Advanced BRAFV600 Wild-type Melanoma Clinical Trial
Official title:
A Phase III, Open-Label, Multicenter, Two Arm, Randomized Study to Investigate the Efficacy and Safety of Cobimetinib Plus Atezolizumab Versus Pembrolizumab in Patients With Previously Untreated Advanced BRAF V600 Wild-Type Melanoma
| Verified date | August 2022 |
| Source | Hoffmann-La Roche |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
This is a Phase III, multicenter, open-label, randomized study designed to evaluate the efficacy, safety, and pharmacokinetics of cobimetinib plus atezolizumab compared with pembrolizumab in treatment-naive participants with advanced BRAFV600 wild-type melanoma.
| Status | Terminated |
| Enrollment | 446 |
| Est. completion date | February 19, 2021 |
| Est. primary completion date | April 15, 2019 |
| Accepts healthy volunteers | No |
| Gender | All |
| Age group | 18 Years and older |
| Eligibility | Inclusion Criteria: Disease-Specific Inclusion Criteria - Histologically confirmed locally advanced and unresectable or metastatic melanoma - Naive to prior systemic anti-cancer therapy for melanoma - Documentation of BRAFV600 wild-type status in melanoma tumor tissue through use of a clinical mutation test approved by the local health authority - A representative, formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or 20 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report prior to study entry. If 20 slides are not available or the tissue block is not of sufficient size, the patient may still be eligible for the study, after discussion with and approval by the Medical Monitor - Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 - Age >=18 years at time of signing Informed Consent Form - Ability to comply with the study protocol, in the investigator's judgment - Histologically or cytologically confirmed BRAFV600 wild-type melanoma - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 - Life expectancy >=3 months - Adequate hematologic and end-organ function - For women of childbearing potential: agreement to remain abstinent or use at least two forms of effective contraceptive with a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of cobimetinib and at least 5 months after the last dose of atezolizumab or pembrolizumab - For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures (e.g. condom), and agreement to refrain from donating sperm, for at least 3 months after the last dose of cobimetinib - Willingness and ability of patients to report selected study outcomes (e.g., GHS and HRQoL) using an electronic device or paper backup questionnaires. Exclusion Criteria: General Exclusion Criteria - Inability to swallow medications - Malabsorption condition that would alter the absorption of orally administered medications - Pregnancy, breastfeeding, or intention of becoming pregnant during the study - History of severe hypersensitivity reactions to components of the cobimetinib, atezolizumab, or pembrolizumab formulations - Current or recent treatment with therapeutic antibiotics, live attenuated vaccines or systemic immunostimulatory/immunosuppresive medication - 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 Cancer-Related Exclusion Criteria - Ocular melanoma - Major surgery or radiotherapy within 21 days prior to Day 1 of Cycle 1 or anticipation of needing such procedure while receiving study treatment - Uncontrolled tumor-related pain - Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage more than once every 28 days - Active or untreated central nervous system (CNS) metastases Exclusions Related to Cardiovascular Disease - Unstable angina, new-onset angina within last 3 months, myocardial infarction within the last 6 months prior to Day 1 of Cycle 1, or current congestive heart failure classified as New York Heart Association Class II or higher - Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or <50%, whichever is lower - Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic baseline hypertension consistently above 159/99 mmHg despite optimal medical management - History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third degree heart block, or evidence of prior myocardial infarction Exclusions Related to Infections - HIV infection - Active tuberculosis infection - Severe infections within 4 weeks prior to Day 1 of Cycle 1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia - Signs or symptoms of clinically relevant infection within 2 weeks prior to Day 1 of Cycle 1 - Treatment with oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1 - Active or chronic viral hepatitis B or C infection Exclusions Related to Ocular Disease - Known risk factors for ocular toxicity Exclusions Related to Autoimmune Conditions and Immunomodulatory Drugs - Active or history of autoimmune disease or immune deficiency - Prior allogeneic stem cell or solid organ transplantation - History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan - Treatment with systemic immunosuppressive medications within 2 weeks prior to Day 1, Cycle 1 Exclusions Related to Other Medical Conditions or Medications - Active malignancy (other than melanoma) or a prior malignancy within the past 3 years - Any Grade >=3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1 - History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to Day 1 - Proteinuria >3.5 gm/24 hr - Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 enzyme inducers or inhibitors at least 7 days prior to Day 1 of Cycle 1 and during study treatment |
| Country | Name | City | State |
|---|---|---|---|
| Australia | Cairns Base Hospital | Cairns | Queensland |
| Australia | Townsville General Hospital | Douglas | Queensland |
| Australia | Royal Hobart Hospital | Hobart | Tasmania |
| Australia | Fiona Stanley Hospital | Murdoch | Western Australia |
| Australia | Princess Alexandra Hospital | Woolloongabba | Queensland |
| Belgium | Cliniques Universitaires St-Luc | Bruxelles | |
| Belgium | AZ Groeninge | Kortrijk | |
| Belgium | UZ Leuven Gasthuisberg | Leuven | |
| Brazil | Hospital das Clinicas - UFRGS | Porto Alegre | RS |
| Brazil | Instituto Nacional de Cancer - INCa; Oncologia | Rio de Janeiro | RJ |
| France | Hopital Avicenne; Dermatologie | Bobigny | |
| France | Hopital Saint Andre CHU De Bordeaux; Dermatologie | Bordeaux | |
| France | Chu Site Du Bocage;Dermatologie | Dijon | |
| France | CHU de Grenoble - Hôpital Nord | Grenoble | |
| France | Centre Hospitalier Le Mans; Dermatologie | Le Mans | |
| France | Hopital Claude Huriez; Sce Dermatologie | Lille | |
| France | Hopital Timone Adultes; Dermatologie | Marseille | |
| France | CHU de Nantes; Cancéro-dermatologie | Nantes | |
| France | Hopital l Archet 2; Ginestriere, Service de; Dermatologie | Nice cedex 3 | |
| France | Groupe Hospitalier Bichat Claude Bernard | Paris | |
| France | Hopital Saint Louis; Dermatologie 1 | Paris | |
| France | Hopital Robert Debre; DERMATOLOGIE | Reims | |
| France | Centre Eugene Marquis; Service d'oncologie | Rennes | |
| France | Hopital Charles Nicolle; Dermatologie Serv. | Rouen | |
| France | Institut Universitaire du Cancer - Oncopole Toulouse (IUCT-O) | Toulouse | |
| France | Institut Gustave Roussy; Dermatologie | Villejuif | |
| Germany | Universitätsklinikum "Carl Gustav Carus"; Klinik und Poliklinik für Dermatologie | Dresden | |
| Germany | HELIOS Klinikum Erfurt; Klinik für Dermatologie & Allergologie | Erfurt | |
| Germany | Universitatsklinikum Essen; Klinik für Dermatologie | Essen | |
| Germany | Klinik Johann Wolfgang von Goethe Uni; Klinik für Dermatologie, Venerologie und Allergologie | Frankfurt | |
| Germany | SRH Wald-Klinikum Gera; Klinik für Hautkrankheiten und Allergologie | Gera | |
| Germany | Medizinische Hochschule Hannover; Klinik für Dermatologie, Allergologie und Venerologie | Hannover | |
| Germany | UKSH Kiel; Klinik für Dermatologie, Venerologie und Allergologie | Kiel | |
| Germany | Universitatsklinikum Mainz; Klinik und Poliklinik fur Dermatologie | Mainz | |
| Germany | Klinikum Mannheim Klinik fuer Dermatologie, Venerologie und Allergologie | Mannheim | |
| Germany | Johannes Wesling Klinikum Minden; Hämatologie, Onkologie, Hämostaseologie und Palliativmedizin | Minden | |
| Germany | Klinikum der Ludwigs-Maximilians-Universität München; Dermatologie | München | |
| Germany | Fachklinik Hornheide; Dermatologie | Münster | |
| Germany | Zentrum für Dermatoonkologie, Universitäts-Hautklinik Tübingen | Tübingen | |
| Greece | Anticancer Hospital Ag. Savas ; 2Nd Dept. of Oncology - Internal Medicine | Athens | |
| Greece | Laiko General Hospital Athen | Athens | |
| Greece | Metropolitan Hospital; Dept. of Oncology | Pireaus | |
| Greece | Bioclinic Thessaloniki | Thessaloniki | |
| Hungary | Orszagos Onkologiai Intezet; Borgyogyaszati Osztaly | Budapest | |
| Hungary | Pecsi Tudomanyegyetem AOK; Borgyogyaszati Klinika | Pecs | |
| Hungary | University of Szeged Szent-Györgyi Albert Clinical Center; Department of Dermatology and Allergology | Szeged | |
| Italy | A.O.U. Cons. Policlinico Bari - Consorzlale Policlinico; Scienze Biomediche e Oncologia Umana | Bari | Puglia |
| Italy | Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico | Candiolo | Piemonte |
| Italy | IRCCS Istituto Nazionale Per La Ricerca Sul Cancro (IST); Oncologia Medica A | Genova | Liguria |
| Italy | Irccs Istituto Europeo Di Oncologia (IEO); Oncologia Medica | Milano | Lombardia |
| Italy | Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 2 | Milano | Lombardia |
| Italy | A.O. Universitaria Policlinico Di Modena; Ematologia | Modena | Emilia-Romagna |
| Italy | Azienda Osp Uni Seconda Università Degli Studi Di Napoli; Unità Operativa Oncologia Medica | Napoli | Campania |
| Italy | IRCCS Istituto Nazionale Tumori Fondazione Pascale; Oncologia Medica B | Napoli | Campania |
| Italy | IOV - Istituto Oncologico Veneto IRCCS | Padova | Veneto |
| Italy | Azienda Ospedaliero - Universitaria Pisana U.O. Oncologia Medica 2 Universitaria - Polo Oncologico | Pisa | Toscana |
| Italy | IFO - Istituto Regina Elena; Oncologia Medica | Roma | Lazio |
| Korea, Republic of | Asan Medical Center | Seoul | |
| Korea, Republic of | Samsung Medical Center | Seoul | |
| Korea, Republic of | Seoul National University Hospital | Seoul | |
| Korea, Republic of | Severance Hospital, Yonsei University Health System | Seoul | |
| Netherlands | Antoni Van Leeuwenhoek Ziekenhuis; Inwendige Geneeskunde | Amsterdam | |
| Netherlands | Amphia Ziekenhuis, locatie Langendijk;Oncology | Breda | |
| Netherlands | Erasmus Mc - Daniel Den Hoed Kliniek; Interne Oncologie | Rotterdam | |
| Netherlands | Zuyderland ziekenhuis locatie Geleen | Sittard-Geleen | |
| Poland | Copernicus Podmiot Medyczny Sp. z o.o. Wojewodzkie Centrum Onkologii | Gdansk | |
| Poland | COZL Oddzial Onkologii Klinicznej z pododdzialem Chemioterapii Dziennej | Lublin | |
| Poland | Szpital Kliniczny im. Heliodora Swiecickiego UM w Poznaniu. | Poznan | |
| Poland | Zachodniopomorskie Centrum Onkologii, Osrodek Innowacyjnosci, Rozwoju i Badan Klinicznych | Szczecin | |
| Poland | Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy | Warszawa | |
| Poland | Dolnoslaskie Centrum Onkologii, Pulmonologii i Hematologii | Wroclaw | |
| Russian Federation | Moscow City Oncology Hospital #62 | Moscovskaya Oblast | Moskovskaja Oblast |
| Russian Federation | FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin" | Moscow | |
| Russian Federation | FBI "Scientific Research Institute of Oncology n. a. N. N. Petrov" | Saint-Petersburg | |
| Russian Federation | St. Petersburg Oncology Hospital | St Petersburg | |
| Spain | Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia | Badalona | Barcelona |
| Spain | Hospital Clínic i Provincial; Servicio de Oncología | Barcelona | |
| Spain | Hospital Univ Vall d'Hebron; Servicio de Oncologia | Barcelona | |
| Spain | Hospital Universitario Materno Infantil de Gran Canaria; Servicio de Oncologia | Las Palmas de Gran Canaria | LAS Palmas |
| Spain | Hospital General Universitario Gregorio Marañon; Servicio de Oncologia | Madrid | |
| Spain | Hospital Ramon y Cajal; Servicio de Oncologia | Madrid | |
| Spain | Hospital Universitario 12 de Octubre; Servicio de Oncologia | Madrid | |
| Spain | Hospital Universitario La Paz; Servicio de Oncologia | Madrid | |
| Spain | Hospital Universitario Son Espases; Servicio de Oncologia | Palma De Mallorca | Islas Baleares |
| Spain | Clinica Universitaria de Navarra; Servicio de oncología | Pamplona | Navarra |
| Spain | Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia | Santiago de Compostela | LA Coruña |
| Spain | Hospital Universitario Virgen Macarena; Servicio de Oncologia | Sevilla | |
| Spain | Hospital General Universitario de Valencia; Servicio de oncologia | Valencia | |
| Spain | Instituto Valenciano Oncologia; Oncologia Medica | Valencia | |
| Spain | Hospital Universitario Miguel Servet; Servicio Oncologia | Zaragoza | |
| United Kingdom | BRISTOL ONCOLOGY CENTRE; CLINICAL TRIALS UNIT; R & D department | Bristol | |
| United Kingdom | Western General Hospital; Edinburgh Cancer Center | Edinburgh | |
| United Kingdom | Leicester Royal Infirmary; Dept. of Medical Oncology | Leicester | |
| United Kingdom | Guys & St Thomas Hospital; Department of Oncology | London | |
| United Kingdom | University College London Hospital | London | |
| United Kingdom | University Hospitals of North Midlands NHS Trust-Royal Stoke University Hospital | Stoke-On-Trent | |
| United Kingdom | Singleton Hospital; Pharmacy | Swansea | |
| United Kingdom | Royal Cornwall Hospital | Truro | |
| United States | University of Michigan; Michigan Institute for Clinical and Health Research (MICHR) | Ann Arbor | Michigan |
| United States | St. Luke's University Health network | Bethlehem | Pennsylvania |
| United States | Massachusetts General Hospital;Hematology/ Oncology | Boston | Massachusetts |
| United States | SCRI Tennessee Oncology Chattanooga | Chattanooga | Tennessee |
| United States | Northwestern University | Chicago | Illinois |
| United States | TriHealth Hatton Institute; Surgical Education | Cincinnati | Ohio |
| United States | City of Hope Comprehensive Cancer Center | Duarte | California |
| United States | M.D Anderson Cancer Center; Uni of Texas At Houston | Houston | Texas |
| United States | Dartmouth-Hitchcock Medical Center; Hematology/Oncology | Lebanon | New Hampshire |
| United States | USC Norris Cancer Center | Los Angeles | California |
| United States | West Virginia University Hospitals Inc | Morgantown | West Virginia |
| United States | Morristown Medical Center | Morristown | New Jersey |
| United States | Sarah Cannon Research Institute | Nashville | Tennessee |
| United States | USC Norris Cancer Center; USC Oncology Hematology Newport Beach | Newport Beach | California |
| United States | University of California at Irvine Medical Center; Department of Oncology | Orange | California |
| United States | UF Health Cancer Center at Orlando Health | Orlando | Florida |
| United States | Thomas Jefferson University Hospital;Medical Oncology | Philadelphia | Pennsylvania |
| United States | Florida Cancer Specialist, North Region | Saint Petersburg | Florida |
| United States | Stanford Comprehensive Cancer Center | Stanford | California |
| United States | Moffitt Cancer Center | Tampa | Florida |
| United States | University of Arizona Cancer Center | Tucson | Arizona |
| United States | Florida Cancer Specialists | West Palm Beach | Florida |
| United States | Forsythe Memorial Hospital Inc., dba Novant Health Oncology Specialists | Winston-Salem | North Carolina |
| Lead Sponsor | Collaborator |
|---|---|
| Hoffmann-La Roche |
United States, Australia, Belgium, Brazil, France, Germany, Greece, Hungary, Italy, Korea, Republic of, Netherlands, Poland, Russian Federation, Spain, United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Progression Free Survival (PFS) as Determined by the Independent Review Committee (IRC) | PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions. | Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months | |
| Secondary | PFS as Determined by the Investigator | PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions. | Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months | |
| Secondary | Objective Response as Determined by the Investigator | Objective response rate is defined as the percentage of participants with a complete response (CR) or a partial response (PR) on two consecutive occasions >/=4 weeks apart, as determined by the investigator through the use of RECIST v1.1. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis). | Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months | |
| Secondary | Objective Response as Determined by IRC | Objective response, defined as a complete response or partial response on two consecutive occasions =4 weeks apart, as determined by IRC according to RECIST v1.1 | Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months | |
| Secondary | Disease Control Rate (DCR) | DCR is defined as the proportion of participants with a complete response, a partial response, or stable disease at 16 weeks. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis). Stable disease (SD): neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. | Week 16 | |
| Secondary | Overall Survival (OS) | OS is defined as the time from randomization to death from any cause. | From randomization up to approximately 3 years | |
| Secondary | Duration of Objective Response Determined by the IRC | Duration of objective response, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first. | Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months | |
| Secondary | Duration of Objective Response Determined by the Investigator | Duration of objective response is defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator through use of RECIST v1.1, or death from any cause, whichever occurs first. | Up to 3 years | |
| Secondary | Two-year Landmark Survival | Two-year landmark survival is defined as the rate of survival at 2 years. Two-year landmark survival is defined as the rate of survival at 2 years and was calculated using Kaplan-Meier analysis, which is commonly used to estimate the probability of an event at time 't.' | At 2 years | |
| Secondary | Change From Baseline in Health-related Quality of Life (HRQoL) Scores | HRQoL scores are assessed through global health status (GHS)/ quality of life (QoL) subscale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30). These are based on questions 29 and 30 of the EORTC QLQ-C30. These questions on global health status/QoL scale are coded on 7-point scale (1=very poor to 7=excellent). Raw scores will be linearly transformed to obtain the score ranging from 0 to 100, where higher score represents a higher ("better") level of functioning. | Up to approximately 16 months. Follow up is reported at weeks after participant treatment discontinuation, which could occur at any time during the study. Total time frame does not exceed 16 months. | |
| Secondary | Number of Participants With Adverse Events (AEs) | An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. | Up to approximately 16 months | |
| Secondary | Number of Participants With Abnormal Vital Signs | Vital signs will include temperature, pulse rate, respiratory rate, and systolic and diastolic blood pressure. | From baseline up to approximately 3 years | |
| Secondary | Number of Participants With Laboratory Abnormalities | Participants with laboratory abnormalities (values outside of a defined range) will be reported. | Up to approximately 16 months | |
| Secondary | Plasma Concentration of Cobimetinib | Days 1 and 15 of Cycle 1 | ||
| Secondary | Serum Concentration of Atezolizumab | Day 1 of Cycles 1, 2, and 3 | ||
| Secondary | Percentage of Participants With Anti-drug Antibodies (ADAs) | Participants with ADAs during the study relative to the prevalence of ADAs at baseline will be reported. | Day 1 of Cycle 1, 2, 3 and 30 days after treatment discontinuation |