| Eligibility |
<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.
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