A Study of HX008 Compared to Chemotherapy in the First-Line Treatment of Subjects With MSI-H/dMMR Metastatic Colorectal Cancer

Prior treatment

• Prior systemic treatment for metastatic colorectal cancer (subjects who received neoadjuvant/adjuvant therapy with disease progression should be completed \> 6 months prior to the neoadjuvant/adjuvant therapy were enrolled.)
• Subjects diagnosed with any other malignancy within 5 years prior to randomization, except for malignancies with a low risk of metastasis and death (5-year survival rate \> 90%), such as adequately basal cell or squamous cell skin cancer or carcinoma in situ of the cervix and other carcinomas in situ;
• Had prior treatment with any anti-PD-1, anti-PD-L1, PD-L2, or CTLA-4 agent or any other drug targeting T cell co-stimulation or immune checkpoint pathway;
• Need to receive systemic corticosteroids (dose equivalent to \> 10 mg prednisone/day) or other immunosuppressive drugs within 14 days before enrollment or during the study period. Those under the following conditions are eligible:
  • Locally external use or inhaled corticosteroids;
  • short-term (≤ 7 days) use of glucocorticoids for the prevention or treatment of nonautoimmune allergic diseases;
• Has had prior radiation therapy or has not recovered (≤ Grade 1 or at Baseline) from Adverse events(AEs) due to a previous radiation therapy;
• Has received a significant surgery, open biopsy, or severe trauma within 4 weeks prior to randomization; Definition of major surgery: the minimum of 3 weeks of post-operative recovery time is required to undergo this study, any wound-related AE must be resolved prior to randomization;
• Has severe infection within 4 weeks or active infection requiring IV infusion or oral administration of antibiotics within 2 weeks prior to randomization;
• Treatment with investigational products or devices from other clinical trials within 4 weeks prior to randomization;
• Has a history or current interstitial pneumonia, or current non--infectious pneumonitis treatment with corticosteroids
• Alcohol dependence or drug abuse within the past 1 year;
• Has received a live vaccine within 30 days prior to the first dose of trial treatment. Subjects are permitted to receive inactivated vaccines including those for seasonal influenza, intranasal influenza vaccines are not allowed;

Other illness

• Has active autoimmune disease (except for psoriasis), that has required systemic treatment in the past 2 years((eg, corticosteroids or immunosuppressive drugs). Except for alternative therapies (eg, thyroxine, insulin or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency);
• Has incomplete intestinal obstruction, active gastrointestinal hemorrhage, or perforation;
• Participants with inadequately controlled cardiovascular diseases judged by the investigator as unsuitable for participation in this trial, including but not limited to: (1) NYHA Class II or above cardiac function, (2) Angina unstable;
• Subjects with active tuberculosis;
• History of human immunodeficiency virus infection, acquired or congenital immunodeficiency disease, organ transplantation, or stem cell transplantation;
• Active chronic hepatitis B or active hepatitis C. Except for hepatitis B virus carriers or those with stable disease after drug treatment, and participants with HBV DNA titer ≤ 500 IU/mL or \< 2500 copies/mL are eligible. Active hepatitis C is defined as known positive hepatitis C antibody with known hepatitis C RNA quantitative results above the lower limit of detection of the analytical method;
• Known to be allergic to macromolecular protein agents or monoclonal antibodies. Known to have a history of severe allergies to any of the chemotherapy drugs in the study ;

Lab values

• Presence of other serious physical or mental illness or abnormal laboratory tests that may increase the risk of subjects in the study, or interfere with the study results, and the researchers believe that patients who are not suitable to participate in the trial for other reasons.

Other

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or found during screening;
• Has uncontrolled ascites requiring repeated drainage, pleural effusion, or pericardial effusion;

• Voluntarily sign the Informed Consent Form（ICF）, understand the study, be willing to follow and be able to complete all test procedures;
• Male or female, age ≥ 18 years on the day of signing the informed consent form;
• Histologically or cytologically confirmed adenocarcinoma of the colon or rectum, classified as Stage IV according to the AJCC (8th edition, 2017) TNM staging system for colorectal cancer;
• Confirmed MSI-H/dMMR status by the central laboratory;
• No prior systemic treatment for metastatic colorectal cancer; subjects received neoadjuvant/adjuvant therapy with disease progression should be completed \> 6 months prior to the neoadjuvant/adjuvant therapy were enrolled.
• Has at least one measurable extracranial lesion (Lesions with the longest diameter ≥ 10mm, or lymph nodes with a short diameter ≥ 15mm) according to Response Evaluation Criteria in Solid Tumors Version 1.1(RECIST1.1), which has not been treated with local treatment(Lesions located in the area of previous radiation therapy can also optional if the progression is confirmed);
• Eastern Cooperative Oncology Group (ECOG) of 0 or 1;
• Estimated life expectancy of ≥12 weeks;
• Adequate organ and hematopoietic function (no blood transfusion within 14 days prior to hematology tests, and no use of any hematopoietic growth factors or/and thrombopoietic agents within 7 days), based on the following laboratory tests (retesting is allowed only once during the screening period. If the retest results meet the inclusion criteria, the baseline values will be based on the retest results.):
  • Absolute neutrophil count (ANC)≥1.5×10\^9/L
  • White blood cell count (WBC)≥3×10\^9/L
  • Platelet count (PLT)≥100×10\^9/ L
  • Hemoglobin (HGB)≥90 g/L
  • Serum creatinine (Scr) ≤1.5×ULN
  • Alanine aminotransferase (ALT) 、Aspartate aminotransferase (AST) ≤2.5× (upper limit of normal, ULN) . Patients with liver metastases require ALT and AST≤5×ULN,
  • TBIL≤1.5×ULN
  • International normalized ratio (INR) ≤ 2×ULN; or activated partial thromboplastin time (APTT)≤ 1.5×ULN;(except for patients on anticoagulant therapy);
• Women of childbearing age must have a negative pregnancy test within 72 hours before the first dose of trial treatment. Reproductive men and women of childbearing age are willing to take adequate contraceptive measures (such as oral contraceptives, intrauterine contraceptives, sexual abstinence, or barrier contraceptives combined with spermicide) from signing the informed consent form to 12 months after the last administration of the trial drug;
• Participants must have good compliance.