Tiragolumab, Atezolizumab and Bevacizumab for the Treatment of Previously Treated, Microsatellite Stable, Metastatic Colorectal Adenocarcinoma

Inclusion Criteria

• Provision to sign and date the consent form
• Stated willingness and ability to comply with all study procedures and be available for the duration of the study
• Age ≥ 18 years at the time of signing the informed consent
• Histologically confirmed, unresectable, metastatic colorectal adenocarcinoma
• Measurable disease, as assessed by the investigator per RECIST v 1.1. Previously irradiated lesions are not considered measurable unless progression has been unequivocally documented in the lesion after the time of radiation. Lesions intended to be biopsied should not be target lesions
• If in cohort A, * the patient must state willingness to undergo pre- and on-treatment biopsies, and * the patient’s disease must be amenable to biopsy without exposing the patient to substantially increased risks of complications, per the Investigator’s judgment
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Documented microsatellite stable (MSS) and/or proficient mismatch repair (pMMR) status. Only one of these criteria is required to be eligible (e.g. either MSI or MMR testing completed with results consistent with MSS or pMMR disease). However, in the unusual case of discordant results if both MSI and MMR testing is completed, consultation with the Principal Investigator and pathology review will be required to determine eligibility
• Documented testing for KRAS, NRAS, and BRAF V600E mutation status. Patients with BRAF V600E mutation will be excluded. Patients with KRAS or NRAS mutation will be included
• Progression on or intolerance to prior therapy for unresectable, metastatic CRC including at least * fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy AND * EGFR inhibitor therapy for patients with KRAS/NRAS/BRAF wild-type, left-sided disease. Prior EGFR inhibitor therapy is not required for patients with right-sided disease and/or KRAS/NRAS mutations. ** Chemotherapy given with curative intent may be considered as a prior therapy for this eligibility criteria if it was administered within 6 months of diagnosis of unresectable, metastatic CRC. ** Fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy may have been given in any combination (e.g., fluorouracil, oxaliplatin, leucovorin, [FOLFOX], fluorouracil, irinotecan, leucovorin [FOLFIRI], fluorouracil, oxaliplatin, irinotecan, leucovorin [FOLFOXIRI]), as long as all 3 agents were used in a prior line of therapy. ** Prior therapy with bevacizumab is permitted
• Absolute neutrophil count (ANC) ≥ 1.2 × 10^9/L, without granulocyte colony-stimulating factor support in the prior 4 weeks (results obtained within 28 days prior to the first dose of study treatment)
• Lymphocyte count ≥ 0.5 x 109/L (500/uL) (results obtained within 28 days prior to the first dose of study treatment)
• Platelet count ≥ 100 × 109/L, without transfusion in the prior week (results obtained within 28 days prior to the first dose of study treatment)
• Hemoglobin ≥ 9 g/dL; patients may be transfused to meet this criterion (results obtained within 28 days prior to the first dose of study treatment)
• Serum total bilirubin ≤ 1.5 x the upper limit of normal (ULN); patients with known Gilbert’s disease may have a bilirubin ≤ 3.0 × ULN (results obtained within 28 days prior to the first dose of study treatment)
• Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) ≤ 2.5 × ULN (results obtained within 28 days prior to the first dose of study treatment) with the following exceptions: * For patients with documented liver metastases, AST and/or ALT ≤ 5 × ULN * For patients with documented liver or bone metastases, ALP ≤ 5 × ULN
• Serum albumin ≥ 25 g/L (2.5 g/dL) (results obtained within 28 days prior to the first dose of study treatment)
• Creatinine clearance ≥ 45 mL/min as calculated using the Cockcroft-Gault formula or measured using a 24-hour urine collection (results obtained within 28 days prior to the first dose of study treatment)
• For patients not receiving therapeutic anticoagulation, international normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (results obtained within 28 days prior to the first dose of study treatment)
• Patients receiving therapeutic anticoagulation must be on a stable regimen, with INR and aPTT within the expected therapeutic range of intended use of the anticoagulant
• Negative HIV testing at screening, or, for those with known history of HIV, documented control of infection on anti-retroviral therapy with evidence of undetectable viral load and CD4 count of >500 cells/microL for a least 6 months prior to enrollment
• Negative hepatitis B surface antigen (HBsAg) test at screening
• Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb test at screening accompanied by either of the following: * Negative total hepatitis B core antibody (HBcAb) * Positive total HBcAb test followed by quantitative hepatitis B virus (HBV) deoxyribonucleic acid (DNA) < 500 IU/mL. The HBV DNA test will be performed only for patients who have a negative HBsAg test, a negative HBsAb test, and a positive total HBcAb test
• Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV ribonucleic acid (RNA) test at screening. * The HCV RNA test will be performed only for patients who have a positive HCV antibody test
• For women of childbearing potential (WOCBP): agreement to refrain from heterosexual intercourse or use contraception as defined below: * A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), has not undergone surgical sterilization (i.e., removal of ovaries, fallopian tubes, and/or uterus), and does not have another cause of permanent sterilization or infertility as determined by the investigator (e.g., Müllerian agenesis). Per this definition, a woman with a tubal ligation is considered to be of childbearing potential. * WOCBP must refrain from heterosexual intercourse or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the final dose of atezolizumab, 6 months after the final dose of bevacizumab, and 90 days after the final dose of tiragolumab. * Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception.
• Women who would like to become pregnant after study treatment discontinuation should seek advice on oocyte cryopreservation prior to initiation of study treatment because of the possibility of increased risk of ovarian failure with bevacizumab, noting that ovarian function has been shown to recover in the majority of women after treatment discontinuation
• For men: agreement to refrain from heterosexual intercourse or use a condom, and agreement to refrain from donating sperm, as defined below: * With a female partner of childbearing potential or a pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 6 months after the final dose of bevacizumab and 90 days after the final dose of tiragolumab to avoid exposing the embryo. Men must refrain from donating sperm during this same period. * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception

Exclusion Criteria

• Illness or condition that may interfere with a patient’s capacity to understand, follow, and/or comply with study procedures
• Known microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status, or unknown status for both MSI and MMR
• Prior testing documenting a BRAF V600E mutation, or unknown testing results for KRAS, NRAS, and BRAF
• A limited number of patients with active liver metastases will be permitted in this trial. Additional patients with active liver metastases will be excluded. In this study, active liver metastases are defined as the presence of metastatic disease in the liver per CT and/or MRI imaging. * Those with a history of definitively treated liver metastases (e.g., with surgical resection or stereotactic body radiation therapy [SBRT]) 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
• Known symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. Asymptomatic patients with treated CNS lesions are eligible, provided that all of the following criteria are met: * Measurable disease, per RECIST v1.1, must be present outside of the CNS. * The patient has no history of intracranial hemorrhage or spinal cord hemorrhage related to metastatic disease. * Any treatment received for CNS disease, including radiation therapy or surgery, was completed at least 28 days prior to initiation of study treatment. * The patient has no ongoing requirement for corticosteroids as therapy for CNS disease. Anti-convulsant therapy at a stable dose is permitted. * There is no evidence of interim progression between completion of CNS-directed therapy and initiation of study treatment. Imaging to confirm stability of CNS disease must be performed during screening for patients with known history of CNS involvement
• History of leptomeningeal disease or carcinomatous meningitis
• Spinal cord compression not definitively treated with surgery and/or radiation
• Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at study entry. * Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Radiation should be completed at least 14 days prior to initiation of study treatment, and patients should be recovered from the effects of radiation prior to enrollment. * Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
• 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 (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ
• 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 (see Appendix 7 for a more comprehensive list of autoimmune diseases and immune deficiencies), 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 (e.g., patients with psoriatic arthritis are excluded) 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 and 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
• Prior allogeneic stem cell or solid organ transplantation
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
• Known history of tuberculosis and/or active tuberculosis
• Active bowel inflammation on imaging at the time of enrollment (including diverticulitis)
• History of abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess
• Clinical signs or symptoms of GI obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
• Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
• 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
• Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg and based on an average of ≥ 3 blood pressure readings on ≥ 2 sessions). Anti-hypertensive therapy to achieve these parameters is allowed
• History of hypertensive crisis or hypertensive encephalopathy
• Grade ≥ 2 proteinuria, as demonstrated by ≥ 2+ protein on dipstick urinalysis and ≥ 1.0 g of protein in a 24-hour urine collection. * 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
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to initiation of study treatment
• History of grade 4 venous thromboembolism
• History of grade ≥ 2 hemoptysis (defined as ≥ 2.5 mL of bright red blood per episode), or other serious hemorrhage or bleeding risk, within 1 month prior to screening
• History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (e.g. in the absence of therapeutic anticoagulation)
• 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. * Study-related biopsies are not considered major surgical procedures in this study
• Minor surgical procedures, including placement of a vascular access device, within 7 days prior to initiation of study treatment, with the following exceptions: * Study-related biopsies are NOT considered as surgical procedures under the exclusion criteria. Pre-treatment study biopsies should be performed at least 3 days prior to study treatment initiation. * Patients must have sufficiently recovered from any prior surgery, including adequate wound healing
• Serious, non-healing wound, active ulcer, or untreated bone fracture
• 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
• 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 in cases where there is a clinical suspicion for active infection (ie positive EBV viral capsid antigen IgM). Patients with a positive EBV PCR test and clinical presentation consistent with acute or chronic active EBV infection are excluded
• 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
• 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, as per exclusion criteria. * The patient has no persisting bleeding diathesis or anatomic or pathologic condition that significantly increases the risk of hemorrhage
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. * Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
• 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
• Current treatment with anti-viral therapy for HBV
• Treatment with any systemic anti-cancer therapy within 21 days or 5 half-lives of starting study treatment, whichever is shorter
• Treatment with an investigational therapy within 42 days of initiation of study treatment
• 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
• 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
• 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
• 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 (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids (< 10 mg prednisone per day or an equivalent dose of an alternative corticosteroid) for orthostatic hypotension or adrenal insufficiency are eligible for the study. * Patients requiring chronic use of ≥ 10 mg prednisone per day or equivalent dose of other anti-inflammatory corticosteroids are excluded
• 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
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab, bevacizumab, or tiragolumab formulations
• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment, within 90 days after the final dose of tiragolumab, 5 months after the final dose of atezolizumab, or 6 months after the final dose of bevacizumab. Women of childbearing potential must have a negative serum pregnancy test result within 28 days prior to initiation of study treatment, and a negative urine pregnancy test within 72 hours of each study treatment
• 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 complications