Group Web
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
2014-005277-36
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
GEM-01-15
Identifier Type: -
Identifier Source: org_study_id
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