A Study Evaluating the Safety and Efficacy of Cobimetinib Plus Atezolizumab in BRAFV600 Wild-type Melanoma With Central Nervous System Metastases and Cobimetinib Plus Atezolizumab and Vemurafenib in BRAFV600 Mutation-positive Melanoma With Central Nervous System Metastases

NCT ID: NCT03625141

Last Updated: 2024-04-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-12-13
• Study Completion Date: 2023-04-13

Brief Summary

This study will evaluate the efficacy and safety of cobimetinib plus atezolizumab in participants with BRAFV600 wild-type melanoma with central nervous system (CNS) metastases and of cobimetinib plus atezolizumab and vemurafenib in BRAFV600 mutation-positive melanoma patients with CNS metastases.

Conditions

Metastatic Melanoma

Study Design

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

Study Groups

Cohort 1- cobimetinib and atezolizumab

Participants with BRAFV600 wild-type disease will be administered cobimetinib on Days 1-21 of each 28-day cycle; and atezolizumab on Days 1 and 15 of each treatment cycle.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

60 mg (three tablets of 20 mg each) orally (PO) once a day (QD) on Days 1-21 of each 28-day cycle.

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be given at a fixed dose of 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.

Only for cohort 2, no dose of atezolizumab will be given during the run-in period (cycle 1).

Cohort 2 - cobimetinib, atezolizumab and vemurafenib

Participants with BRAFV600 mutation-positive disease will be administered cobimetinib, atezolizumab and vemurafenib in 28-day treatment cycles. Treatment includes a 28-day run-in period where participants will receive cobimetinib and vemurafenib only. Upon completion of the 28-day run-in period, atezolizumab will be added to their treatment regimen.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

60 mg (three tablets of 20 mg each) orally (PO) once a day (QD) on Days 1-21 of each 28-day cycle.

Atezolizumab

Intervention Type: DRUG

Atezolizumab will be given at a fixed dose of 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.

Only for cohort 2, no dose of atezolizumab will be given during the run-in period (cycle 1).

Vemurafenib

Intervention Type: DRUG

Participants will receive vemurafenib 960 mg (four 240 mg tablets) orally (PO) twice daily (BID) on days 1-21 of the run-in period (cycle 1); thereafter, they will receive vemurafenib 720 mg dose (three 240 mg tablets) PO BID on days 22-28 of cycle 1 and on days 1-28 of all subsequent cycles.

Interventions

Cobimetinib

60 mg (three tablets of 20 mg each) orally (PO) once a day (QD) on Days 1-21 of each 28-day cycle.

Intervention Type: DRUG

Atezolizumab

Atezolizumab will be given at a fixed dose of 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle.

Only for cohort 2, no dose of atezolizumab will be given during the run-in period (cycle 1).

Intervention Type: DRUG

Vemurafenib

Participants will receive vemurafenib 960 mg (four 240 mg tablets) orally (PO) twice daily (BID) on days 1-21 of the run-in period (cycle 1); thereafter, they will receive vemurafenib 720 mg dose (three 240 mg tablets) PO BID on days 22-28 of cycle 1 and on days 1-28 of all subsequent cycles.

Intervention Type: DRUG

Other Intervention Names

Cotellic; Tecentriq; Zelboraf

Eligibility Criteria

Inclusion Criteria

• Histologically confirmed melanoma with radiologically confirmed brain metastases
• Documented BRAFV600 mutation status of melanoma tumour tissue using a validated genetic test.
• Measurable brain metastases

• Age ≥18 years
• Able to comply with the study protocol, in the investigator's judgment
• ECOG Performance Status ≤ 2
• Life expectancy of > 3 months
• Willing and able to complete health and quality of life questionnaires required by the protocol
• Adequate hematologic and end-organ function
• Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use two effective forms of contraception during the course of this study and for at least six months after completion of study therapy.
• Male patients must agree to refrain from donating sperm for at least six months after the last dose of cobimetinib

Exclusion Criteria

• Prior SRT or surgical therapy of ≤ 10 brain metastases is allowed but prior WBRT is not allowed
• Adverse effects of all prior systemic or local treatment must have either returned to baseline or become stable and manageable prior to initiation of study treatment.

• Ocular melanoma
• Leptomeningeal involvement
• Uncontrolled tumour-related pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage more than once every 28 days.
• Prior WBRT treatment for CNS disease
• Increasing corticosteroid dose during the seven days prior to initiation of study treatment or current dexamethasone or equivalent dose of > 8 mg/day
• Prior treatment with a BRAF or MEK inhibitor
• For patients assigned to Cohort 1 only: prior immunotherapy in the metastatic setting is not allowed. Prior immunotherapy is allowed in the adjuvant setting, provided it is completed ≥ 90 days prior to study treatment initiation.

For patients assigned to Cohort 2 only: prior immunotherapy in either the adjuvant or metastatic setting is not allowed.

• Major surgical procedure other than for diagnosis within four weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study
• Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells or to any formulation component of cobimetinib or atezolizumab or, for patients assigned to Cohort 2 only, vemurafenib
• Any anti-cancer therapy, including chemotherapy, hormonal therapy and radiotherapy, within two weeks prior to initiation of study treatment
• Patients assigned to Cohort 2 only: Concomitant treatment with anticonvulsants other than gabapentin, vigabatrin and levetiracetam
• Patients assigned to Cohort 2 only: acetaminophen is prohibited within seven days prior to initiation of study treatment unless the patient has an absolute contraindication to the to the use of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin
• Active malignancy (other than melanoma) or a prior malignancy within the past three years

• Known risk factors for ocular toxicity
• History of clinically significant cardiac dysfunction
• Inability to swallow medications
• Malabsorption condition that would alter the absorption of orally administered medications
• Traumatic injury within two weeks prior to initiation of study treatment
• Prior allogeneic stem cell or solid organ transplantation
• Active or history of autoimmune disease or immune deficiency
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• Uncontrolled diabetes or symptomatic hyperglycaemia
• Any Grade ≥ 3 haemorrhage or bleeding event within 28 days of study treatment initiation
• History of stroke, reversible ischemic neurological defect, or transient ischemic attack within six months prior to study treatment initiation
• Positive human immunodeficiency virus (HIV) test at screening
• Hepatitis B virus (HBV) infection (chronic or acute)
• Active hepatitis C virus (HCV) infection
• Active tuberculosis
• History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Severe infection within four weeks prior to initiation of study treatment
• Signs or symptoms of infection within two weeks prior to initiation of study treatment
• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in, and completion of, the study
• Any psychological, familial, sociological, or geographical condition that may hamper compliance with the protocol and follow-up after treatment discontinuation
• Pregnancy, breastfeeding, or intention of becoming pregnant during the study. Women of childbearing potential must have a negative serum pregnancy test result within seven days prior to initiation of study treatment.
• Treatment with therapeutic oral or IV antibiotics within two weeks prior to initiation of study treatment
• Administration of a live, attenuated vaccine within four weeks prior to initiationof study treatment or anticipation of need for such a vaccine during the study
• Treatment with systemic immunostimulatory agents within 28 days or 5 half-lives of the drug, whichever is shorter, prior to study treatment initiation
• Treatment with systemic immunosuppressive medications within two weeks prior to study treatment initiation
• Treatment with investigational drug within 28 days or 5 half-lives of the drug, whichever is longer, prior to initiation of study treatment
• For patients to be assigned to Cohort 2 only: anticipated use of any concomitant medication during or within seven days prior to initiation of study treatment that is known to cause QT prolongation
• Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 enzyme inducers or inhibitors at least seven days prior to initiation of study treatment.

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

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Instituto Nacional de Cancer - INCa; Oncologia

Rio de Janeiro, Rio de Janeiro, Brazil

Oncosite - Centro de Pesquisa Clinica Em Oncologia Ltda

Ijuí, Rio Grande do Sul, Brazil

Hospital das Clinicas - UFRGS

Porto Alegre, Rio Grande do Sul, Brazil

CHU de Nantes; Cancéro-dermatologie

Nantes, , France

Institut Claudius Regaud; Departement Oncologie Medicale

Toulouse, , France

Institut Gustave Roussy; Dermatologie

Villejuif, , France

Universitätsklinikum "Carl Gustav Carus"; Klinik und Poliklinik fur Dermatologie

Dresden, , Germany

Orszagos Onkologiai Intezet; Borgyogyaszati Osztaly

Budapest, , Hungary

IRCCS Istituto Nazionale Tumori Fondazione Pascale; Oncologia Medica B

Napoli, Campania, Italy

Istituto Dermopatico dell'Immacolata (IDI)-IRCCS; IV Divisione Oncologica e Dermatologia Oncologica

Rome, Lazio, Italy

IRCCS Istituto Nazionale Per La Ricerca Sul Cancro (IST); Oncologia Medica A

Genoa, Liguria, Italy

Irccs Istituto Europeo Di Oncologia (IEO); Oncologia Medica

Milan, Lombardy, Italy

Azienda Ospedaliero - Universitaria Pisana U.O. Oncologia Medica 2 Universitaria ? Polo Oncologico

Pisa, Tuscany, Italy

IOV - Istituto Oncologico Veneto IRCCS

Padua, Veneto, Italy

Riga East Clinical University Hospital Latvian Oncology Centre

Riga, , Latvia

Onkologikoa - Instituto Oncológico de Donostia

Donostia / San Sebastian, Guipuzcoa, Spain

Hospital Clínic i Provincial; Servicio de Hematología y Oncología

Barcelona, , Spain

Institut Catala d Oncologia Hospital Duran i Reynals

Barcelona, , Spain

Hospital General Universitario Gregorio Marañon; Servicio de Oncologia

Madrid, , Spain

Hospital Universitario Virgen Macarena; Servicio de Oncologia

Seville, , Spain

Hospital General Universitario de Valencia; Servicio de oncologia

Valencia, , Spain

Universitätsspital Zürich; USZ Flughafen / H13-7-609

Zurich, , Switzerland

Countries

Brazil; France; Germany; Hungary; Italy; Latvia; Spain; Switzerland

References

Dummer R, Queirolo P, Gerard Duhard P, Hu Y, Wang D, de Azevedo SJ, Robert C, Ascierto PA, Chiarion-Sileni V, Pronzato P, Spagnolo F, Mujika Eizmendi K, Liszkay G, de la Cruz Merino L, Tawbi H. Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2023 Dec;24(12):e461-e471. doi: 10.1016/S1470-2045(23)00334-0. Epub 2023 Jul 14.

Reference Type: DERIVED

PMID: 37459873 (View on PubMed)

Dummer R, Queirolo P, Abajo Guijarro AM, Hu Y, Wang D, de Azevedo SJ, Robert C, Ascierto PA, Chiarion-Sileni V, Pronzato P, Spagnolo F, Mujika Eizmendi K, Liszkay G, de la Cruz Merino L, Tawbi H. Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2022 Sep;23(9):1145-1155. doi: 10.1016/S1470-2045(22)00452-1. Epub 2022 Aug 5.

Reference Type: DERIVED

PMID: 35940183 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2018-000759-41

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MO39136

Identifier Type: -

Identifier Source: org_study_id