A Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC)

Study Overview
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Brief Summary
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This open-label, exploratory study is designed to evaluate the safety and efficacy of targeted therapies or immunotherapy as single agents or combinations, in participants with metastatic colorectal cancer (mCRC) whose tumors are biomarker positive as per treatment arm-specific definition. Eligible participants with mCRC will be enrolled into specific treatment arms based on their biomarker assay results.

Official Title
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A Phase I/Ib Global, Multicenter, Open-label Umbrella Study Evaluating the Safety and Efficacy of Targeted Therapies in Subpopulations of Patients With Metastatic Colorectal Cancer (INTRINSIC)

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Inavolisib
* Drug: Bevacizumab
* Drug: Cetuximab
* Drug: Atezolizumab
* Drug: Tiragolumab
* Drug: SY-5609
* Drug: Divarasib
* Drug: FOLFOX
* Drug: FOLFIRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Signed cohort-specific Informed Consent Form Age >= 18 years at time of signing Informed Consent Form Biomarker eligibility as determined at a College of American Pathologists/clinical laboratory improvement amendments (CAP/CLIA)-certified or equivalently accredited diagnostic laboratory using a validated test Eastern Cooperative Oncology Group (ECOG) Performance Status of <= 1 Life expectancy >= 3 months, as determined by the investigator Histologically confirmed adenocarcinoma originating from the colon or rectum Metastatic disease Prior therapies for metastatic disease Ability to comply with the study protocol, in the investigators judgment Measurable disease (at least one target lesion) according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) Baseline tumor tissue samples will be collected from all patients for exploratory biomarker research Adequate hematologic and organ function within 14 days prior to initiation of study treatment For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm Exclusion Criteria Current participation or enrollment in another interventional clinical trial. Patients who are participating in the follow-up period of an interventional clinical trial are eligible for the study. Any systemic anti-cancer treatment within 2 weeks or 5 half-lives (whichever is shorter) prior to start of study treatment Treatment with investigational therapy within 28 days prior to initiation of study treatment Pregnant or breastfeeding, or intending to become pregnant during the study History of or concurrent 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 or confounds the ability to interpret data from the study Severe infection within 4 weeks prior to initiation of study treatment or any active infection that, in the opinion of the investigator, could impact patient safety Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy of study treatment Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) Uncontrolled tumor-related pain Uncontrolled or symptomatic hypercalcemia Clinically significant and active liver disease Negative HIV test at screening, with the following exception: Patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy for at least 4 weeks, have a CD4 count greater than or equal to 200/uL, have an undetectable viral load, and have not had a history of opportunistic infection attributable to AIDS within the last 12 months. Symptomatic, untreated, or actively progressing CNS metastases History of leptomeningeal disease or carcinomatous meningitis History of malignancy other than CRC within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death Any other disease, unresolved toxicity from prior therapy, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications Requirement for treatment with any medicinal product that contraindicates the use of any of the study treatments, may interfere with the planned treatment, affects patient compliance, or puts the patient at higher risk for treatment-related complications

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inavolisib + Cetuximab<br>Participants will receive 9 milligrams (mg) of inavolisib by mouth once daily (QD) on Days 8-28 of Cycle 1, then QD on Days 1-28 from Cycle 2 onwards (1 cycle=28 days). Participants will also receive cetuximab intravenous (IV) infusion 400 mg/m2 body surface area on Day 1 of Cycle 1. All subsequent weekly (QW) doses will be 250 mg/m2 each. | Drug: Inavolisib<br>* Inavolisib will be administered orally as per schedule specified in the respective arms.<br>Drug: Cetuximab<br>* Cetuximab IV will be administered as per schedule specified in the respective arm.<br>|
| Experimental: Inavolisib + Bevacizumab<br>Participants will receive 9 mg of inavolisib by mouth QD combined with bevacizumab 15 milligram/kilogram (mg/kg) IV once every three weeks (Q3W) on Day 1 of each cycle (1 cycle=21 days). | Drug: Inavolisib<br>* Inavolisib will be administered orally as per schedule specified in the respective arms.<br>Drug: Bevacizumab<br>* Bevacizumab IV will be administered as per schedule specified in the respective arm.<br>* Other names: Avastin;|
| Experimental: Atezolizumab + Tiragolumab + Bevacizumab<br>Participants in this randomized cohort will receive 1200 mg of atezolizumab by IV infusion on Day 1 of each cycle, combined with tiragolumab at a dose of 600 mg IV infusion on Day 1 of each cycle and bevacizumab IV infusion at a dose of 15 mg/kg on Day 1 of each cycle. (Cycle length=21 days) | Drug: Bevacizumab<br>* Bevacizumab IV will be administered as per schedule specified in the respective arm.<br>* Other names: Avastin;Drug: Atezolizumab<br>* Atezolizumab IV infusion will be administered as per schedule specified in the respective arm.<br>* Other names: Tecentriq;Drug: Tiragolumab<br>* Tiragolumab IV infusion will be administered as per schedule specified in the respective arm.<br>|
| Experimental: Atezolizumab + Tiragolumab<br>Participants in this randomized cohort will receive 1200 mg of atezolizumab by IV infusion on Day 1 of each cycle combined with tiragolumab 600 mg IV infusion on Day 1 of each cycle. (Cycle length=21 days) | Drug: Atezolizumab<br>* Atezolizumab IV infusion will be administered as per schedule specified in the respective arm.<br>* Other names: Tecentriq;Drug: Tiragolumab<br>* Tiragolumab IV infusion will be administered as per schedule specified in the respective arm.<br>|
| Experimental: Atezolizumab + SY-5609<br>Participants will receive 1680 mg of atezolizumab by IV infusion on Day 1 of each cycle Q4W in repeated 28-day cycles combined with SY-5609 at a dose of 3, 4, 5, 6, 7 or 10 mg by mouth for 7 days, followed by 7 days off. (Cycle length=28 days) Open in the United States only. Enrollment is closed. | Drug: Atezolizumab<br>* Atezolizumab IV infusion will be administered as per schedule specified in the respective arm.<br>* Other names: Tecentriq;Drug: SY-5609<br>* SY-5609 will be administered by mouth as per schedule specified in the respective arm.<br>|
| Experimental: Divarasib + Cetuximab + FOLFOX<br>Participants will receive cetuximab IV 500 mg/m2 body surface area on Days 1 and 15 and FOLFOX on Days 1 and 15 with divarasib PO QD on Days 1-28. (Cycle length=28 days) | Drug: Cetuximab<br>* Cetuximab IV will be administered as per schedule specified in the respective arm.<br>Drug: Divarasib<br>* Divarasib will be administered orally as per schedule specified in the respective arms.<br>* Other names: GDC-6036;Drug: FOLFOX<br>* FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) IV will be administered as per schedule specified in the respective arm.<br>|
| Experimental: Divarasib + Cetuximab<br>Participants will receive cetuximab IV 500 mg/m2 body surface area on Days 1 and 15 with divarasib PO QD on Days 1-28. (Cycle length=28 days) | Drug: Cetuximab<br>* Cetuximab IV will be administered as per schedule specified in the respective arm.<br>Drug: Divarasib<br>* Divarasib will be administered orally as per schedule specified in the respective arms.<br>* Other names: GDC-6036;|
| Experimental: Divarasib + Cetuximab + FOLFIRI<br>Participants will receive cetuximab IV 500 mg/m2 body surface area on Days 1 and 15 and FOLFIRI on Days 1 and 15 with divarasib PO QD on Days 1-28. (Cycle length=28 days) | Drug: Cetuximab<br>* Cetuximab IV will be administered as per schedule specified in the respective arm.<br>Drug: Divarasib<br>* Divarasib will be administered orally as per schedule specified in the respective arms.<br>* Other names: GDC-6036;Drug: FOLFIRI<br>* FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) IV will be administered as per schedule specified in the respective arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Defined as the proportion of patients with a complete response or partial response, as determined by the investigator according to RECIST v1.1 | Approximately 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1 | Approximately 60 months | 
| Disease Control Rate | Defined as the proportion of patients with stable disease, or a complete or partial response, as determined by the investigator according to RECIST v1.1 | Approximately 60 months | 
| Percentage of Participants with Adverse Events (AEs) | Percentage of participants with adverse events. | Approximately 60 months | 
| Plasma Concentrations of Divarasib | Plasma concentration of divarasib for divarasib + cetuximab + FOLFOX, divarasib + cetuximab, and divarasib + cetuximab+ FOLFIRI treatment arms. | At pre-defined intervals from first administration of study drug up to approximately 60 months |