A Clinical Study to Compare the Efficacy, Safety and Immunogenicity of HLX04 and Bevacizumab Combined XELOX or mFOLFOX6 in the First-line Treatment of mCRC

A Randomized, Double-blind, Parallel Control, Multicenter, Phase III Clinical Study to Compare the Efficacy and to Evaluate the Safety and Immunogenicity of HLX04 and Bevacizumab Combined With Oxaliplatin and Fluoropyrimidine-based Chemotherapy (XELOX or mFOLFOX6) in the First-line Treatment of Metastatic Colorectal Cancer (mCRC)

This trial is conducted in patients with the recurrent lesion(s) post-surgery or the untreated mCRC. After stratification with respect to ECOG PS score, chemo regimen, primary tumor location and KRAS and BRAF genotype (complete wild-type/primal type), eligible patients are randomized into two arms at 1:1 ratio to receive HLX04 (Arm A) or Bevacizumab (Arm B) in combination with one of the protocol-defined chemotherapies, modified FOLFOX6 (mFOLFOX6) or XELOX for mCRC until disease progression (PD) or unacceptable toxicity or achieving an operable contingency, whichever occurs first.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer (mCRC)
• Intervention / Treatment: Drug: HLX04 100 mg in 4 ml Injection; Drug: Avastin 100 mg in 4 ml Injection

• Study Type: Interventional
• Enrollment (Actual): 677
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210002
      • Nanjing Bayi Hospital Ethics Committee

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18-75 years
2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
3. Life expectancy ≥ 6 months
4. Histologically confirmed colorectal cancer with a metastatic / recurrent lesion that cannot be cured by surgery.
5. At least one measurable lesion have been the confirmatory detection within 4 weeks prior to the randomization with respect to RECIST 1.1
6. No prior first-line systemic anti-tumor therapy for mCRC (including systemic chemotherapy, molecular targeted therapy, biotherapy, and other study treatment) have been identified
7. At least 6 months have elapsed if considering the interval from the time of firstly documented metastasis to the post-operational adjuvant chemotherapy termination

8. Adequate organ function as indicated by the following laboratory values:

   1. Absolute neutrophil count (ANC) ≥1,500 /mm3（1.5×109 /L）
   2. Platelets ≥80,000 / mm3（80×109 /L）
   3. Hemoglobin ≥9 g/dL, within the 2 weeks prior to the screening no need for the transfusion
   4. Serum creatinine ≤1.5 X upper limit of the normal (ULN) or creatinine clearance ≥ 50 mL/min according to Cockcroft-Gault formula
   5. Serum total bilirubin ≤ 1.5 X ULN
   6. AST (SGOT), ALT (SGPT) and alkaline phosphatase (ALK) ≤ 3 X ULN (AST/ALT ≤ 5 X ULN if liver metastatic; ALK ≤ 5 × ULN if liver and/or bone metastastic)
   7. International Normalized Ratio (INR) or Prothrombin Time (PT) or Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 X ULN; ( if patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intent using goal of anticoagulants)
9. The subjects are accredited with good compliance, signed the informed consent, and capable to cooperate, completing the relevant examination and follow-ups.

Exclusion Criteria:

1. Targeted medicine(including Bevacizumab, cetuximab, panedol, arbicip, rigofeni, etc) was used before as adjuvant therapy.
2. Cerebral and/or leptomeningeal metastasis.
3. Bleeding predisposition, high bleeding risk or coagulant disorder, thrombotic event(s) occurrence ≤6 months and/or hemoptysis ≤3 months (≥ 1/2 teaspoons fresh blood each) prior to the screening; use of full dose oral or parenteral anticoagulant or thrombolytic medication (allowing preventative anticoagulation); use of aspirin (> 325 mg/day) or other platelet-inhibition non-steroidal anti-inflammatory drugs within 10 days since the screening; CT/MRI imaging evidence, testimony of the main arteries/veins (such as pulmonary artery or superior vena cava) being infringed, encroached.
4. Subjects with uncontrolled hypertension and with a medical history of hypertensive crisis or hypertensive encephalopathy; serious cardiovascular and cerebrovascular diseases, including cerebrovascular accident (CVA) ≤6 months before the screening, transient ischemic attack (TIA), myocardial infarction and significant vascular disease (including but not limited to aortic aneurysms with need for surgical repair or recent evidence of arterial thrombosis), unstable angina, heart failure and serious arrhythmias that are uncontrolled by drugs (New York Heart Association Class ≥2).
5. Subjects with non-healing wounds, active peptic ulcer or fracture and active infection; tracheal esophageal fistula, gastrointestinal perforation or gastrointestinal fistula and abdominal abscess in the 6 months prior to the screening;Uncontrolled infection,including HIV,HBV,HCV and syphilis .
6. Subjects allergic to bevacizumab, oxaliplatin, 5-FU/capecitabine or folinic acid injection and the relevant ingredients and excipients.
7. Pregnant women and lactating women; women of potential childbearing age and male subjects do not use effective contraception during the study period, and during the 6 months after the last study drug administration effective contraception cannot be assured.
8. Presence of other active malignancies or a history of other malignancies within the past 5 years, except for carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent.
9. Subject is currently enrolled in, or ≤4 weeks since subject participating another investigational device or drug study(s), or subject is receiving other investigational agent(s).
10. Any other medical condition that renders disqualification for the inclusion in the study according to the investigator discretionary judgment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HLX04	Drug: HLX04 100 mg in 4 ml Injection; 7.5 mg/kg iv (XELOX+HLX04) 5 mg/kg iv (mFOLFOX6 + HLX04)
Active Comparator: Bevacizumab	Drug: Avastin 100 mg in 4 ml Injection; 7.5 mg/kg iv (XELOX+HLX04) 5 mg/kg iv (mFOLFOX6 + HLX04)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFSR9m	Progression free survival rate (PFS rate) at Month 9 (PFSR9m)	0 to 36 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BORR	Best objective response rate (BORR) up to Week 48	0 to 48 weeks
ORR	Objective response rate (ORR) at Weeks 6, 12, 18, 24, 36，42,48	6 to 48 weeks
OSR	Overal survival rate: the time from the date of randomization to the date of documented clinical or radiological progression or death due to any cause within 48 weeks after first visit	0 to 48 weeks
TTR	Time to response (TTR)	0-48 weeks
DOR	Duration of response (DOR)	0-48 weeks
SAE	incidence of serious adverse events (SAE)	0-48 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax	Cmax following first dose and the dose of Week 18;	0 to 54 weeks
Ctrough	Ctrough before the first dose of Cycle2, Week 18, Week 36;	0 to 54 weeks

Collaborators and Investigators

• Sponsor: Shanghai Henlius Biotech

Publications and helpful links

General Publications

• Zhu X, Qian H, Sun J, Wu M, Yu C, Ding Y, Zhang X, Chai K, Li X. A phase 1 randomized study compare the pharmacokinetics, safety and immunogenicity of HLX04 to reference bevacizumab sourced from the United States, the European Union, and China in healthy Chinese male volunteers. Cancer Chemother Pharmacol. 2021 Sep;88(3):465-474. doi: 10.1007/s00280-021-04297-z. Epub 2021 Jun 4.
• Qin S, Li J, Bai Y, Shu Y, Li W, Yin X, Cheng Y, Sun G, Deng Y, Zhong H, Li Y, Qian X, Zhang L, Zhang J, Chen K, Kang W; HLX04-mCRC03 Investigators. Efficacy, Safety, and Immunogenicity of HLX04 Versus Reference Bevacizumab in Combination with XELOX or mFOLFOX6 as First-Line Treatment for Metastatic Colorectal Cancer: Results of a Randomized, Double-Blind Phase III Study. BioDrugs. 2021 Jul;35(4):445-458. doi: 10.1007/s40259-021-00484-9. Epub 2021 May 20.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2018
• Primary Completion (Actual): April 15, 2020
• Study Completion (Actual): April 20, 2023

Study Registration Dates

• First Submitted: March 21, 2018
• First Submitted That Met QC Criteria: April 27, 2018
• First Posted (Actual): April 30, 2018

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 29, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Antineoplastic Agents, Immunological; Antineoplastic Agents; Physiological Effects of Drugs; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: HLX04 mCRC03

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No