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

The main purpose of this study is to compare the clinical benefit, as measured by Progression-Free Survival (PFS), achieved by HX008 or Investigator's Choice Chemotherapy in participants with Microsatellite Instability High (MSI-H) or Mismatch Repair Deficient (dMMR) metastatic colorectal cancer (mCRC).


Eligibility Criteria:
Inclusion Criteria:

1. Voluntarily sign the Informed Consent Form（ICF）, understand the study, be willing to follow and be able to complete all test procedures;
2. Male or female, age ≥ 18 years on the day of signing the informed consent form;
3. Subjects with colorectal cancer confirmed by histology are stage IV according to the 8th edition of the American Joint Committee on Cancer (AJCC) colorectal cancer tumor/node/metastasis (TNM) staging in 2017;
4. Confirmed MSI-H/dMMR status by the central laboratory;
5. 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.
6. 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);
7. Eastern Cooperative Oncology Group (ECOG) of 0 or 1;
8. Estimated life expectancy of ≥12 weeks;
9. Has sufficient organ and bone marrow function((no blood transfusions allowed for 14 days prior to blood routine, no any cell growth factors or/and platelet-raising drugs) to meet the following laboratory examination standards:

   1. Absolute neutrophil count (ANC)≥1.5×10\^9/L
   2. White blood cell count (WBC)≥3×10\^9/L
   3. Platelet count (PLT)≥100×10\^9/ L
   4. Hemoglobin (HGB)≥90 g/L
   5. Serum creatinine (Scr) ≤1.5×ULN
   6. Alanine aminotransferase (ALT) 、Aspartate aminotransferase (AST) ≤2.5× (upper limit of normal, ULN) . Patients with liver metastases require ALT and AST≤5×ULN,
   7. TBIL≤1.5×ULN
   8. International normalized ratio (INR) ≤ 2×ULN; or activated partial thromboplastin time (APTT)≤ 1.5×ULN;(except for patients on anticoagulant therapy);
10. 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;
11. The informed consent was voluntarily signed and the expected compliance was good.

Exclusion Criteria:

1. 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.)
2. 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;
3. 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;
4. 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);
5. 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:

   1. Locally external use or inhaled corticosteroids;
   2. short-term (≤ 7 days) use of glucocorticoids for the prevention or treatment of nonautoimmune allergic diseases;
6. Has had prior radiation therapy or has not recovered (≤ Grade 1 or at Baseline) from Adverse events(AEs) due to a previous radiation therapy;
7. 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;
8. Has severe infection within 4 weeks or active infection requiring IV infusion or oral administration of antibiotics within 2 weeks prior to randomization;
9. Has participated in other drug or device clinical trials within 4 weeks prior to randomization;
10. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or found during screening;
11. Has uncontrolled ascites requiring repeated drainage, pleural effusion, or pericardial effusion;
12. Has incomplete intestinal obstruction, active gastrointestinal hemorrhage, or perforation;
13. Has a history or current interstitial pneumonia, or current non--infectious pneumonitis treatment with corticosteroids
14. Has uncontrolled cardiovascular disease, including but not limited to:

    1. heart failure greater than New York Heart Association (NYHA) class II
    2. unstable angina pectoris
    3. has myocardial infarction within 1 year
    4. supraventricular or ventricular arrhythmias with clinical significance poorly controlled without or despite clinical intervention;
15. Has uncontrolled systemic diseases, for instance, diabetes(Fasting Plasma Glucose ≥ 10 mmol/L or hypertension(systolic blood pressure ≥ 150 mmHg and / or diastolic blood pressure ≥ 100 mmHg);
16. Subjects with active tuberculosis;
17. History of human immunodeficiency virus infection, acquired or congenital immunodeficiency disease, organ transplantation, or stem cell transplantation;
18. Subjects with chronic hepatitis B or active hepatitis C. Except for Hepatitis B virus carriers or those with stable hepatitis B after drug treatment with DNA titer no higher than 500 IU/ml or copy number \<2500 copies/ml, and cured hepatitis C patients (HCV RNA test negative);
19. 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 ;
20. Alcohol dependence or drug abuse within the past 1 year;
21. 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;
22. 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.