Bioequivalence Study Bevacizumab Biosimilar (BEVZ92) Versus Bevacizumab (AVASTIN®) in First-line Treatment mCRC Patients

Study Overview
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Brief Summary
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This is a multicenter, open label, randomized bioequivalence study of BEVZ92 (bevacizumab biosimilar) and Avastin® with 2 parallel arms to compare the pharmacokinetic (PK) profile of BEVZ92 and Avastin® in combination with FOLFOX (any) or FOLFIRI chemotherapy. FOLFOX (any) or FOLFIRI will be chosen as per investigator criteria based on the hospital standard of care.

Detailed Description
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Planned enrolment duration: 12 months. Pre-treatment period (included in enrolment period): 1 month. Treatment period: Patients will continue treatment until disease progression or unacceptable toxicity, or withdrawal of consent.

Official Title
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Open Label Randomized Bioequivalence Study to Evaluate the Pharmacokinetic and Safety Profile of Bevacizumab Biosimilar (BEVZ92) vs Bevacizumab (AVASTIN®), Both With FOLFOX or FOLFIRI, in First-line Treatment for mCRC Patients

Conditions
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Metastatic Colorectal Cancer (mCRC)

Intervention / Treatment
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* Drug: Bevacizumab biosimilar (BEVZ92)
* Drug: Avastin® (bevacizumab, reference product)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must not have had prior chemotherapy for advanced or metastatic disease. Patients could have received adjuvant chemotherapy or adjuvant chemo-radiotherapy. Patient with mCRC for whom bio-chemotherapy is indicated. Patients must have at least one measurable non-irradiated site of disease according to RECIST (version 1.1) criteria. If the patient has had previous irradiation of the marker lesion(s), there must be evidence of progression since the radiation. Minimum of 4 weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Adequate bone marrow function Adequate liver function defined within specific parameters Adequate renal function defined within specific parameters Adequate coagulation parameters defined within specific parameters Negative pregnancy test for females of a childbearing potential. Use of an effective form of contraception during the study (for subjects of childbearing potential and their partners). Life expectation ≥ 3 months Exclusion Criteria: Prior treatment for advanced or metastatic colorectal cancer. Prior treatment with an anti-angiogenesis agent, in either the neoadjuvant or adjuvant setting. Concurrent use of investigational anti-neoplastic agents (including up to 4 weeks prior to enrolment). History of any other malignancy unless the malignancy is in complete remission and the patient has been off all therapy for that malignancy for at least 5 years. Chronic treatment with systemic steroids or other immunosuppressive agents; topical or inhaled corticosteroids are allowed. Scheduled immunization with attenuated live vaccines during study period or within 1 week prior to study entry. Uncontrolled brain or lepto-meningeal metastases, including patients who continue to require glucocorticoids for brain or lepto-meningeal metastases. Patients with active bleeding or history of bleeding diathesis on oral anti-vitamin K medication (except low dose coumadin) within the past 6 month prior to randomization or coagulopathy. Patients with history of cerebral vascular accident, transient ischemic attack, or subarachnoid haemorrhage within the past 6 month prior to randomization. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study Patients with serious non-healing wound, ulcer, bone fracture, or with a major surgical procedure, or significant traumatic injury within 4 weeks prior to randomization Patients with clinical symptoms or signs of gastrointestinal obstruction that require parenteral hydration and/or nutrition. Patients with history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months prior to randomization. Patients with history of hypersensitivity to any of the study drugs or ingredients.

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab biosimilar (BEVZ92)<br>Bevacizumab 25 mg/mL (strength: 100 mg/4 mL). | Drug: Bevacizumab biosimilar (BEVZ92)<br>* Active ingredient Bevacizumab 25 mg/mL (strength = 100 mg/4 mL). 30-minute* IV infusion (5 mg/kg) every 2 weeks, prior to chemotherapy (Folfox any or Folfiri). FOLFIRI = Folinic Acid + Fluorouracil + Irinotecan FOLFOX = Folinic Acid + Fluorouracil + Oxaliplatin Treatment will continue until disease progression, unacceptable toxicity, patient withdraws consent or death (whichever occurs first). *The first infusion will be given over 90 minutes. If it is well tolerated, the second infusion can be given over 60 minutes. If it is well tolerated, subsequent infusions can be given over 30 minutes. The FOLFOX (any) or FOLFIRI regimen will be chosen as per investigator's criteria based on the hospital standard of care.<br>* Other names: FOLFIRI = Folinic acid + Fluorouracil + Irinotecan;|
| Active Comparator: Avastin® (bevacizumab, ref. product)<br>Bevacizumab 25mg/ml (strength: 100mg/4ml) | Drug: Avastin® (bevacizumab, reference product)<br>* Active ingredient: Bevacizumab 25 mg/mL (strength: 100 mg/4 mL). 30-minute* IV infusion (5 mg/kg) every 2 weeks, prior to administration of chemotherapy. Treatment will continue until disease progression, unacceptable toxicity, patient withdraws consent or death (whichever occurs first). *The first infusion will be given over 90 minutes. If the first infusion is well tolerated, the second infusion can be given over 60 minutes. If this infusion is well tolerated, subsequent infusions can be given over 30 minutes. The FOLFOX (any) or FOLFIRI regimen will be chosen as per investigator's criteria based on the hospital standard of care.<br>* Other names: FOLFIRI = Folinic acid + Fluorouracil + Irinotecan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-versus-time Curve (AUC) at Cycle 1 (AUC0-336h) of BEVZ92 and Avastin® | To compare the pharmacokinetic (PK) profile of BEVZ92 and Avastin®, both administered in combination with FOLFOX (any) or FOLFIRI, by means of comparing the truncated AUC calculated from start of the first infusion until start of the second infusion (i.e. at Cycle 1; AUC0-336h) For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 80-125%. | AUC0-336 hrs: 0 to 336 hours after start of the first infusion | 
| AUC at Steady State (AUCss) of BEVZ92 and Avastin® | To compare the PK profile of BEVZ92 and Avastin®, both administered in combination with FOLFOX (any) or FOLFIRI, by means of comparing the truncated area under the concentration-versus-time curve calculated over a dosage interval at steady state (i.e. at Cycle 7; AUCss). For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 80-125%. | AUCss: 0 to 336 hours after the administration of Cycle 7 infusion (Week 13). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Compare the safety profile by means of the frequency and severity of TEAEs and SAEs reported in each treatment arm. | From first study dose and up to 30 days after the end of study treatment for each patient, for an average of 11 months | 
| Anti-Drug Antibody (ADA) of BEVZ92 and Avastin® | Immunogenicity profile by means of measurement of ADA developed de novo (seroconversion) after cycle 5, cycle 8, and 12 months after first drug administration (pre-dose). | At baseline, and on Day 1 (pre-dose) of Cycles: 1, 5 and 8, and 12 months after first drug administration | 
| Objective Response Rate (ORR) of BEVZ92 and Avastin® | To compare efficacy in terms of ORR between arms. Clinical and radiological tumor assessments were performed according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 using computed tomography (CT) or magnetic resonance imaging (MRI) scans. Objective response (OR) is defined as a best overall response of partial response (PR) or complete response (CR) as defined by RECIST v1.1. All participants who did not meet the criteria for CR or PR by the end of the study were considered non-responders. | Every four weeks. Up to 48 weeks | 
| Cmax,sd of BEVZ92 and Avastin® | Secondary PK endpoints included the Cmax calculated at Cycle 1 (Cmax,sd ) | Cmax, sd: 0 to 336 hours after start of the first infusion. | 
| Progression-free Survival (PFS) of BEVZ92 and Avastin® | Compare PFS between the randomized treatment arms. Progression-free survival (PFS) was defined as the time from the randomization date to the date of disease progression using RECIST v1.1, or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions plus 5 mm absolute increase, and/or unequivocal progression of known non-target lesion, and/or the appearance of new lesions. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 weeks. | 
| Cmax,ss of BEVZ92 and Avastin® | Secondary PK endpoints included the Cmax calculated at Cycle 7 (Cmax, ss ) | Cmax, ss: 0 to 336 hours post-dose after the administration of Cycle 7 infusion (Week 13) | 
| Ctrough,sd of BEVZ92 and Avastin® | Secondary PK endpoints included the Ctrough calculated at Cycle 1 (Ctrough,sd ) | Ctrough, sd: 0 to 336 hours after start of the first infusion. | 
| Ctrough,ss of BEVZ92 and Avastin® | Secondary PK endpoints included the Ctrough calculated at Cycle 7 (Ctrough,ss) | Ctrough, ss: 0 to 336 hours after the administration of the Cycle 7 infusion. | 
| Elimination Half-life (t1/2) of BEVZ92 and Avastin® | Secondary PK endpoints included the t1/2 calculated at Cycle 7 | t1/2: 0 to 336 hours after the administration of the Cycle 7 infusion. | 
| Elimination Rate Constant (Kel) of BEVZ92 and Avastin® | Secondary PK endpoints included the Kel calculated at Cycle 7 (Ctrough,ss) | Kel: 0 to 336 hours after the administration of the Cycle 7 infusion. | 
| Volume of Distribution (Vd) of BEVZ92 and Avastin® | Secondary PK endpoints included the Vd calculated at Cycle 7 | Vd: 0 to 336 hours after the administration of the Cycle 7 infusion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colorectal cancer, metastatic, first-line treatment, comparability