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

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ClinicalTrials.gov Identifier: NCT02069704
Recruitment Status : Completed
First Posted : February 24, 2014
Results First Posted : July 23, 2019
Last Update Posted : July 23, 2019
Sponsor:
Collaborators:
Laboratorio Elea S.A.C.I.F. y A.
Libbs Farmacêutica LTDA
Information provided by (Responsible Party):
mAbxience S.A

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Metastatic Colorectal Cancer (mCRC) Drug: Bevacizumab biosimilar (BEVZ92) Drug: Avastin® (bevacizumab, reference product) Phase 1

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 142 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 29, 2014
Actual Primary Completion Date : October 2015
Actual Study Completion Date : June 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Bevacizumab

Arm Intervention/treatment
Experimental: Bevacizumab biosimilar (BEVZ92)
Bevacizumab 25 mg/mL (strength: 100 mg/4 mL).
Drug: Bevacizumab biosimilar (BEVZ92)

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.

Other Names:
  • FOLFOX = Folinic acid + Fluorouracil + Oxaliplatin
  • FOLFIRI = Folinic acid + Fluorouracil + Irinotecan

Active Comparator: Avastin® (bevacizumab, ref. product)
Bevacizumab 25mg/ml (strength: 100mg/4ml)
Drug: Avastin® (bevacizumab, reference product)

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.

Other Names:
  • FOLFOX = Folinic acid + Fluorouracil + Oxaliplatin
  • FOLFIRI = Folinic acid + Fluorouracil + Irinotecan




Primary Outcome Measures :
  1. Area Under the Concentration-versus-time Curve (AUC) at Cycle 1 (AUC0-336h) of BEVZ92 and Avastin® [ Time Frame: AUC0-336 hrs: 0 to 336 hours after start of the first infusion ]

    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%.


  2. AUC at Steady State (AUCss) of BEVZ92 and Avastin® [ Time Frame: AUCss: 0 to 336 hours after the administration of Cycle 7 infusion (Week 13). ]

    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%.



Secondary Outcome Measures :
  1. Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® [ Time Frame: From first study dose and up to 30 days after the end of study treatment for each patient, for an average of 11 months ]
    Compare the safety profile by means of the frequency and severity of TEAEs and SAEs reported in each treatment arm.

  2. Anti-Drug Antibody (ADA) of BEVZ92 and Avastin® [ Time Frame: At baseline, and on Day 1 (pre-dose) of Cycles: 1, 5 and 8, and 12 months after first drug administration ]
    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).

  3. Objective Response Rate (ORR) of BEVZ92 and Avastin® [ Time Frame: Every four weeks. Up to 48 weeks ]

    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.


  4. Cmax,sd of BEVZ92 and Avastin® [ Time Frame: Cmax, sd: 0 to 336 hours after start of the first infusion. ]
    Secondary PK endpoints included the Cmax calculated at Cycle 1 (Cmax,sd )

  5. Progression-free Survival (PFS) of BEVZ92 and Avastin® [ Time Frame: 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. ]
    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".

  6. Cmax,ss of BEVZ92 and Avastin® [ Time Frame: Cmax, ss: 0 to 336 hours post-dose after the administration of Cycle 7 infusion (Week 13) ]
    Secondary PK endpoints included the Cmax calculated at Cycle 7 (Cmax, ss )

  7. Ctrough,sd of BEVZ92 and Avastin® [ Time Frame: Ctrough, sd: 0 to 336 hours after start of the first infusion. ]
    Secondary PK endpoints included the Ctrough calculated at Cycle 1 (Ctrough,sd )

  8. Ctrough,ss of BEVZ92 and Avastin® [ Time Frame: Ctrough, ss: 0 to 336 hours after the administration of the Cycle 7 infusion. ]
    Secondary PK endpoints included the Ctrough calculated at Cycle 7 (Ctrough,ss)

  9. Elimination Half-life (t1/2) of BEVZ92 and Avastin® [ Time Frame: t1/2: 0 to 336 hours after the administration of the Cycle 7 infusion. ]
    Secondary PK endpoints included the t1/2 calculated at Cycle 7

  10. Elimination Rate Constant (Kel) of BEVZ92 and Avastin® [ Time Frame: Kel: 0 to 336 hours after the administration of the Cycle 7 infusion. ]
    Secondary PK endpoints included the Kel calculated at Cycle 7 (Ctrough,ss)

  11. Volume of Distribution (Vd) of BEVZ92 and Avastin® [ Time Frame: Vd: 0 to 336 hours after the administration of the Cycle 7 infusion. ]
    Secondary PK endpoints included the Vd calculated at Cycle 7



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient must not have had prior chemotherapy for advanced or metastatic disease. Patients could have received adjuvant chemotherapy or adjuvant chemo-radiotherapy.
  2. Patient with mCRC for whom bio-chemotherapy is indicated.
  3. 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.
  4. Minimum of 4 weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy
  5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  6. Adequate bone marrow function
  7. Adequate liver function defined within specific parameters
  8. Adequate renal function defined within specific parameters
  9. Adequate coagulation parameters defined within specific parameters
  10. Negative pregnancy test for females of a childbearing potential.
  11. Use of an effective form of contraception during the study (for subjects of childbearing potential and their partners).
  12. Life expectation ≥ 3 months

Exclusion Criteria:

  1. Prior treatment for advanced or metastatic colorectal cancer.
  2. Prior treatment with an anti-angiogenesis agent, in either the neoadjuvant or adjuvant setting.
  3. Concurrent use of investigational anti-neoplastic agents (including up to 4 weeks prior to enrolment).
  4. 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.
  5. Chronic treatment with systemic steroids or other immunosuppressive agents; topical or inhaled corticosteroids are allowed.
  6. Scheduled immunization with attenuated live vaccines during study period or within 1 week prior to study entry.
  7. Uncontrolled brain or lepto-meningeal metastases, including patients who continue to require glucocorticoids for brain or lepto-meningeal metastases.
  8. 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.
  9. Patients with history of cerebral vascular accident, transient ischemic attack, or subarachnoid haemorrhage within the past 6 month prior to randomization.
  10. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study
  11. 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
  12. Patients with clinical symptoms or signs of gastrointestinal obstruction that require parenteral hydration and/or nutrition.
  13. Patients with history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months prior to randomization.
  14. Patients with history of hypersensitivity to any of the study drugs or ingredients.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02069704


Locations
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Argentina
Hospital de Gastroenterologia "Dr. Carlos Bonorino Udaondo"
Buenos Aires, Argentina
Instituto Oncológico de Rosario
Rosario, Argentina
Brazil
Fundaçáo Pio XII - Hospital do Cancer de Barretos
Barretos, Brazil
Hospital Caridade
Ijui, Brazil
Hospital Sao Lucas da Pucrs
Porto Alegre, Brazil
Centro de Pesquisa do Instituto Brasileiro de Controle do Câncer - IBCC
São Paulo, Brazil
Hosp. A.C Camargo
São Paulo, Brazil
Instituto do Cancer del estado de S. Paulo (ICEPS )
São Paulo, Brazil
India
M S Patel Cancer Centre- Shree Krishna Hospital
Karamsad, Gujarat, India, 388 325
Sri Ramachandra Hospital
Chennai, India
Tata Hospital
Mumbai, India
Central India Canter Research Institute
Nagpur, India
Curie Manavta Cancer Center
Nashik, India
Regional Cancer Center & Medical College
Thiruvananthapuram, India
Spain
Centro Oncológico Clara Campal
Madrid, Spain
Ukraine
Dnipropetrovsk City Multiple-discipline Clinical Hospital №4
Dnipropetrovsk, Ukraine
Kharkiv Regional Clinical Oncology Center
Kharkiv, Ukraine
Danylo Halytskiy Lviv National Medical University
Lviv, Ukraine
Sponsors and Collaborators
mAbxience S.A
Laboratorio Elea S.A.C.I.F. y A.
Libbs Farmacêutica LTDA

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: mAbxience S.A
ClinicalTrials.gov Identifier: NCT02069704     History of Changes
Other Study ID Numbers: BEVZ92-A-01-13
BEVZ92-A-01-13 ( Registry Identifier: BEVZ92-A-01-13 )
First Posted: February 24, 2014    Key Record Dates
Results First Posted: July 23, 2019
Last Update Posted: July 23, 2019
Last Verified: July 2019
Keywords provided by mAbxience S.A:
colorectal cancer
metastatic
first-line treatment
comparability
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Folic Acid
Bevacizumab
Oxaliplatin
Irinotecan
Fluorouracil
Levoleucovorin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites