A Clinical Study to Evaluate Efficacy and Safety of Serplulimab（HLX10） Combined With Bevacizumab（HLX04) and Chemotherapy (XELOX) in Patients With Metastatic Colorectal Cancer (mCRC)

Study Overview
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Brief Summary
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This is a two-arm, randomized, double-blinded, multicenter phase III clinical study to evaluate the clinical efficacy of Serplulimab (HLX10) in Combination With Bevacizumab (HLX04) and Chemotherapy (XELOX) Versus Placebo in Combination With Bevacizumab (HLX04) and Chemotherapy (XELOX) in First-line Treatment of Patients With Metastatic Colorectal Cancer (mCRC)

Detailed Description
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Patients with confirmed unresectable metastatic/recurrent colorectal adenocarcinoma who have not received systemic anti-neoplastic therapy for metastatic/recurrent lesions will be included in this study.Approximately 6-12 patients will be enrolled in the Part I (Safety Run-in Period).Approximately 100 patients will be enrolled in the Part II (Phase II study, 50 in the test group and 50 in the control group).Approximately 654 patients will be enrolled in the Part III (Phase III study, 327 in the test group and 327 in the control group). Part II (Phase II study): Approximately 40 study sites in China will participate. Part III (Phase III study): A total of approximately 75 study sites in 7 countries(including China, the United States, Brazil, Indonesia, Russia, Poland, Spain, etc.) will participate. The study consists of a screening period (up to 28 days), a treatment period (3-week cycle, up to 2 years), and a follow-up period (including a safety follow-up period, and a survival follow-up every 12 weeks).

Official Title
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A Randomized, Double-blind, Multicenter, PhaseⅡ/Ⅲ Clinical Study of Serplulimab (HLX10) in Combination With Bevacizumab (HLX04) and Chemotherapy (XELOX) Versus Placebo in Combination With Bevacizumab (HLX04) and Chemotherapy (XELOX) in First-line Treatment of Patients With Metastatic Colorectal Cancer (mCRC)

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: HLX10
* Drug: HLX04、


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients are eligible for the study if they meet all of the following criteria: Male or female aged 18-75 years (inclusive) at the time of signing the informed consent form (ICF) Histopathologically confirmedunresectable metastatic/recurrent colorectal adenocarcinoma Expected survival ≥ 12 weeks Have not received any previous systemic antineoplastic drug therapy for metastatic/recurrent colorectal adenocarcinoma Time from last treatment to recurrence or progression ≥ 12 monthsforpatients who have previously received neoadjuvant/adjuvant therapy Time from the end of previous traditional Chinese medicine to the first dose of the study drugs ≥ 2 weeks Recovering to ≤ Grade 1 of any AE related with the previous treatment according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (except for alopecia) At least one measurable lesion assessed by central imaging according to RECIST v1.1, the measurable lesion should not have received local treatment such as radiotherapy (lesions located in the previous irradiated area may also be considered as acceptable measurable lesions if progression is confirmed) Paitent agrees to provide sufficient archival tumor tissue specimen or perform biopsy for determination of PD-L1 expression and second generation genome sequencing ECOG PS score of 0-1 within 7 days prior to the first dose of the studydrugs Negative (-) hepatitis B surface antigen (HBsAg), negative (-) hepatitis B core antibody (HBcAb), and the absence of active hepatitis as clinically determined. In case of positive (+) HBsAg or HBcAb, hepatitis B virus deoxyribonucleic acid (HBV-DNA) should be < 1000 copies/mL or 200 IU/mL before enrollment (if the lower limit of detection of the study site is > 200 IU/mL, patient with HBV-DNA below the lower limit of detection is allowed to be enrolled) Negative (-) hepatitis C virus (HCV) antibody; in case of positive (+) HCV antibody, a negative HCV-RNA test is required for enrollment. Patients with co-infection with hepatitis B and C should be excluded (positive for HBsAg or HBcAb and positive for HCV antibody) Adequate major organs function as indicated by the following laboratory criteria (no treatment with blood transfusions, albumin, recombinant human thrombopoietin, or colony-stimulating factor [CSF] within 14 days prior to the first dose of study drugs): Hematological System:Neutrophils (ANC): ≥ 1.5×10 9 /L; Platelets (PLT) ≥ 100×10 9 /L;Hemoglobin (Hb) ≥ 90g/L Hepatic Function:Total bilirubin (TBIL) ≤ 1.5×upper limit of normal(ULN) Glutamate aminotransferase (ALT) : ≤ 2.5×ULN; ≤ 5.0×ULN for patients with liver metastases Aspartate aminotransferase (AST) ≤ 2.5×ULN; ≤ 5.0×ULN for patients with liver metastases Alkaline Phosphatase(ALP): ≤ 2.5×ULN; ≤ 5.0×ULN for patients with liver and/or bone metastases; Albumin ≥ 30 g/L Renal Function: Creatinine (Cr) ≤ 1.5×ULN; Creatinine clearance ≥ 50mL/min if Cr > 1.5 × ULN; (Calculated by Cockcroft-Gault formula) Coagulation Activated partial thromboplastin time(APTT) ≤ 1.5×ULN Prothrombin time (PT) ≤ 1.5×ULN International Normalized Ratio (INR) ≤ 1.5×ULN Urinalysis/24-hour urine protein Urine protein Qualitative examination on urine protein ≤ 1+; in case of ≥ 2+, a 24-hour urine protein test will be required, and if the 24-hour urine protein is <1g, the enrollment will be allowed Female patients of childbearing potential should have a negative serum pregnancy test within 7 days prior to the first dose of study drugs. For female patients of childbearing potential, and male patients with partners of childbearing potential, at least one medically acceptable contraceptive measure (e.g., intrauterine device, contraceptives or condom) is required and will continue for the duration of the study treatment, and for at least 3 months after the last dose of HLX10/placebo, HLX04/Avastin ® , and for at least 6 months after the last dose of chemotherapy, whichever occurs later Provide signed ICF and is willing to comply with all study procedures and rules as specified in the protocol Exclusion Criteria: Patients will be excluded from the study if they meet any of the following exclusion criteria: Other active malignancies within 5 years prior to the first dose of study drugs. Patients with localized tumors that have been cured, such as basal cell carcinoma of skin, squamous cell carcinoma of skin, superficial bladder cancer, carcinoma in situ of prostate, carcinoma in situ of cervix, carcinoma in situ of breast, etc., may be enrolled in the study Presence of central nervous system (CNS) or leptomeningeal metastases Radiation therapy within 6 months prior to initiation of study treatment with the exception of palliative radiation therapy for bone disorders at least 14 days prior to initiation of study treatment; radiation therapy covering more than 30% of the bone marrow area within 28 days prior to the first dose is not allowed Prior postoperative adjuvant therapy with targeted agents targeting EGFR or VEGF/vascular endothelial growth factor receptor (VEGFR) (including bevacizumab, cetuximab, panitumumab, aflibercept, regorafenib, or biosimilars of these agents, etc.) Prior treatment with any T-cell costimulation or immune checkpoint inhibitors, including but not limited to CTLA-4 inhibitors, PD-1 inhibitors, PD-L1/2 inhibitors, or other drugs targeting T cells Known history of severe allergy to any monoclonal antibody or study drug excipients Uncontrolled pleural effusion, pericardial effusion, or ascites requiring frequent drainage after appropriate intervention Cerebrovascular accident, myocardial infarction, unstable angina, poorly controlled arrhythmia (including QTc interval ≥ 450 ms in males and ≥ 470 ms in females) within 6 months (QTc interval is calculated by Fridericia's formula) A cardiac insufficiency of Grade III or IV according to the New York Heart Association (NYHA) criteria, or a left ventricular ejection fraction (LVEF) < 50% based on echocardiography Known history of immunodeficiency, including positive human immunodeficiency virus (HIV) antibody test, or other acquired, congenital immunodeficiency disorders, or history of organ transplantation and allogeneic bone marrow transplantation History of active tuberculosis Patients with previous and current interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, severely impaired lung function, etc. that may interfere with the detection and management of suspected drug-related pulmonary toxicity Patients with currently active or a history of autoimmune diseases (e.g., interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, including but not limited to these diseases or syndromes). The following patients are allowed: patients with vitiligo or recovered childhood asthma/allergy without need of any intervention in adulthood; patients with autoimmune- mediated hypothyroidism treated with a stable dose of thyroid replacement hormone; patients with type I diabetes mellitus with a stable dose of insulin Treatment with live attenuated vaccine within 28 days before the first dose of study drug Patients who require continuous (for > 7 days) systemic treatment with corticosteroids (> 10mg/day prednisone or equivalents) or other immunosuppressive agents within 14 days before the first dose of study drug or during the study period. Inhaled or topical steroids or adrenal replacement at doses ≤ 10mg/day prednisone or equivalent dose are permitted in the absence of active autoimmune disease Severe infection (CTCAE>Grade 2) occurred within 4 weeks prior to the first dose of study drugs, such as severe pneumonia, bacteremia and infection complications requiring hospitalization; active pulmonary inflammation accompanied with relevant clinical symptoms or signs based on chest X-ray at baseline; symptoms and signs of infection requiring oral or intravenous antibiotic therapy within 2 weeks prior to the first dose of study drugs, except prophylactic use of antibiotics Major surgery within 28 days prior to the first dose of study drugs. A major surgery is defined as a surgery that takes at least 3 weeks of postoperative recovery before receiving treatment in this study Have previously received intestinal stent implantation and the intestinal stent has not been explanted until screening Inadequately controlled hypertension (defined as systolic blood pressure ≥ 150 mmHg and/or diastolic blood pressure ≥ 100 mmHg) after more than 2 years of antihypertensive therapy Prior history of hypertensive crisis or hypertensive encephalopathy CT/MRI images showing tumor encircling or invading a large vascular lumen (e.g., pulmonary artery or superior vena cava) Bleeding outside the gastrointestinal tract (including hemoptysis, abnormal vaginal bleeding, etc.) at screening, or Grade 2 bleeding outside the gastrointestinal tract within 3 months, or Grade 3 or higher bleeding outside the gastrointestinal tract within 6 months prior to signing the ICF Currently receiving or have received aspirin (> 325mg/day) or dipyridamole, ticlopidine, clopidogrel, and cilostazol within 7 days before the first dose of study drugs Currently receving or have received full-dose of anticoagulants or thrombolytic agents via oral or injection for therapeutic purposes within 7 days prior to the first dose of study drugs. Prophylactic anticoagulation therapyis allowed for open intravenous infusion systems as long as the international normalized ratio (INR) < 1.5×ULN) and partial thromboplastin time (APTT) is within normal range thereafter within 14 days prior to the first dose of study drug. Prophylactic use of low molecular weight heparin (i.e. enoxaparin at 40mg/day) is allowed Long-term treatment with daily administration of nonsteroidal anti-inflammatory drugs (NSAIDs). Occasional use of NSAIDs to relieve medical symptoms such as headache or fever is allowed Evidence showing the presence of meteorismthat cannot be explained by puncture or recent surgery Presence of severe, unhealed or split wounds and active ulcers or untreated fractures Presence of any of the following medical conditions within 6 months prior to the first dose of study drugs: Gastrointestinal bleeding (macroscopic melena, bloody stool, etc., except for hemorrhoidal bleeding) Abdominal or tracheoesophageal fistula, gastrointestinal perforation or intra-abdominalabscess, massive ascites identified by investigator (defined as patients requiring drainage or management within 2 weeks), or significant peritoneal metastases Intestinal obstruction and/or previous clinical signs or symptoms of gastrointestinal obstruction, including incomplete obstruction associated with a preexisting disease or requiring routine parenteral hydration, parenteral nutrition, or tube feeding. Patients with incomplete obstruction/obstruction syndrome/signs or symptoms of intestinal obstruction at the time of initial diagnosis may be eligible for study enrollment if they receive definitive (surgical) treatment to resolve symptoms Intra-abdominal inflammation, including but not limited to peptic ulcer, diverticulitis or colitis Major vascular disease (e.g., aortic aneurysm requiring surgical repair or associated with recent peripheral artery thrombosis) Known history of psychotropic substance abuse or drug use Participating in another clinical study, or have completed the treatment of another clinical study within 14 days before the planned study treatment in this study Pregnant or lactating women Any other factors that may lead to study discontinuation assessed by the investigator, such as other severe diseases (including mental disease) that require concomitant therapy, seriousabnormalities in laboratory findings, family or social factors, and other conditions possibly affecting the safety or study data collection of the patient

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Serplulima +Bevacizumab+XELOX<br>Serplulimab (HLX10) in Combination With Bevacizumab and chemotherapy (XELOX) | Drug: HLX10<br>* a single fixed dose of 300 mg, intravenous infusion (IV), every 3 weeks (Day 1 of each cycle [D1]), non-reducible.<br>* Other names: serplulimab;Drug: HLX04、<br>* 7.5mg/kg, IV, every 3 weeks (D1 of each cycle), non-reducible.<br>* Other names: Bevacizumab;|
| Placebo Comparator: placebo + Bevacizumab+XELOX<br>placebo in combination with Bevacizumab and chemotherapy (XELOX) | Drug: HLX04、<br>* 7.5mg/kg, IV, every 3 weeks (D1 of each cycle), non-reducible.<br>* Other names: Bevacizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | Progression-free survival (assessed by independent radiological review committee (IRRC) based on RECIST v1.1) | from the first dose until firstly confirmed and recorded disease progression or death (whichever occurs earlier),assessed up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS | Overall survival (OS) | from the date of first dose unitl the date of death from any cause，assessed up to 2 years | 
| PFS | Progression-free survival (assessed by independent radiological review committee (IRRC) based on iRECIST，by the investigators based on RECIST v1.1)) | from the first dose until firstly confirmed and recorded disease progression or death (whichever occurs earlier),assessed up to 2 years | 
| ORR | Objective response rate (assessed by independent radiological review and the investigators based on RECIST v1.1)) | up to 2 years | 
| Duration of response | Duration of response | from the date when CR or PR (whichever recorded earlier) is firstly achieved until the date when disease progression or death is firstly recorded (whichever occurs earlier),assessed up to 2 years | 
| DCR | Disease control rate | the proportion of patients with the best overall response of CR, PR, or stable disease (SD) persisting for 12 weeks |