A Randomized Phase III Study of HX008 (a Humanized Monoclonal Antibody Against PD-1) Compared to Investigator's Choice Chemotherapy in the First-Line Treatment of Subjects With Microsatellite Instability-High (MSI-H)/Deficient DNA Mismatch Repair (dMMR) Metastatic Colorectal Cancer

Official Summary

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 Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: SINGLE
• Enrollment: 190 participants

Study Arms

• HX008(Pucotenlimab) (EXPERIMENTAL)
  Subjects receive HX008 200 mg intravenous (IV) every 3 weeks (Q3W)
• Investigator's Choice Chemotherapy (ACTIVE_COMPARATOR)
  1. mFOLFOX6 2. mFOLFOX6+Bevacizumab 3. mFOLFOX6+Cetuximab 4. FOLFORI 5. FOLFORI+Bevacizumab 6. FOLFORI+Cetuximab 7. CAPEOX 8. CAPEOX+ Bevacizumab

Interventions

• DRUG: HX008(Pucotenlimab) — Drug: HX008(Pucotenlimab) 200 mg ,Q3W
• DRUG: Investigator's Choice Chemotherapy — Drug: bevacizumab 5mg/kg given by IV every 14 days. Other Name: Avastin Drug: cetuximab 400 mg/m2 for the first dose, then 250 mg/sqm, intravenous infusion, repeated weekly; or Cetuximab 500 mg/ sqm, intravenous infusion, D1, repeated every 2 weeks. Other Name: Erbitux Drug: oxaliplatin 85 mg/sqm by IV, day1. Component of mFOLFOX6. Drug: irinotecan 180 mg/sqm by IV, day1.Component of FOLFORI. Drug: calcium Folinate 400 mg/sqm by IV, day1.Component of mFOLFOX6 or FOLFORI. Drug: 5-fluorourac

Primary Outcomes

• Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Independent Review Committee(IRC) (2 years)

Secondary Outcomes

• Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Investigators (2 years)
• Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by IRC or investigators (2 years)
• Disease Control Rate (DCR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by IRC or investigators (2 years)
• Duration of Response (DOR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by IRC or investigators (2 years)
• Overall Survival (OS) (2 years)

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. 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;
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. 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.):

   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. Participants must have good compliance.

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. Treatment with investigational products or devices from other 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

Trial Locations

• The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
• The Fifth Affiliated Hospital of Anhui Medical University, Fuyang, Anhui, China
• Anhui Provincial Cancer Hospital, Hefei, Anhui, China
• Beijing Friendship Hospital, Capital Medical University, Beijing, Beijing Municipality, China
• Cancer Hospital Chinese Academy of Medical Sciences, Beijing, Beijing Municipality, China
• Peking Union Medical College Hospital, Beijing, Beijing Municipality, China
• Peking University Cancer Hospital, Beijing, Beijing Municipality, China
• Peking University First Hospital, Beijing, Beijing Municipality, China
• Fujian Medical University Union Hospital, Fuzhou, Fujian, China
• Gansu Provincial People's Hospital, Lanzhou, Gansu, China
• ...and 10 more locations

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