Metastatic Colorectal Cancer (mCRC)
Conditions
Keywords
colorectal cancer, metastatic, first-line treatment, comparability
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.
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.
Interventions
DRUGBevacizumab 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.
DRUGAvastin® (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.
Sponsors
Laboratorio Elea Phoenix S.A.
Libbs Farmacêutica LTDA
mAbxience Research S.L.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-versus-time Curve (AUC) at Cycle 1 (AUC0-336h) of BEVZ92 and Avastin® | 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%. |
| AUC at Steady State (AUCss) of BEVZ92 and Avastin® | 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
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) of BEVZ92 and Avastin® | 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. |
| Cmax,sd of BEVZ92 and Avastin® | Cmax, sd: 0 to 336 hours after start of the first infusion. | Secondary PK endpoints included the Cmax calculated at Cycle 1 (Cmax,sd ) |
| Progression-free Survival (PFS) of BEVZ92 and Avastin® | 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. |
| Cmax,ss of BEVZ92 and Avastin® | 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 ) |
| Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | 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. |
| Ctrough,ss of BEVZ92 and Avastin® | 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) |
| Elimination Half-life (t1/2) of BEVZ92 and Avastin® | 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 |
| Elimination Rate Constant (Kel) of BEVZ92 and Avastin® | 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) |
| Volume of Distribution (Vd) of BEVZ92 and Avastin® | Vd: 0 to 336 hours after the administration of the Cycle 7 infusion. | Secondary PK endpoints included the Vd calculated at Cycle 7 |
| Ctrough,sd of BEVZ92 and Avastin® | Ctrough, sd: 0 to 336 hours after start of the first infusion. | Secondary PK endpoints included the Ctrough calculated at Cycle 1 (Ctrough,sd ) |
| Anti-Drug Antibody (ADA) of BEVZ92 and Avastin® | 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). |
Countries
Argentina, Brazil, India, Spain, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab Biosimilar (BEVZ92) Bevacizumab biosimilar (BEVZ92): Bevacizumab biosimilar (BEVZ92), Active ingredient Bevacizumab 25 mg/mL (strength = 100mg/mL). 30-minute\* IV infusion (5 mg/kg) every 2 weeks, prior to chemotherapy (Folfox any or Folfiri). | 69 |
| Avastin® (Bevacizumab, Ref. Product) Avastin® (bevacizumab, reference product): 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 (Folfox any or Folfiri). | 71 |
| Total | 140 |
Baseline characteristics
| Characteristic | Bevacizumab Biosimilar (BEVZ92) | Avastin® (Bevacizumab, Ref. Product) | Total |
|---|---|---|---|
| Age, Continuous | 56.3 years STANDARD_DEVIATION 12.9 | 56.7 years STANDARD_DEVIATION 11.6 | 56.5 years STANDARD_DEVIATION 12.2 |
| Age, Customized Aged < 65 years | 49 Participants | 51 Participants | 100 Participants |
| Age, Customized Aged >= 65 years | 20 Participants | 20 Participants | 40 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 0 | 7 Participants | 18 Participants | 25 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 1 | 57 Participants | 43 Participants | 100 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status 2 | 5 Participants | 10 Participants | 15 Participants |
| Extent of disease Liver disease only | 7 Participants | 5 Participants | 12 Participants |
| Extent of disease Other | 62 Participants | 66 Participants | 128 Participants |
| Months since diagnosis of metastatic colorectal cancer | 13.0 months STANDARD_DEVIATION 14.7 | 13.0 months STANDARD_DEVIATION 17.5 | 13.0 months STANDARD_DEVIATION 16.1 |
| Number of target lesions 1 | 9 Participants | 11 Participants | 20 Participants |
| Number of target lesions 2 | 29 Participants | 31 Participants | 60 Participants |
| Number of target lesions >=3 | 31 Participants | 29 Participants | 60 Participants |
| Previous treatment Chemotherapy | 24 participants | 23 participants | 47 participants |
| Previous treatment Radiotherapy | 14 participants | 15 participants | 29 participants |
| Previous treatment Surgery | 55 participants | 53 participants | 108 participants |
| Race/Ethnicity, Customized Race Asian | 14 Participants | 12 Participants | 26 Participants |
| Race/Ethnicity, Customized Race Black | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Other | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Race White | 50 Participants | 55 Participants | 105 Participants |
| Sex: Female, Male Female | 30 Participants | 32 Participants | 62 Participants |
| Sex: Female, Male Male | 39 Participants | 39 Participants | 78 Participants |
| Tumor, lymph Nodes and Metastases (TNM) stage IVa | 30 Participants | 32 Participants | 62 Participants |
| Tumor, lymph Nodes and Metastases (TNM) stage IVb | 38 Participants | 38 Participants | 76 Participants |
| Tumor, lymph Nodes and Metastases (TNM) stage missing | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 69 | 7 / 71 |
| other Total, other adverse events | 66 / 69 | 71 / 71 |
| serious Total, serious adverse events | 19 / 69 | 21 / 71 |
Outcome results
Primary
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%.
Time frame: AUC0-336 hrs: 0 to 336 hours after start of the first infusion
Population: Overall number of participants Analyzed equals to number of subjects who contributed to summary statistics.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bevacizumab Biosimilar (BEVZ92) | Area Under the Concentration-versus-time Curve (AUC) at Cycle 1 (AUC0-336h) of BEVZ92 and Avastin® | 16500000 ng.h/mL | Geometric Coefficient of Variation 30.7 |
| Avastin® (Bevacizumab, Ref. Product). | Area Under the Concentration-versus-time Curve (AUC) at Cycle 1 (AUC0-336h) of BEVZ92 and Avastin® | 16600000 ng.h/mL | Geometric Coefficient of Variation 31.8 |
Comparison: Based on previously published PK data for reference bevacizumab in metastatic colorectal cancer, we assumed a conservative inter-participant coefficient of variation for AUC of around 35%. A sample size of 51 patients in each treatment arm could show bioequivalence with a nominal power of 90% and an α of 0·05, if the 90% CIs for the ratio of BEVZ92 to reference bevacizumab of the geometric means for AUC0-336h and AUCss were within the acceptance interval of 80%-125%.90% CI: [90.5, 109]
Primary
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%.
Time frame: AUCss: 0 to 336 hours after the administration of Cycle 7 infusion (Week 13).
Population: In the Avastin arm there were 3 missing samples at the timepoint required for the specific PK parameters within Cycle 7.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bevacizumab Biosimilar (BEVZ92) | AUC at Steady State (AUCss) of BEVZ92 and Avastin® | 35900000 ng.h/mL | Geometric Coefficient of Variation 34.8 |
| Avastin® (Bevacizumab, Ref. Product). | AUC at Steady State (AUCss) of BEVZ92 and Avastin® | 35700000 ng.h/mL | Geometric Coefficient of Variation 36.6 |
90% CI: [90.2, 112]
Secondary
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).
Time frame: At baseline, and on Day 1 (pre-dose) of Cycles: 1, 5 and 8, and 12 months after first drug administration
Population: All patients receiving at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab Biosimilar (BEVZ92) | Anti-Drug Antibody (ADA) of BEVZ92 and Avastin® | Seroconversion | 2 participants |
| Bevacizumab Biosimilar (BEVZ92) | Anti-Drug Antibody (ADA) of BEVZ92 and Avastin® | No seroconversion | 67 participants |
| Avastin® (Bevacizumab, Ref. Product). | Anti-Drug Antibody (ADA) of BEVZ92 and Avastin® | Seroconversion | 0 participants |
| Avastin® (Bevacizumab, Ref. Product). | Anti-Drug Antibody (ADA) of BEVZ92 and Avastin® | No seroconversion | 71 participants |
Secondary
Cmax,sd of BEVZ92 and Avastin®
Secondary PK endpoints included the Cmax calculated at Cycle 1 (Cmax,sd )
Time frame: Cmax, sd: 0 to 336 hours after start of the first infusion.
Population: Overall number of participants Analyzed equals to number of subjects who contributed to summary statistics.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bevacizumab Biosimilar (BEVZ92) | Cmax,sd of BEVZ92 and Avastin® | 120000 ng/mL | Geometric Coefficient of Variation 30 |
| Avastin® (Bevacizumab, Ref. Product). | Cmax,sd of BEVZ92 and Avastin® | 123000 ng/mL | Geometric Coefficient of Variation 27.2 |
Secondary
Cmax,ss of BEVZ92 and Avastin®
Secondary PK endpoints included the Cmax calculated at Cycle 7 (Cmax, ss )
Time frame: Cmax, ss: 0 to 336 hours post-dose after the administration of Cycle 7 infusion (Week 13)
Population: In the Avastin arm there were 3 missing samples at the timepoint required for the specific PK parameter within Cycle 7.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bevacizumab Biosimilar (BEVZ92) | Cmax,ss of BEVZ92 and Avastin® | 195000 ng/mL | Geometric Coefficient of Variation 29.5 |
| Avastin® (Bevacizumab, Ref. Product). | Cmax,ss of BEVZ92 and Avastin® | 200000 ng/mL | Geometric Coefficient of Variation 30.7 |
Secondary
Ctrough,sd of BEVZ92 and Avastin®
Secondary PK endpoints included the Ctrough calculated at Cycle 1 (Ctrough,sd )
Time frame: Ctrough, sd: 0 to 336 hours after start of the first infusion.
Population: In the Avastin arm there was 1 missing samples at the timepoint required for the specific PK parameter within Cycle 1.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bevacizumab Biosimilar (BEVZ92) | Ctrough,sd of BEVZ92 and Avastin® | 344 ng/mL | Geometric Coefficient of Variation 12.5 |
| Avastin® (Bevacizumab, Ref. Product). | Ctrough,sd of BEVZ92 and Avastin® | 349 ng/mL | Geometric Coefficient of Variation 13.7 |
Secondary
Ctrough,ss of BEVZ92 and Avastin®
Secondary PK endpoints included the Ctrough calculated at Cycle 7 (Ctrough,ss)
Time frame: Ctrough, ss: 0 to 336 hours after the administration of the Cycle 7 infusion.
Population: There were 4 missing samples (1 in the BEVZ92 and 3 in the Avastin arm) at the timepoint required for the specific PK parameter within Cycle 7.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bevacizumab Biosimilar (BEVZ92) | Ctrough,ss of BEVZ92 and Avastin® | 69600 ng/mL | Geometric Coefficient of Variation 52.1 |
| Avastin® (Bevacizumab, Ref. Product). | Ctrough,ss of BEVZ92 and Avastin® | 69300 ng/mL | Geometric Coefficient of Variation 50.5 |
Secondary
Elimination Half-life (t1/2) of BEVZ92 and Avastin®
Secondary PK endpoints included the t1/2 calculated at Cycle 7
Time frame: t1/2: 0 to 336 hours after the administration of the Cycle 7 infusion.
Population: In the Avastin arm there were several missing samples at the timepoint required for the specific PK parameter
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bevacizumab Biosimilar (BEVZ92) | Elimination Half-life (t1/2) of BEVZ92 and Avastin® | 294 h | Geometric Coefficient of Variation 33.3 |
| Avastin® (Bevacizumab, Ref. Product). | Elimination Half-life (t1/2) of BEVZ92 and Avastin® | 289 h | Geometric Coefficient of Variation 32.8 |
Secondary
Elimination Rate Constant (Kel) of BEVZ92 and Avastin®
Secondary PK endpoints included the Kel calculated at Cycle 7 (Ctrough,ss)
Time frame: Kel: 0 to 336 hours after the administration of the Cycle 7 infusion.
Population: Overall number of participants Analyzed equals to number of subjects who contributed to summary statistics.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bevacizumab Biosimilar (BEVZ92) | Elimination Rate Constant (Kel) of BEVZ92 and Avastin® | 0.00236 l/h | Geometric Coefficient of Variation 33.3 |
| Avastin® (Bevacizumab, Ref. Product). | Elimination Rate Constant (Kel) of BEVZ92 and Avastin® | 0.00240 l/h | Geometric Coefficient of Variation 32.8 |
Secondary
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.
Time frame: Every four weeks. Up to 48 weeks
Population: Intent-to-treat population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bevacizumab Biosimilar (BEVZ92) | Objective Response Rate (ORR) of BEVZ92 and Avastin® | Stable disease | 27 Participants |
| Bevacizumab Biosimilar (BEVZ92) | Objective Response Rate (ORR) of BEVZ92 and Avastin® | ORR (CR+PR) | 35 Participants |
| Bevacizumab Biosimilar (BEVZ92) | Objective Response Rate (ORR) of BEVZ92 and Avastin® | unevaluable | 5 Participants |
| Bevacizumab Biosimilar (BEVZ92) | Objective Response Rate (ORR) of BEVZ92 and Avastin® | Progressive disease | 4 Participants |
| Avastin® (Bevacizumab, Ref. Product). | Objective Response Rate (ORR) of BEVZ92 and Avastin® | unevaluable | 4 Participants |
| Avastin® (Bevacizumab, Ref. Product). | Objective Response Rate (ORR) of BEVZ92 and Avastin® | ORR (CR+PR) | 40 Participants |
| Avastin® (Bevacizumab, Ref. Product). | Objective Response Rate (ORR) of BEVZ92 and Avastin® | Progressive disease | 2 Participants |
| Avastin® (Bevacizumab, Ref. Product). | Objective Response Rate (ORR) of BEVZ92 and Avastin® | Stable disease | 25 Participants |
Secondary
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.
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.
Population: Intent-to-treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab Biosimilar (BEVZ92) | Progression-free Survival (PFS) of BEVZ92 and Avastin® | 10.8 months |
| Avastin® (Bevacizumab, Ref. Product). | Progression-free Survival (PFS) of BEVZ92 and Avastin® | 11.1 months |
Secondary
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.
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
Population: All patients receiving at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab Biosimilar (BEVZ92) | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any treatment-related TEAE | 63 participants |
| Bevacizumab Biosimilar (BEVZ92) | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any grade >=3 treatment-related TEAE | 63 participants |
| Bevacizumab Biosimilar (BEVZ92) | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any TEAE (any causality) | 66 participants |
| Bevacizumab Biosimilar (BEVZ92) | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any serious TEAE | 19 participants |
| Bevacizumab Biosimilar (BEVZ92) | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any TEAE leading to discontinuation | 13 participants |
| Bevacizumab Biosimilar (BEVZ92) | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any bleeding event | 14 participants |
| Bevacizumab Biosimilar (BEVZ92) | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any grade>=3 TEAE | 44 participants |
| Avastin® (Bevacizumab, Ref. Product). | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any bleeding event | 19 participants |
| Avastin® (Bevacizumab, Ref. Product). | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any TEAE (any causality) | 71 participants |
| Avastin® (Bevacizumab, Ref. Product). | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any grade>=3 TEAE | 49 participants |
| Avastin® (Bevacizumab, Ref. Product). | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any TEAE leading to discontinuation | 6 participants |
| Avastin® (Bevacizumab, Ref. Product). | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any grade >=3 treatment-related TEAE | 70 participants |
| Avastin® (Bevacizumab, Ref. Product). | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any serious TEAE | 21 participants |
| Avastin® (Bevacizumab, Ref. Product). | Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin® | Any treatment-related TEAE | 70 participants |
Secondary
Volume of Distribution (Vd) of BEVZ92 and Avastin®
Secondary PK endpoints included the Vd calculated at Cycle 7
Time frame: Vd: 0 to 336 hours after the administration of the Cycle 7 infusion.
Population: In the Avastin arm there were several missing samples at the timepoint required for the specific PK parameter
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bevacizumab Biosimilar (BEVZ92) | Volume of Distribution (Vd) of BEVZ92 and Avastin® | 4.06 L | Geometric Coefficient of Variation 37.7 |
| Avastin® (Bevacizumab, Ref. Product). | Volume of Distribution (Vd) of BEVZ92 and Avastin® | 3.86 L | Geometric Coefficient of Variation 39.4 |