Clinical trial NCT03511963: 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
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Metastatic Colorectal Cancer (mCRC)
Lead sponsor: Shanghai Henlius Biotech
Sponsor class: INDUSTRY
First posted: 2018-04-30
Enrollment: 677
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: PFSR9m
timeFrame: 0 to 36 weeks
Secondary outcomes:
measure: BORR
timeFrame: 0 to 48 weeks
measure: ORR
timeFrame: 6 to 48 weeks
measure: OSR
timeFrame: 0 to 48 weeks
measure: TTR
timeFrame: 0-48 weeks
measure: DOR
timeFrame: 0-48 weeks
measure: SAE
timeFrame: 0-48 weeks
Other outcomes:
measure: Cmax
timeFrame: 0 to 54 weeks
measure: Ctrough
timeFrame: 0 to 54 weeks
Locations:
city: Nanjing
country: China
facility: Nanjing Bayi Hospital Ethics Committee
state: Jiangsu
Study officials:
References:
citation: 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.
citation: 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.