Y-90, Capecitabine, and Atezolizumab for Oligometastatic CRC

Inclusion Criteria:

1. Histologically confirmed diagnosis of colorectal adenocarcinoma

2. Surgically unresectable, liver-isolated or liver-dominant, RECIST measurable,metastatic disease

3. Age ≥18 years at the time of signing informed consent

4. ECOG performance status 0 or 1

5. Progression on 2 or more lines of systemic therapy

6. Agreeable to providing tumor tissue and blood for exploratory correlative analyses

7. Less than 50% of liver volume replaced by metastatic disease (as determined byinvestigator)

8. Demonstrate adequate organ function as defined in table below (all screening labsshould be performed within 14 days of atezolizumab initiation): Hematologic Absolute neutrophil count (ANC) ≥1,500 /mcL or ≥1,200 /mcL for thosewith benign ethnic neutropenia Absolute Lymphocyte Count (ALC) ≥ 0.5 x 109/L (500/uL) Platelets ≥100,000 / mcL Hemoglobin ≥9 g/dL or ≥5.6 mmol/L within 7 days ofassessment. Patient may be transfused or receive EPO to meet this criterion Renal Serum creatinine OR measured or calculated creatinine clearance ≤1.5 X upperlimit of normal (ULN) OR (GFR can also be used in place of creatinine or CrCl) ≥60mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjectswith total bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 5 X ULN AlkalinePhosphatase ≤ 5 X ULN Albumin ≥2.5 mg/dL Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) ActivatedPartial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receivinganticoagulant therapy. For patients receiving therapeutic anticoagulation: stableanticoagulant regimen

≤1.5 X ULN unless subject is receiving anticoagulant therapy. For patients receivingtherapeutic anticoagulation: stable anticoagulant regimen Creatinine clearance should be calculated per institutional standard. Exceptions canbe made for patients with known Gilbert disease (≤ 3X ULN)

9. Female subjects of childbearing potential must be willing to use an adequate methodof contraception from the time of the negative pregnancy test until a minimum of 6months after the last dose of study drug. Effective forms of contraception includeabstinence, hormonal contraceptive (injectable or implantable), or intrauterinedevice in conjunction with a barrier method. Breast feeding subjects must be willingto discontinue at treatment start and for 5 months post-treatment.

10. Male subjects of childbearing potential must agree to use an adequate method ofcontraception with female partners of childbearing potential including abstinence orcondoms plus an additional contraceptive method such as hormonal contraceptive (injectable or implantable), or intrauterine device during the study and for up to 3months after the last dose of study drug.

11. Ability to understand and the willingness to sign a written informed consentdocument and to comply with the study protocol procedures

Exclusion Criteria:

1. Prior yttrium-90 therapy

2. Prior external beam radiation therapy to the liver

3. Predicted life expectancy of less than 3 months

4. Known mismatch repair deficiency (dMMR), microsatellite instability (MSI-H), or hightumor mutational burden (TMB-H) defined as ≥ 10 mutations per megabase

5. Known metastasis to the peritoneum or central nervous system. Exceptions includesubjects with untreated brain metastases ≤ 1 cm, if asymptomatic and not requiringimmediate radiation or steroids, and subjects with brain metastases that are treatedand stable for 1 month

6. Treatment with investigational therapy within the 28 days of initiation of studytreatment

7. Systemic treatment within 14 days or 5 half-lives of the drug (whichever is longer)prior to initiation of study treatment

8. Prior treatment with CD137 agonists or anti-PD1, anti-PD-L1, anti-CTLA4 antibodies

9. A history of or current evidence of any condition (e.g. known deficiency of theenzyme dihydropyrimidine dehydrogenase [DPD]), therapy, or laboratory abnormalitythat might confound the results of the trial, interfere with the subject'sparticipation for the full duration of the trial, or is not in the best interest ofthe subject to participate, in the opinion of the treating investigator

10. Known New York Heart Association class 3/4 congestive heart failure, leftventricular ejection fraction <40% (if previously measured), myocardial infarctionwithin 6 months prior to enrollment, unstable angina, or unstable arrhythmia

11. Chronic obstructive pulmonary disease (COPD) requiring oral corticosteroids orchronic oxygen

12. History of autoimmune disease, including, but not limited to myasthenia gravis,myositis, autoimmune hepatitis, idiopathic pulmonary fibrosis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipidsyndrome, granulomatosis with polyangiitis, Guillain-Barré syndrome, multiplesclerosis, vasculitis, or glomerulonephritis, with the exception of: hypothyroidism (on stable dose of thyroid replacement therapy), asthma managed with inhaledmedications only; type 1 diabetes mellitus on stable insulin regimen, Sjögrensyndrome, immune thrombocytopenia or autoimmune hemolytic anemia that does notrequire systemic therapy; dermatologic condition (including eczema, psoriasis,lichen simplex chronicus, or vitiligo) with skin manifestations with rash covering <10% of body surface area and not requiring treatment other than low-potency topicalcorticosteroids for >12 months prior to registration

13. Treatment with systemic immunosuppressive medication (including, but not limited to,corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-TNF-agents) within 2 weeks prior to initiation of study treatment, oranticipation of need for systemic immunosuppressive medication during studytreatment, with the following exceptions:

• Patients who received acute, low-dose systemic immunosuppressant medication ora one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hoursof 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, orlow-dose corticosteroids for orthostatic hypotension or adrenal insufficiencyare eligible for the study.

14. Positive for HIV at screening or any time prior to screening: patients without priorpositive HIV test result will undergo an HIV test at screening, unless not permittedunder local regulations

15. Active Hepatitis B virus (HBV) infection (chronic or acute): defined as having apositive hepatitis B surface antigen (HBsAg) test at screening. Patients with a pastor resolved HBV infection, defined as having a negative HBsAg test and a positivetotal hepatitis B core antibody test at screening, are eligible for the study

16. Active hepatitis C virus (HCV) infection: defined as positive HCV antibody testfollowed by a positive HCV RNA test at screening. The HCV RNA test will be performedonly for patients who have a positive HCV antibody test

17. Active TB (Mycobacterium tuberculosis)

18. Administration of a live, attenuated vaccine within 28 days before firstatezolizumab dose or anticipation that such a live, attenuated vaccine will berequired during the study or within 5 months after the final dose of atezolizumab

19. History of severe allergic anaphylactic reactions to chimeric or humanizedantibodies. Known hypersensitivity to Chinese hamster ovary cell products or to anycomponent of the atezolizumab formulation

20. Inability to swallow medication

21. History of other malignancy that could affect compliance with the protocol orinterpretation of results; patients with a curatively treated skin cancer, in situcervical cancer, or non-CRC malignancy are eligible if the non-CRC malignancy iscontrolled and will not interfere with measurement of treatment efficacy or safety

22. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment or any major episodeof infection requiring treatment with IV antibiotics or hospitalization within 28days before the first dose of atezolizumab.

23. Any major surgery or significant traumatic injury within 28 days of initiating studytreatment or anticipation of need for a major surgical procedure during the study

24. Evidence of other significant or uncontrolled medical or psychiatric conditions thatcould affect compliance with the protocol

25. Pregnancy, breast-feeding, or prisoner status

26. History of leptomeningeal disease

27. Uncontrolled tumor-related pain

28. Patients requiring pain medication must be on a stable regimen at study entry.

29. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement)amenable to palliative radiotherapy should be treated prior to enrollment. Patientsshould be recovered from the effects of radiation. There is no required minimumrecovery period. Asymptomatic metastatic lesions that would likely cause functional deficits orintractable pain with further growth (e.g., epidural metastasis that is notcurrently associated with spinal cord compression) should be considered forloco-regional therapy if appropriate prior to enrollment. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (once monthly or more frequently).

• Patients with indwelling catheters (e.g., PleurX) are allowed.

30. Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, calcium 12mg/dL or corrected serum calcium ULN)

31. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis on screening chest computed tomography (CT) scan.

• History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

32. Prior allogeneic stem cell or solid organ transplantation

33. Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding that contraindicates the use of an investigational drug, mayaffect the interpretation of the results, or may render the patient at high riskfrom treatment complications

34. 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