Treatment of Colorectal Liver Metastases With Immunotherapy and Bevacizumab
Treatment of Colorectal Liver Metastases With Immunotherapy and Bevacizumab
Liver is the most common site of metastases from colorectal cancer. Neoadjuvant chemotherapy
 with targeted agents is usually recommended for borderline-resectable liver metastases that
 are technically difficult to resect for conversion to resectable disease and control of
 metastatic spread. However, the prognosis of these patients are still poor, and long term
 disease-free survival over 3 years is rare and <20%. More effective measures to prevent
 recurrence are needed before or after resection of colorectal liver metastases.
-  Atezolizumab is a humanized immunoglobulin G1 monoclonal antibody that targets
 Programmed Death-Ligand 1(PD-L1) and inhibits the interaction between PD-L1 and its
 receptors, Programmed cell Death protein 1(PD-1) and B7.1. Therapeutic blockade of PD-L1
 binding by atezolizumab has been shown to enhance the magnitude and quality of tumor
 specific T cell responses, resulting in improved anti tumor activity.

 -  Bevacizumab is a recombinant, humanized therapeutic antibody directed against vascular
 endothelial growth factor(VEGF). In addition to its well-characterized role in
 angiogenesis, VEGF is also believed to be involved in cancer immune evasion via the
 induction of myeloid- derived suppressor cells(MDSCs). These VEGF-induced MDSCs can
 suppress both T-cell and dendritic-cell function. Bevacizumab can restore and/or
 maintain the antigen presentation capacity of dendritic cells, leading to enhanced
 T-cell infiltration in tumors. When used in combination, VEGF targeting agents such as
 bevacizumab promote the normalization of tumor vasculature and may thereby increase
 access of therapeutic agents.

 -  Atezolizumab with bevacizumab, levoleucovorin, oxaliplatin, and 5-fluorouracil(FOLFOX).
 A translational study for renal cell carcinoma showed bevacizumab resulted in modulation
 of tumor immune microenvironment with Th1-related signatures, which was more potentiated
 by subsequent treatment with atezolizumab. This suggests potentiation of anti-tumor
 immunity with the combination of bevacizumab and atezolizumab.
<Inclusion Criteria>

 Patient-related consideration

 1. Have provided written informed consent prior to any study specific procedures

 2. Willing and able to comply with the protocol

 3. ≧ 20 years of age at the time of signing Informed Consent Form

 4. Eastern Cooperative Oncology Group (ECOG) status of ≤1

 Disease-related consideration

 1. Histologically diagnosed colorectal adenocarcinoma

 2. Liver metastases from colorectal adenocarcinoma confirmed through biopsy

 3. Liver metastatic lesions should be considered to be potentially resectable after
 conversion chemotherapy by multi-disciplinary team and should meet one of the
 following criteria:

 -  Number of metastatic deposit ≧ 4

 -  Possibility of resection margin could be involved

 -  Involvement of major hepatic vessels

 -  Presence of extrahepatic metastases (if they are supposed to be treated with
 curative aim and not to alter a plan for hepatic metastasectomy)

 -  High likelihood of insufficient residual hepatic volume after surgery

 4. Measurable by RECIST criteria 1.1.

 5. One or more hepatic lesions should be accessible for biopsy

 6. Archival tumor tissue from the metastatic liver lesion obtained at the time of the
 initial diagnosis must be available.

 7. Adequate major organ functions as following:

 -  Hematopoietic function: Absolute neutrophil count(ANC) ≧ 1,500/mm3, Platelet ≧
 100,000/mm3

 -  Hepatic function: serum bilirubin ≦ 2 x Upper limit of normal(ULN), Aspartate
 aminotransferase(AST)/Alanine aminotransferase(ALT) ≦ levels 5 x ULN

 -  Renal function: serum creatinine ≦ 1.5 x ULN

 8. International normalised ratio(INR) < 1.5 or Activated partial thromboplastin(aPTT) <
 1.5 x ULN within 14 days prior to the start of study treatment for patients not
 receiving anti-coagulation. For patients receiving anticoagulants, INR and aPTT must
 be within the medical standard of enrolling institution.

 Other considerations

 1. For women of childbearing potential: agreement to remain abstinent (refrain from
 heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per
 year during the treatment period and for 6 months after the last dose of study
 treatment after the last dose of study treatment

 i. A woman is considered to be of childbearing potential if she is postmenarcheal, 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).

 ii. 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.

 2. For men, they must practice abstinence or condom use, and abstain from sperm donation
 during the treatment period and for 6 months after their last dose of study treatment
 during the treatment period and for 6months after the last dose of study treatment.

 <Exclusion Criteria>

 Patients who meet any of the following criteria will be excluded from study entry:

 1. Extrahepatic metastases that are not candidates for treatment of curative aim (e.g.
 resection, radiation or radiofrequency ablation)

 2. Presence of central nervous system (CNS) metastases

 3. Concurrent or previous history of another primary cancer within 3 years prior to study
 treatment except for curatively treated cervical cancer in situ, non-melanomatous skin
 cancer, superficial bladder cancer (pTis or pT1) and curatively treated thyroid cancer
 of any stage. Concurrent, histologically confirmed, unresected thyroid cancer without
 distant metastasis could be allowed with the agreement of the principal investigator.

 4. Chronic alcoholic hepatitis or cirrhosis

 5. Chronic hepatitis B, defined as HBV DNA (> 2,000 IU / mL) and ALT> upper limit of
 normal range, must be treated with antiviral drugs before enrollment to reach
 appropriate viral suppression (HBV DNA <2000 IU / mL), and the antiviral drugs must be
 maintained during the study treatment period and for 6 months after the last dose of
 study treatment.

 6. Prior chemotherapy for metastatic disease

 7. Uncontrolled medical illness congestive heart failure, myocardial infarction within 6
 months including medically uncontrolled infection, uncontrolled hypertension, unstable
 angina, symptomatic congestive heart failure, myocardial infarction within 6 months

 8. Prior adjuvant FOLFOX chemotherapy

 9. Prior adjuvant chemotherapy, if administered within 6 months before study entry

 10. Current or recent (within 10 days of start of study treatment) use of aspirin
 (>325mg/day), clopidogrel (>75mg/day), therapeutic or parenteral anticoagulants or
 thrombolytic agents for therapeutic purposes (therapeutic anticoagulation on a stable
 dose for at least 2 weeks prior to the start of study treatment is allowed)

 11. Known alcohol or drug abuse

 12. Active infection requiring intravenous antibiotics at the start of study treatment

 13. Inadequately controlled hypertension (defined as systolic blood pressure >150mmHg
 and/or diastolic blood pressure >100mmHg)

 14. Prior history of hypertensive crisis or hypertensive encephalopathy

 15. History or evidence upon physical or neurological examination of CNS disease (e.g.
 seizures) unrelated to cancer unless adequately treated with standard medical therapy

 16. Uncontrolled chronic peripheral neuropathy ≥ CTCAE grade 2

 17. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent
 arterial thrombosis) within 6 months of start of study treatment

 18. Any previous venous thromboembolism > CTCAE Grade 3 within 12 months prior to start of
 study treatment

 19. History of haemoptysis ≥ Grade 2 (defined as ≥ 2.5 mL bright red blood per episode)
 within 1 month of start of study treatment

 20. History or evidence of inherited bleeding diathesis or significant coagulopathy at
 risk of bleeding (i.e. in the absence of therapeutic anticoagulation)

 21. 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 start of study treatment, or anticipation of need for
 major surgical procedure (other than hepatic metastasectomy) during the course of the
 study

 22. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or
 active GI bleeding within 6 months prior to start of study treatment

 23. Serious, non-healing wound, active ulcer, or untreated bone fracture

 24. Known hypersensitivity to any component of any of the study medication

 25. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
 chimeric or humanised antibodies or fusion proteins

 26. Known dihydropyrimidine dehydrogenase deficiency

 27. Pregnant or breastfeeding, or intending to become pregnant during the study or within
 6 months after the last dose of study treatment

 28. Women of childbearing potential must have a negative serum or urine pregnancy test
 result within 14 days prior to initiation of study treatment.

 29. Known hypersensitivity or allergy to Chinese hamster ovary cell products

 30. 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's 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

 31. Prior allogeneic bone marrow transplantation or prior solid organ transplantation

 32. 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.)

 33. Positive test for human immunodeficiency virus (HIV)

 34. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody
 test followed by a positive HCV RNA test at screening

 -  The HCV RNA test will be performed only for patients who have a positive HCV
 antibody test.

 -  Patients positive for HCV antibody are eligible only if polymerase chain reaction
 (PCR) is negative for HCV RNA.

 35. Active tuberculosis

 36. Administration of a live, attenuated vaccine within 4 weeks prior to start of study
 maintenance treatment or anticipation that such a live attenuated vaccine will be
 required during the study

 37. Prior treatment with Cluster of differentiation(CD)137 agonists, anti-cytotoxic
 T-lymphocyte-associated antigen(CTLA)4, anti-PD-1, or anti-PD-L1 therapeutic antibody
 or pathway-targeting agents

 38. Treatment with systemic immunostimulatory agents (including but not limited to
 interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever
 is longer, prior to start of study maintenance treatment

 39. Treatment with systemic corticosteroids or other systemic immunosuppressive
 medications (including but not limited to prednisone, dexamethasone, cyclophosphamide,
 azathioprine, methotrexate, thalidomide, and anti-Tumour Necrosis Factor agents)
 within 2 weeks prior to start of study maintenance treatment, or requirement for
 systemic immunosuppressive medications during the trial.