E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
METASTATIC COLORECTAL CANCER |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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E.2.2 | Secondary objectives of the trial |
• OS • ORR • Disease control rate (DCR) • Time to treatment response (TTR) • Duration of response (DoR) • Change in ECOG performance status • Incidence, nature and severity of adverse events (AEs) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male and female patients >/= 18 years of age - Eastern Cooperative Oncology Group (ECOG) performance status of </= 2 - At least 16 weeks of life expectancy at time of entry into the study - Histologically confirmed metastatic colorectal cancer (CRC) - Measureable, unresectable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 - No prior chemotherapy for CRC in the metastatic setting - Archival tumor formalin-fixed paraffin-embedded tissue block from the primary tumor obtained at the time of the initial diagnosis is available - Adequate hematological, liver and renal function - Agreement to use highly effective measures of contraception
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E.4 | Principal exclusion criteria |
• Less than six months from completion of any prior adjuvant chemotherapy, radiotherapy or surgery • Prior or current treatment with bevacizumab or any other anti-angiogenic drug (i.e. VEGF or vascular endothelial growth factor receptor [VEGFR] therapies or tyrosine kinase inhibitors) • Current or recent (within 10 days of study enrollment) use of aspirin (> 325 mg/day), clopidogrel (> 75 mg/day), or current or recent (within 10 days prior to the start of study induction treatment) use of therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes (prophylactic uses allowed) • Active infection requiring intravenous antibiotics at the start of study induction treatment • Previous or concurrent malignancy, except for adequately treated basal or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for five years prior to study entry • Inadequately controlled hypertension; prior history of hypertensive crisis or hypertensive encephalopathy • Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular accidents </= 6 months prior to start of study induction treatment, myocardial infarction </= 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Functional Classification Grade II or greater congestive heart failure, or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment • Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of start of study induction treatment • Active or untreated CNS metastases; treatment of brain metastases, either by surgical or radiation techniques, must have been completed > 4 weeks prior to start of study induction treatment. Patients with evidence of interim progression between the completion of CNS-directed therapy and study baseline disease assessments are excluded from the study. • Known hypersensitivity to any component of bevacizumab or any of the study medications • Pregnancy or lactation
Cohort 1 BRAF (mut) Exclusion Criteria • Inability to swallow pills • Refractory nausea and vomiting, malabsorption, external biliary shunt or significant bowel resection that would preclude adequate absorption • History or presence of clinically significant ventricular or atrial dysrhythmias • Corrected QT (QTc) interval >/= 480 msec at baseline or history of congenital long QT syndrome or uncorrectable electrolyte abnormalities
Cohort 2 No Biomarker Exclusion Criteria • History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis • Prior allogeneic bone marrow transplantation or prior solid organ transplantation • History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis at Screening • Positive test for human immunodeficiency virus (HIV) • Active hepatitis B or hepatitis C at Screening • Active tuberculosis • Administration of a live, attenuated vaccine within four weeks prior to start of maintenance treatment or anticipation that such a live attenuated vaccine will be required during the remainder of the study • Prior treatment with CD137 agonists, anti-CTLA4, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents • Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within four weeks or five half-lives of the drug, whichever is longer, prior to start of maintenance treatment • Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to start of maintenance treatment, or anticipated requirement for systemic immunosuppressive medications during the remainder of the study. The use of inhaled corticosteroids and mineralocorticoids is allowed. - If receiving a RANKL inhibitor (e.g. denosumab), unwilling to adopt alternative treatment such as (but not limited to) bisphosphonates, while receiving atezolizumab.
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival (PFS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From randomization until disease progression ordeath from any cause |
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E.5.2 | Secondary end point(s) |
1) Overall survival 2) Overall response rate, calculated as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) determined according to RECIST 1.1 3) Disease control rate (DCR), calculated as the proportion of patients with a best overall response of CR, PR or stable disesase (SD) as determined according to RECIST 1.1 4) Time to treatment response (TTR), calculated as the time from randomization to the first occurrence of a documented objective response (CR or PR) determined according to RECIST 1.1 5) Duration of response (DoR), defined as the time from the first assessment of CR or PR until disease progression or death from any cause, whichever occurs first 6) Change in ECOG performance status 7) Incidence of adverse events (AEs) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) From randomization until death from any cause 2) From randomization until disease progression 3) From randomization until disease progression 4) From randomization until disease progression or death from any cause 5) From randomization until disease progression or death from any cause 6) From baseline until end of study (up to 5 years) 7) From baseline until end of study (up to 5 years) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Assessment of dynamic biomarkers and genetic biomarkers |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 144 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Algeria |
Argentina |
Austria |
Belgium |
Brazil |
China |
Denmark |
Egypt |
France |
Germany |
Greece |
Italy |
Macedonia, the former Yugoslav Republic of |
Mexico |
Netherlands |
Poland |
Portugal |
Russian Federation |
Serbia |
Slovakia |
Spain |
Sweden |
Turkey |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the date when the last patient, last visit (LPLV) occurs at the end of the Post-treatment Follow-up. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |