A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)

Colorectal Cancer Clinical Trial

Official title:

A Phase III, Open-Label, Multicenter, Three-Arm, Randomized Study to Investigate the Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy vs. Regorafenib in Patients With Previously Treated Unresectable Locally Advanced or Metastatic Colorectal Adenocarcinoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02788279
• Other study ID #: GO30182
• Secondary ID: 2016-000202-11
• Status: Completed
• Phase: Phase 3
• Start date: July 5, 2016
• Est. completion date: December 26, 2018

Study information

• Verified date: November 2019
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 363
• Est. completion date: December 26, 2018
• Est. primary completion date: March 9, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Disease-specific inclusion criteria:

• Histologically confirmed adenocarcinoma originating from the colon or rectum (Stage 4 American Joint Committee on Cancer [AJCC] 7th edition)

• Experienced disease progression or was intolerant to at least two systemic chemotherapy regimens for metastatic colorectal cancer that must have included fluroropyrimidines, irinotecan, and oxaliplatin; adjuvant regimen can be considered as one chemotherapy regimen for metastatic disease if the participant had disease recurrence within 6 months of completion; disease progression must have occurred within 3 months of the last systemic therapy administration

General inclusion criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Anticipated life expectancy greater than or equal to (>=) 3 months

• Adequate hematologic and end organ function

• Women of childbearing potential must agree to appropriately use an effective form of contraception (failure rate of less than [<] 1 percent [%] per year) during the treatment period, within 5 months after the last dose of atezolizumab, and within 3 months after the last dose of cobimetinib and regorafenib

• Men must agree not to donate sperm or have intercourse with a female partner without using appropriate barrier contraception during the treatment period and for 3 months after the last dose of either cobimetinib or regorafenib

• Provide an archival or newly obtained tumor tissue sample

Exclusion Criteria:

• After the approximate 5% cap for microsatellite (MSI)-high participants is reached, only MSI-stable participants will be eligible

• Once the 50% cap for wild-type RAS has been reached, only extended RAS-mutant participants will be eligible

• Major surgery or radiotherapy within 21 days prior to Cycle 1 Day 1 or anticipation of needing such procedure while receiving study treatment

• Treatment with any anti-cancer agent within 14 days prior to Cycle 1 Day 1

• Uncontrolled tumor-related pain. Participants requiring narcotic pain medication must be on a stable regimen at study entry

• Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage more than once every 28 days. Indwelling drainage catheters (e.g., PleurX®) are allowed

• Active or untreated central nervous system (CNS) metastases are excluded

• Prior therapy with any cancer immunotherapy, MEK inhibitor, or regorafenib

• Participants with active malignancy (other than CRC) or a prior malignancy within the past 3 years are excluded. Participants with completely resected cutaneous melanoma (early stage), basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in-situ, breast carcinoma in-situ, and localized prostate cancer are eligible

• Unstable angina, new onset angina within last 3 months, myocardial infarction within last 6 months and current congestive heart failure New York Heart Association Class II or higher

• Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or below 50%, whichever is lower

• Poorly controlled hypertension, defined as a blood pressure consistently above 150/90 millimeters of Mercury (mmHg) despite optimal medical management

• Human immunodeficiency virus (HIV) infection

• Active tuberculosis infection

• Severe infections within 2 weeks prior to Cycle 1 Day 1

• Active or chronic viral hepatitis B or C infection

• History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for central serous retinopathy, retinal vein occlusion, or neovascular macular degeneration

• Participants will be excluded if they currently have any of the risk factors as defined in the study protocol for retinal vein occlusion

• History of autoimmune disease

• History of idiopathic pulmonary fibrosis, organizing pneumonia, bronchiolitis obliterans, drug-induced pneumonitis, or idiopathic pneumonitis

• History of organ transplantation including allogeneic bone marrow transplantation

• Inability to swallow medications

• Malabsorption condition that would alter the absorption of orally administered medications

• Pregnant, lactating, breastfeeding, or intending to become pregnant during the study

• Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation of a live attenuated vaccine will be required during the study

Related Conditions & MeSH terms

• Adenocarcinoma
• Colorectal Cancer

Intervention

Drug:
• Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody
Participants will receive atezolizumab IV at 840 mg on Day 1 and Day 15 in a 28-day cycle as a combination therapy or at 1200 mg on Day 1 in a 21-day cycle as a monotherapy until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
• Cobimetinib
Participants will receive cobimetinib 60 mg orally on Days 1 to 21 in a 28-day cycle as a combination therapy until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
• Regorafenib
Participants will receive regorafenib 160 mg orally on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.

Locations

Country	Name	City	State
Australia	Monash Medical Centre; Oncology	Clayton	Victoria
Australia	Peninsula and South Eastern Haematology and Oncology Group	Frankston	Victoria
Australia	Austin Health; Cancer Clinical Trial Centre	Heidelberg	Victoria
Australia	Port Macquarie Base Hospital;North Coast Cancer Institute	Port Macquarie	New South Wales
Australia	Northern Cancer Institute	St Leonards	New South Wales
Australia	Sydney Adventist Hospital; Clinical Trial Unit	Sydney	New South Wales
Belgium	Imeldaziekenhuis	Bonheiden
Belgium	Cliniques Universitaires St-Luc	Bruxelles
Belgium	GHdC Site Notre Dame	Charleroi
Belgium	AZ Groeninge	Kortrijk
Belgium	UZ Leuven Gasthuisberg	Leuven
Canada	Tom Baker Cancer Centre-Calgary	Calgary	Alberta
Canada	Cross Cancer Institute; Clinical Trials	Edmonton	Alberta
Canada	Hopital du Sacre-Coeur	Montreal	Quebec
Canada	McGill University Health Center, Cedar Cancer Center	Montreal	Quebec
Canada	The Ottawa Hospital	Ottawa	Ontario
Canada	CHU de Québec	Quebec City	Quebec
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	BCCA-Vancouver Cancer Centre	Vancouver	British Columbia
Hong Kong	Queen Mary Hospital; Dept. of Clinical Oncology	Hong Kong
Hong Kong	Tuen Mun Hospital; Clinical Oncology	Hong Kong
Hong Kong	Prince of Wales Hosp; Dept. Of Clinical Onc	Shatin
Italy	Istit. Naz. per la Ricerca sul Cancro - Az. Osped. S. Martino	Genova	Liguria
Italy	Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia	Milano	Lombardia
Italy	Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 1	Milano	Lombardia
Italy	A.O. Universitaria Policlinico Di Modena; Oncologia	Modena	Emilia-Romagna
Italy	Azienda Osp Uni Seconda Università Degli Studi Di Napoli; Unità Operativa Oncologia Medica	Napoli	Campania
Italy	A.O. Universitaria Pisana; Oncologia	Pisa	Toscana
Italy	IRCCS Ospedale Casa Sollievo Della Sofferenza; Oncologia	San Giovanni Rotondo	Puglia
Korea, Republic of	National Cancer Center	Gyeonggi-do
Korea, Republic of	Chonnam National University Hwasun Hospital	Jeollanam-do
Korea, Republic of	Asan Medical Center - Oncology	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Yonsei University Health System/Severance Hospital	Seoul
Poland	Centrum Onkologii im. Prof. F. Lukaszczyka w Bydgoszczy	Bydgoszcz
Poland	Uniwersyteckie Centrum Kliniczne; Klinika Onkologii i Radioterapii	Gdansk
Poland	Szpitale Pomorskie Sp. z o. o.	Gdynia
Poland	Szpital Uniwersytecki w Krakowie, Oddzial Kliniczny Kliniki Onkologii	Krakow
Poland	Woj.Wielospecjalistyczne Centrum Onkologii i Traumatologii; Oddz.Hematologii Pododz.Chemioterapii	Lodz
Russian Federation	Arkhangelsk Regional Clinical Oncology Dispensary	Arkhangelsk
Russian Federation	N.N.Burdenko Main Military Clinical Hospital; Oncology Dept	Moscow
Russian Federation	BHI of Omsk region Clinical Oncology Dispensary	Omsk
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona
Spain	Hospital Clinico San Carlos; 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 de Navarra; Servicio de Oncologia	Navarra
Spain	Hospital Clínico Universitario de Valencia; Servicio de Oncología	Valencia
United Kingdom	Birmingham Heartlands Hospital; Dept of Oncology	Birmingham
United Kingdom	Royal Marsden Hospital - Fulham; Oncology Department	London
United Kingdom	The Christie; GI Research Office	Manchester
United Kingdom	Churchill Hospital; Department of Oncology	Oxford
United Kingdom	Queen's Hospital	Romford
United Kingdom	Weston Park Hospital; Cancer Clinical Trials Centre	Sheffield
United Kingdom	Royal Marsden Hospital; Dept of Medical Oncology	Sutton
United States	SCRI Tennessee Oncology Chattanooga	Chattanooga	Tennessee
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	North Shore Hem Onc Associates	East Setauket	New York
United States	Southdale Cancer Clinic U of M Medical Center, Fairview- Edina	Edina	Minnesota
United States	Florida Cancer Specialists; SCRI	Fort Myers	Florida
United States	Ingalls Cancer Research Center	Harvey	Illinois
United States	MD Anderson Cancer Center	Houston	Texas
United States	Cancer Specialists; North Florida ;Jacksonville (AC Skinner Pkwy)	Jacksonville	Florida
United States	Sarah Cannon Research Inst.	Nashville	Tennessee
United States	Yale Cancer Center; Medical Oncology	New Haven	Connecticut
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	INTEGRIS Cancer Inst of OK	Oklahoma City	Oklahoma
United States	University of Pittsburgh Cancer Institute; Division of Medical Oncology	Pittsburgh	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Florida Cancer Specialists.	Saint Petersburg	Florida
United States	Medical Oncology Associates	Spokane	Washington
United States	Georgetown University	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Hong Kong,  Italy,  Korea, Republic of,  Poland,  Russian Federation,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	Overall survival is defined as the time (in months) between the date of randomization and the date of death due to any cause. Participants who were not reported as having died at the date of analysis were censored at the date when they were last known to be alive. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.	From randomization up to death due to any cause (up to approximately 20 months)
Secondary	Progression-Free Survival (PFS) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)	PFS was defined as the time from randomization to disease progression as determined by the investigator with the use of RECIST v1.1 or death due to any cause, whichever occurred earlier. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). For non-target lesions, disease progression was defined as unequivocal progression of existing lesions. The appearance of one or more new lesions was also considered progression. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.	From randomization up to disease progression or death due to any cause (up to approximately 20 months)
Secondary	Percentage of Participants With Investigator-Assessed Objective Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.1	PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions). Objective response and its 95% CI were calculated using the Clopper-Pearson method.	From randomization up to death due to any cause (up to approximately 20 months)
Secondary	Duration of Response (DOR) According to RECIST Version 1.1	DOR is defined as the period measured from the date of the first occurrence of a CR or PR (whichever status is recorded first) until the first date that progressive disease or death is documented. Disease progression was determined on the basis of investigator assessment with use of RECIST v1.1. Median DOR was estimated using the Kaplan-Meier method, and the 95% CI was calculated using the method of Brookmeyer and Crowley.	From first occurrence of CR or PR up to disease progression or death due to any cause (up to approximately 20 months)
Secondary	Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire (EORTC QLQ-C30) Physical Functioning Sub-scale Score	The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.	Baseline, end of the study (up to approximately 2.5 years)
Secondary	Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire (EORTC QLQ-C30) Global Quality of Life Sub-scale Score at the End of the Study	The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.	Baseline, end of the study (up to approximately 2.5 years)
Secondary	Percentage of Participants With Adverse Events (AEs)		Baseline, end of the study (up to approximately 2.5 years)
Secondary	Plasma Concentration of Cobimetinib		Predose (0 hours) and 3 to 6 hours after dose on Day 15 of Cycles 1 and 4 (1 cycle = 28 days) (up to approximately 2.5 years).
Secondary	Serum Concentration of Atezolizumab	Pre-infusion (0 hours) on Day 1 of Cycles 1 to 4; 30 minutes post-infusion on Day 1 of Cycles 1 and 4; pre-infusion (0 hours) on Day 1 of Cycle 8 and every 8 cycles thereafter; at treatment discontinuation; 120 days after treatment discontinuation (up to approximately 2.5 years) (1 cycle = 28 days)	Pre-infusion (0 hours) on Day 1 of Cycle 1 up to approximately 2.5 years. Detailed time frame is explained in the outcome measure description field.
Secondary	Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab		Pre-infusion (0 hours) on Day 1 of Cycles 1 to 4, 8, and every 8 cycles thereafter; at treatment discontinuation; 120 days after treatment discontinuation (up to approximately 2.5 years) (1 cycle = 28 days)