Evaluating Response to Atezolizumab and Bevacizumab Treatment in Patients with Gastrointestinal Cancers and Minimal Residual Disease using ctDNA

Inclusion Criteria

• Signed informed consent form
• Age >= 18 years at time of signing informed consent form
• Ability to comply with the study protocol, in the investigator’s judgment
• Histologically or cytologically confirmed colorectal adenocarcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma, hepatocellular carcinoma, or extra-hepatic/intra-hepatic/gallbladder adenocarcinoma. Patients may be enrolled irrespective of any mutational analyses
• Must have been diagnosed with any stage disease (including localized and metastatic disease) that was felt to have already been treated completely with curative-intent per investigator’s, primary physician’s, or research team’s judgement. Curative-intent treatment strategies are unique to each tumor type and stage but includes all surgeries and perioperative therapies recommended. If patients were appropriately treated with curative intent but felt to be high-risk for relapse, they may be still be included. This includes: * Colorectal carcinoma (CRC) ** Per American Joint Committee on Cancer (AJCC) TNM staging classification for CRC (8th edition, 2017) ** Clinical and pathologic stage I-III ** Clinical and pathologic stage IV CRCs with synchronous or metachronous oligometastases are potentially curable with metastatectomy. These patients will be allowed on a case-by-case basis and if the investigator, primary physician, and/or research team feels the patient had their primary and metastatic lesions addressed completely with curative surgery or local therapies with/without other perioperative treatments ** Patients with R1 or R2 resections that were subsequently treated with curative intent may be included * Gastric adenocarcinoma ** Per AJCC TNM staging classification for carcinoma of the stomach (8th edition, 2017) ** Clinical stage I-IVA ** Pathologic stage (with or without neoadjuvant therapy) I-III ** Clinical stage IVB (M1 disease) or pathologic stage (with or without neoadjuvant therapy) IV with distant metastatic disease are unlikey to be cured. However, these patients will be considered on a case-by-case basis for enrollment if the investigator, primary physician, and/or research team feels the patient had their primary and metastatic lesions addressed completely with curative surgery or local therapies with/without other perioperative treatments ** Patients with R1 or R2 resections that were subsequently treated with curative intent may be included * Pancreatic ductal adenocarcinoma ** Per AJCC TNM staging of pancreatic cancer (8th edition, 2017) ** Stage I-III ** Clinically resectable patients or borderline resectable/locally advanced patients converted to resectable ** Stage IV (M1, distant metastases) patients are unlikely to be cured. However, these patients will be considered on a case-by-case basis for enrollment if the investigator, primary physician, and/or research team feels the patient had their primary and metastatic lesions addressed completely with curative surgery or local therapies with/without other perioperative treatments * Hepatocellular carcinoma, or extra-hepatic/intra-hepatic/gallbladder adenocarcinoma ** AJCC TNM staging for hepatocellular cancer (8th edition, 2017) ** Any-stage hepatocellular carcinoma patients who underwent curative intent surgery or locoregional therapy that have a Child Pugh A score ** Any resectable biliary tract cancer patients * Patients must have completed all definitive standard of care (SOC) treatment with curative intent (neoadjuvant, surgery, radiation, and adjuvant treatments) for specific tumor-type and stage per investigator’s/primary physician’s or research team’s judgment. Curative treatment regimens including chemotherapy, radiation, treatment sequencing, and surgery should have been followed as per local standards and National Comprehensive Cancer Network (NCCN) guidelines or non-standard curative-intent therapy through a clinical trial at the discretion of the investigator/treating physician
• Patients who have undergone definitive, curative-intent treatment of oligometastatic (synchronous or metachronous) disease with no evidence of disease (NED) per investigator judgement are acceptable for enrollment
• Must have disease-free status documented by complete physical examiniation and imaging studies with no evidence of recurrent, residual, or metastatic disease on standard imaging (chest, abdomen, and pelvis captured by CT chest and CT or MRI of abdomen and pelvis) per investigator assessment within 28 days prior to enrollment
• Must have a tumor-specific ctDNA Signatera (trademark) test with a positive result (any mean tumor molecule/mL) drawn within 1 year of completing all curative-intent treatment and within 28 days prior to enrollment. In the setting of a negative scan for recurrence, this will be defined as subclinical molecular disease
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (1500/uL) without granulocyte colony-stimulating factor support (obtained within 28 days prior to initiation of study treatment)
• Lymphocyte count >= 0.5 x 10^9/L (500/uL) (obtained within 28 days prior to initiation of study treatment)
• Platelet count >= 75 x 10^9/L (75,000/uL) without transfusion (obtained within 28 days prior to initiation of study treatment)
• Hemoglobin >= 90 g/L (9 g/dL) (obtained within 28 days prior to initiation of study treatment) * Patients may be transfused to meet this criterion
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) =< 3 x upper limit of normal (ULN) (obtained within 28 days prior to initiation of study treatment) * Note: for hepatocellular carcinoma (HCC), AST, ALT, and alkaline phosphatase (ALP) =< 5 x upper limit of normal (ULN)
• Serum bilirubin =< 1.5 x ULN with the following exception (obtained within 28 days prior to initiation of study treatment): * Patients with known Gilbert disease or HCC: serum bilirubin =< 3 x ULN
• Serum creatinine =< 1.5 x ULN or creatinine clearance >= 50 mL/min (calculated using the Cockcroft-Gault formula) (obtained within 28 days prior to initiation of study treatment)
• Urine dipstick for proteinuria < 2+ (if >= 2+ proteinuria on dipstick urinalysis, patient should undergo 24-hour urine collection and must demonstrate < 1 g protein in 24 hours) (obtained within 28 days prior to initiation of study treatment)
• Serum albumin >= 25 g/L (2.5 g/dL). Cut-off of >= 28 g/L (2.8 g/dL) will be used for HCC patients (obtained within 28 days prior to initiation of study treatment)
• For patients not receiving therapeutic anticoagulation: international normalized ratio (INR) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN (obtained within 28 days prior to initiation of study treatment) * Note: for HCC patients INR or aPTT should be =< 2 x ULN
• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
• Negative human immunodeficiency virus (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, have a CD4 count >= 200uL, and have an undetectable viral load
• Documented virology status of hepatitis, as confirmed by screening tests for hepatitis B virus (HBV) and hepatitis C virus (HCV): * For patients with active HBV, they will generally be excluded. However, in scenarios where patients have well-compensated, well-controlled, treated HBV (for example, HBV DNA < 500 IU/mL during screening, initiation of anti-HBV treatment at least 14 days prior to study treatment and willingness to continue anti-HBV treatment during the study [per local standard of care; e.g., entecavir]) enrollment may be considered on a case-by-case basis after review by research team * Patients with HCV, either with resolved infection (as evidenced by detectable antibody) or chronic infection (as evidenced by detectable HCV ribonucleic acid [RNA]) are eligible if deemed appropriate by primary physician or research team
• Women of childbearing potential must have a negative serum test result within 28 days prior to initiation of study treatment. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test
• Women must not be breastfeeding
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs as defined below: * Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 5 months after the final dose of atezolizumab and for 6 months after the last dose of bevacizumab. Immunoglobulin Gs (IgGs) are known to cross the placental barrier, and bevacizumab may inhibit angiogenesis in the fetus which is critical to fetal development. In post-marketing setting, cases of fetal abnormalities in women treated with bevacizumab alone or in combination with known embryotoxic chemotherapeutics have been observed. Women must refrain from donating eggs during this same period * 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), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements * 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
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: * With a female partner of childbearing potential who is not pregnant, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 6 months after the final dose of bevacizumab. Men must refrain from donating sperm during this same period * With 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 to avoid exposing the embryo * 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

• There is suspicion or evidence of gross residual, recurrent, or metastatic disease present on physical exam, imaging, or by biopsy within 28 days of starting study treatment
• Patients who were/are eligible for but have not received all guideline-recommended standard of care therapy within the recommended time-frame for definitive treatment. The exception (permitting inclusion) would be if any standard of care treatment was deferred due to valid medical reasoning based on the investigator’s discretion or patient’s preference
• Active or history of autoimmune disease 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 following exceptions: * 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 ** 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
• 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 computed tomography (CT) scan * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Active tuberculosis
• Clinically significant cardiovascular disease, such as cerebrovascular accidents within 12 months prior to randomization, myocardial infarction within 12 months prior to study treatment, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with study treatment
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to randomization
• Inadequately controlled hypertension (defined as systolic blood pressure > 150mmHg and/or diastolic blood pressure > 100 mmHg), based on an average of >= 3 blood pressure (BP) blood pressure readings on >= 2 sessions. Anti-hypertensive therapy to achieve these parameters is allowable
• History of hypertensive crisis or hypertensive encephalopathy
• History of grade >= 4 venous thromboembolism
• History or evidence upon physical or neurological examination of central nervous system bleed
• History of grade >= 2 hemoptysis (defined as >= 2.5 mL of bright red blood per episode) within 1 month prior to screening
• History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e., in the absence of therapeutic anticoagulation)
• Current or recent (< 10 days prior to initiation of study treatment) use of aspirin (> 325 mg/day), or clopidogrel (> 75 mg/day) * Note: The use of full-dose oral or parenteral anticoagulants for therapeutic purpose is permitted as long as the INR and/or aPTT is within therapeutic limits (according to institution standards) within 7 days prior to initiation of study treatment and the patient has been on a stable dose of anticoagulants for >= 2 weeks prior to initiation of study treatment. Prophylactic use of anticoagulants is allowed. For prophylactic use of anticoagulants or thrombolytic therapies, local label approved dose levels may be used. The use of direct oral anticoagulant therapies such as dabigatran (Pradaxa [registered trademark]) and rivaroxaban (Xarelto [registered trademark]) is not recommended due to bleeding risk
• Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID) * Occasional use of NSAIDs for the symptomatic relief of medical conditions such as headache or joint pain is allowed
• Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to initiation of study treatment, or anticipation of need for major surgical procedure during the course of the study
• Local therapy to liver or other organ (e.g. radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound, transarterial chemoembolization, transarterial embolization, etc.) within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure
• Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high risk for bleeding in high-risk patients (patients with HCC, cirrhosis, or other conditions predisposing patients to high-risks of portal hypertension) * High risk patients must undergo an esophagogastroduodenoscopy (EGD) and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrollment. Patients who have undergone an EGD within 6 months prior to initiation of study treatment do not need to repeat the procedure
• A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment
• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to initiation of study treatment
• Placement of a vascular access device should be at least 2 days prior to initiation of study treatment
• Active infection requiring IV antibiotics at the time of initiation of study treatment
• 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
• History of abdominal fistula, GI perforation, intra-abdominal abscess, or active GI bleeding within 6 months prior to study treatment * If GI bleeding was from a lesion or a condition that was appropriately treated and patient is deemed to be low risk for recurrent GI bleed per investigator judgement, enrollment will be allowed
• Serious, non-healing wound, active ulcer, or untreated bone fracture
• Subjects with previous malignancies (separate from the malignancy for which patient is being enrolled) are excluded. Exceptions include another malignancy for which a complete remission was achieved at least 5 years prior to study entry and no additional therapy is required or anticipated to be required during the study period. Other exceptions include malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival [OS] rate > 90%), such as adequately treated carcinoma in situ of the cervix, non melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, stage I uterine cancer or others based on the physician/investigator’s discretion
• Prior allogeneic stem cell or solid organ transplantation
• Any other disease, active infection, 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
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
• Treatment with investigational therapy within 28 days prior to initiation of study treatment
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (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-TNF-alpha 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 after Principal Investigator confirmation has been obtained * Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study
• 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 or bevacizumab formulation
• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 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 or urine pregnancy test result within 28 days prior to initiation of study treatment
• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
• History of leptomeningeal disease
• 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 definitive radiotherapy should have been treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) * Patients with indwelling catheters (e.g., PleurX [registered trademark]) are allowed
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. Brain scans are not required to be performed at screening but can be done at the clinician’s or investigator’s discretion depending on clinical history. * Asymptomatic patients with previous definitively (with curative-intent) treated CNS lesions that are believed to have no evidence of residual disease per investigator judgement are eligible, provided that all of the following criteria are met: ** The patient has no history of intracranial hemorrhage or spinal cord hemorrhage ** The patient has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment ** The patient has no ongoing requirement for corticosteroids as therapy for CNS disease ** If the patient is receiving anti-convulsant therapy, the dose is considered stable