| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The patient population are patients with metastatic or locally advanced unresectable colorectal adenocarcinoma that have received at least two lines of chemotherapy in this setting. The patients must have received 5-FU, oxaliplatin, and irinotecan. Patients who have received an anti-VEGF and anti-EGFR are eligible. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with colorectal cancer that has spread and cannot be removed and have received at least two chemotherapies in this setting. |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052358 |
| E.1.2 | Term | Colorectal cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| The primary objective of this study is to evaluate the efficacy of cobimetinib plus atezolizumab compared to regorafenib on the basis of overall survival (OS). Atezolizumab monotherapy will also be evaluated compared to regorafenib on the basis of OS. |
|
| E.2.2 | Secondary objectives of the trial |
• Investigator-assessed progression free survival and objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 of patients in the cobimetinib plus atezolizumab arm and the atezolizumab monotherapy arm compared to the regorafenib arm.
• Duration of response of patients in the cobimetinib plus atezolizumab arm and atezolizumab monotherapy arm compared to the regorafenib arm
• Impact on functioning and health-related quality of life of cobimetinib plus atezolizumab and atezolizumab monotherapy
• The safety objective for this study is to evaluate the safety profile and adverse events encountered by patients in the cobimetinib plus atezolizumab arm and atezolizumab monotherapy arm compared to the regorafenib arm.
• To characterize the pharmacokinetics of cobimetinib and atezolizumab when used in combination
• The immunogenicity objective for this study is to evaluate the immune response to atezolizumab
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Disease specific inclusion criteria:
• Histologically confirmed adenocarcinoma originating from the colon or rectum (Stage IV American Joint Committee on Cancer 7th edition)
• Experienced disease progression on at least two prior systemic chemotherapy regimens for mCRC
1. Prior systemic cytotoxic chemotherapy must include ALL of the following agents:
a) Fluoropyrimidines
b) Irinotecan
c) Oxaliplatin
2. Patients who have received prior anti-angiogenic therapy (e.g., bevacizumab) and/or anti epidermal growth factor receptor therapy (e.g., cetuximab) are eligible.
3. Patients must have had documented disease progression within 3 months of the last systemic therapy administration.
4. Patients who were intolerant to prior systemic chemotherapy regimens are eligible if there is documented evidence of clinically significant intolerance despite adequate supportive measures.
5. For patients who had disease recurrence within 6 months of completing adjuvant chemotherapy, the adjuvant regimen can be considered as one chemotherapy regimen for metastatic disease.
General inclusion criteria:
• Signed Informed Consent Form
• Age ≥ 18 years
• In the investigator’s judgment, patient is able to comply with the requirements and assessments of the study protocol
•Eastern Cooperative Oncology Group performance status of 0 or 1
•Anticipated life expectancy ≥ 3 months
•Able to comply with the requirements and assessments of the study protocol
•Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to first dose of study drug treatment:
1.Hemoglobin ≥ 9 g/dL, platelet count ≥ 100,000/mm3, ANC ≥ 1500/mm3
2.Creatinine clearance ≥ 30 mL/min
3.Amylase and lipase ≤ 1.5 x the upper limit of normal (ULN)
4.Serum bilirubin ≤ 1.5x ULN; patients with known Gilbert’s disease may have a bilirubin ≤ 3.0x ULN
5.AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 ULN with the following exceptions:
a)Patients with documented liver metastases: AST and/or ALT ≤ 5 x ULN
b)Patients with documented liver or bone metastases: ALP ≤ 5 x ULN
6.INR and PTT ≤ 1.5 x ULN. Patients who are on therapeutic doses of anti coagulants are eligible if they are on a stable dose of anti-coagulant for 28 days with stable INR and PTT values.
•Women of childbearing potential must agree to appropriately use an effective form of contraception (failure rate of < 1% 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
7.A woman of childbearing potential is defined as a sexually mature woman without prior oophorectomy or hysterectomy who have had menses within the last 12 months.
8.A woman is not considered to be of childbearing potential if she has become amenorrheic for > 12 months and has a follicle stimulating hormone level ≥ 40 IU/L.
•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.
•Available and adequate baseline tumor tissue sample (archival or newly obtained biopsy)
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|
| E.4 | Principal exclusion criteria |
Cancer-related exclusion criteria:
•After the approximate 5% cap for MSI-high patients is reached, only MSI-stable patients 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. Patients 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 CNS metastases are excluded. Patients with treated and asymptomatic CNS metastases are eligible,
•Exclusion criteria related to study medication:
Any cancer immunotherapy including CD137 agonists, anti-programmed death-1, anti PD L1, or anti CTLA4; Any MEK or ERK inhibitor; and Regorafenib
•Patients with active malignancy (other than CRC) or a prior malignancy within the past 3 years are excluded. Patients 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.
Exclusion criteria based on organ function or medical history:
Cardiovascular:
•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 below institutional lower limit of normal or below 50%, whichever is lower.
•Poorly controlled hypertension, defined as a blood pressure consistently above 150/90 mmHg despite optimal medical management.
Infections:
•HIV infection
•Severe infections within 2 weeks prior to Cycle 1 Day 1
•Signs or symptoms of significant infection within 2 weeks prior to Cycle 1 Day 1
•Received oral or IV antibiotics within 2 weeks prior to Cycle 1 Day 1
•Active or chronic viral hepatitis B or C infection
Ocular:
•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
•Patients will be excluded if they currently have risk factors for retinal vein occlusion
Autoimmune conditions and immunomodulatory drugs:
•History of autoimmune disease
•History of idiopathic pulmonary fibrosis, organizing pneumonia, bronchiolitis obliterans, drug-induced pneumonitis, or idiopathic pneumonitis
Other medical conditions or medications:
•Any hemorrhage or bleeding event CTCAE Grade 3 or higher within 28 days of Cycle 1 Day 1
•Foods, supplements or drugs that are potent CYP3A4 enzyme inducer or inhibitors are prohibited at least 7 days prior to Cycle 1 Day 1 and during study treatment. General exclusion criteria:
•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
•History of severe hypersensitivity reactions to components of: Cobimetinib formulation, Regorafenib formulation, Atezolizumab formulation, including Chinese hamster ovary cell products, chimeric or humanized antibodies, or fusion proteins.
•Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation of a live attenuated vaccine will be required during the study
•Any anti-cancer therapy, including chemotherapy, or hormonal therapy within 2 weeks prior to initiation of study treatment
•Treatment with systemic immunostimulatory and immunosuppressive agents within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1 Day 1
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is overall survival (OS), which is defined as the time (in months) between the date of randomization and the date of death due to any cause. Comparisons with respect to OS between two treatment arms (i.e., cobimetinib plus atezolizumab vs. regorafenib, atezolizumab vs. regorafenib) will be tested.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The OS final analysis will be conducted when there are approximately 178 deaths for the comparison of cobimetinib plus atezolizumab versus regorafeib and approximately 127 deaths for the comparison of atezolizumab monotherapy versus regorafenib. This is expected to occur approximately 22 months after the first patient is randomized. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints include investigator assessed progression free survival (PFS), overall response rate (ORR), and duration of response (DOR) per RECIST v1.1. PFS is defined as the time between date of randomization and the date of first documented disease progression or death, whichever occurs first. ORR is defined as the proportion of patients who had a confirmed objective response of CR or PR assessed by the investigator according to the RECIST v1.1. 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.
Safety analyses will be performed on the safety population and will include all randomized patients who received at least one dose of study drug. Study drug exposure, including treatment duration, number of doses, and dose intensity, will be summarized for each treatment arm using descriptive statistics. All adverse events and selected laboratory and vital abnormalities that occur during or after the first study drug dose will be summarized by treatment arm and NCI CTCAE grade.
For patient reported outcomes, the EORTC QLQ-C30 questionnaire and two additional items will be scored according to the EORTC Scoring Manual to more fully characterize the clinical profile of cobimetinib plus atezolizumab as compared to regorafenib. In addition, to derive utility for pharmocoeconomic models, patients will complete the EQ 5D 5L.
Cobimetinib and atezolizumab maximum and minimum concentration data (Cmin and Cmax, respectively) will be tabulated and summarized
The relationship between ATA (anti-therapeutic antibody) status and safety, efficacy, and pharmacokinetics will be analyzed and reported descriptively.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The analyses for all secondary endpoints will take place at the time of primary analysis. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Patient reported outcome/ quality of life |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Regorafenib will be a standard of care therapy |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Australia |
| Belgium |
| Canada |
| France |
| Germany |
| Hong Kong |
| Italy |
| Korea, Republic of |
| Poland |
| Russian Federation |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the date at which the last data point required for statistical analysis (i.e., OS) or safety follow up is received from the last patient, whichever occurs later. LPLV is expected to occur 3 years after the first patient is enrolled. The study will end at any time if the Sponsor decides to end the trial. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
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