Trial of Atezolizumab, Bevacizumab, and Tiragolumab in Patients With Microsatellite Stable, Metastatic Colorectal Cancer

Exclusion Criteria

• •1. Illness or condition that may interfere with a patient's capacity to understand, follow, and/or comply with study procedures.
• •2. Known microsatellite instability-high or deficient mismatch repair status, or unknown status for both MSI and MMR.
• •3. Prior testing documenting a BRAF V600E mutation, or unknown testing results for KRAS, NRAS, and BRAF.
• •4. A limited number of patients with active liver metastases will be permitted in this trial. Those with a history of definitively treated liver metastases with treatment occurring at least 6 months prior to enrollment with no evidence of metastatic disease in the liver on subsequent imaging may be eligible to enroll as a patient without active liver disease.
• •5. Known symptomatic, untreated, or actively progressing central nervous system metastases. Asymptomatic patients with treated CNS lesions are eligible, provided that additional criteria are met.
• •6. History of leptomeningeal disease or carcinomatous meningitis.
• •7. Spinal cord compression not definitively treated with surgery and/or radiation.
• •8. Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at study entry.
• •9. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.
• •10. History of malignancy other than colorectal cancer within 3 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death, such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ.
• •11. Active autoimmune disease, history of autoimmune disease requiring treatment with corticosteroids, disease modifying agents, and/or immunosuppressive therapy, or immune deficiency including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the exceptions listed below:
• •* Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study.
• •* Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
• •* Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only are eligible for the study provided all of following conditions are met:
• •* Rash must cover \< 10% of body surface area.
• •* Disease is well controlled at baseline \& requires only low-potency topical corticosteroids.
• •* There has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months.
• •12. Prior allogeneic stem cell or solid organ transplantation.
• •13. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
• •14. Known history of tuberculosis and/or active tuberculosis.
• •15. Active bowel inflammation on imaging at the time of enrollment.
• •16. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess.
• •17. Clinical signs or symptoms of GI obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding.
• •18. Evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
• •19. History of or active clinically significant cardiovascular dysfunction, including the following:
• •* History of stroke or transient ischemic attack within 6 months prior to first dose of study treatment.
• •* History of myocardial infarction within 6 months prior to first dose of study treatment.
• •* Heart failure with New York Heart Association Class II or higher symptoms within 3 months prior to initiation of study treatment.
• •* Unstable arrhythmia.
• •* Coronary heart disease that is symptomatic or unstable angina.
• •20. Inadequately controlled hypertension. Anti-hypertensive therapy to achieve these parameters is allowed.
• •21. History of hypertensive crisis or hypertensive encephalopathy.
• •22. Grade ≥ 2 proteinuria, as demonstrated by ≥ 2+ protein on dipstick urinalysis and ≥ 1.0 g of protein in a 24-hour urine collection.
• •o All patients with ≥ 2+ protein on dipstick urinalysis at screening must undergo a 24-hour urine collection for protein. Patients with \< 2+ protein on dipstick urinalysis are eligible for the study and do not require 24-hour urine collection.
• •23. Significant vascular disease within 6 months prior to initiation of study treatment.
• •24. History of Grade 4 venous thromboembolism.
• •25. History of Grade ≥ 2 hemoptysis, or other serious hemorrhage or bleeding risk, within 1 month prior to screening.
• •26. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding.
• •27. Major surgical procedure, or significant traumatic injury, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study.
• •o Study-related biopsies are not considered major surgical procedures in this study.
• •28. Minor surgical procedures, including placement of a vascular access device, within 7 days prior to initiation of study treatment, with the following exceptions:
• •* Patients must have sufficiently recovered from any prior surgery, including adequate wound healing.
• •29. Serious, non-healing wound, active ulcer, or untreated bone fracture.
• •30. Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact patient safety.
• •31. Positive Epstein-Barr virus (EBV) viral capsid antigen immunoglobulin M (IgM) test at screening. An EBV polymerase chain reaction (PCR) test should be performed as clinically indicated to screen for acute infection or suspected chronic active infection. Patients with a positive EBV PCR test are excluded.
• •32. Current or recent (\< 10 days prior to initiation of study treatment) use of aspirin (\> 325 mg/day), or clopidogrel (\> 75 mg/day), or recent (\< 21 days prior to initiation of study treatment) use of therapeutic thrombolytic agents.
• •33. Recent (\< 21 days prior to initiation of study treatment) initiation of full-dose oral or parenteral anticoagulants. The use of full-dose oral or parenteral anticoagulants is permitted as long as the following criteria are met:
• •* The INR and/or aPTT are within therapeutic limits (according to the medical standard of the enrolling institution).
• •* The patient has been on a stable dose of anticoagulants for at least 21 days prior to initiation of study therapy.
• •* There is no evidence of or clinical concern for new or worsening thromboembolism within 21 days prior to initiation of study treatment.
• •* The patient has no history of serious hemorrhage or bleeding risk.
• •* The patient has no persisting bleeding diathesis or anatomic or pathologic condition that significantly increases the risk of hemorrhage.
• •34. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment.
• •o Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
• •35. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment, within 90 days after the final dose of tiragolumab, or within 5 months after the final dose of atezolizumab.
• •36. Current treatment with anti-viral therapy for HBV.
• •37. Treatment with any systemic anti-cancer therapy within 21 days or 5 half-lives of starting study treatment, whichever is shorter.
• •38. Treatment with an investigational therapy within 42 days of initiation of study treatment.
• •39. Prior treatment with CD137 agonists or investigational immune checkpoint blockade therapies, including anti-LAG3, anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-TIGIT agents.
• •40. Prior radiation therapy within 14 days of Cycle 1, Day 1 of study treatment, and/or persistence of radiation-related adverse effects. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis prior to study treatment start. Palliative radiation therapy (as long as it does not involve target lesions) is permitted on the study.
• •41. Treatment with systemic immunostimulatory agents, including, but not limited to, interferon and IL-2, within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment.
• •42. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-α \[TNF- α\] agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:
• •* Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.
• •* Patients who received mineralocorticoids, corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
• •* Patients requiring chronic use of ≥ 10 mg prednisone per day or equivalent
• •43. Requirement for treatment with any medicinal product that contraindicates the use of any of the study treatments, may interfere with the planned treatment, impact patient compliance, or puts the patient at higher risk for treatment-related complications.
• •44. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.
• •45. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab, bevacizumab, or tiragolumab formulations.
• •46. Pregnancy or breastfeeding, or intention of becoming pregnant.
• •47. Any other disease, 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.