Neoplasms

Digestive System Diseases

All Conditions

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Hematinics

Vitamins

Bevacizumab

Irinotecan

Leucovorin

Fluorouracil

Levoleucovorin

Oxaliplatin

Folic Acid

Vitamin B Complex

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Topoisomerase I Inhibitors

Enzyme Inhibitors

Antidotes

Protective Agents

Trace Elements

Folinic Acid

Folate

Vitamin B9

Bevacizumab 25 mg/mL (strength: 100 mg/4 mL).

Bevacizumab 25mg/ml (strength: 100mg/4ml)

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.

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 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.

Avastin® (bevacizumab, reference product)

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.

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.

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

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

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%.

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%.

Compare the safety profile by means of the frequency and severity of TEAEs and SAEs reported in each treatment arm.

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).

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.

Secondary PK endpoints included the Cmax calculated at Cycle 1 (Cmax,sd )

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".

Secondary PK endpoints included the Cmax calculated at Cycle 7 (Cmax, ss )

Secondary PK endpoints included the Ctrough calculated at Cycle 1 (Ctrough,sd )

Secondary PK endpoints included the Ctrough calculated at Cycle 7 (Ctrough,ss)

Secondary PK endpoints included the t1/2 calculated at Cycle 7

Secondary PK endpoints included the Kel calculated at Cycle 7 (Ctrough,ss)

Secondary PK endpoints included the Vd calculated at Cycle 7

Laboratorio Elea Phoenix S.A.

Libbs Farmacêutica LTDA

mAbxience Research S.L.

Coded according to Medical Dictionary for Regulatory Activities (version 16.0), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.0).

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).

Bevacizumab Biosimilar (BEVZ92)

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).

Avastin® (Bevacizumab, Ref. Product)

Total

Age, Continuous

Aged

Age, Customized

Sex: Female, Male

Race

Race/Ethnicity, Customized

Describes a patient's ability to selfcare, daily activity and physical ability. Grades:

0. Fully active, able to carry on all pre-disease performance without restriction.

1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.
2. Ambulatory and capable of all selfcare but unable to carry out any work activities; about \>50% of waking hours.
3. Capable of only limited selfcare; confined to bed or chair \>50% of waking hours.
4. Completely disabled; cannot carry on any selfcare; totally confined to bed or chair.
5. Dead.

Eastern Cooperative Oncology Group (ECOG) performance status

The TNM Classification of Malignant Tumors describes the stage of a solid tumor according to:

1. Primary tumour (T)- the size and whether it has invaded nearby tissue, from 0 \[no evidence of tumor\] to 4 \[the highest size and/or extension\]
2. Lymph nodes (N) describes nearby (regional) lymph nodes that are involved, from 0 \[no evidence of tumor\] to 3 \[high extension and numerous lymph nodes\],
3. Metastasis (M) describes distant metastasis, from 0 (no metastases) to 1 (yes). Stage IVa: Any T, Any N, M1a (to the other lung); Stage IVb: Any T, Any N, M1b or M1c ( outside of the chest)

Tumor, lymph Nodes and Metastases (TNM) stage

Missing data for two patients in each treatment arm

Months since diagnosis of metastatic colorectal cancer

Number of target lesions

Extent of disease

Surgery

Radiotherapy

Chemotherapy

Previous treatment

Susana Millan

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%.

Avastin® (bevacizumab, reference product).

Avastin® (Bevacizumab, Ref. Product).

Overall number of participants Analyzed equals to number of subjects who contributed to summary statistics.

Area Under the Concentration-versus-time Curve (AUC) at Cycle 1 (AUC0-336h) of BEVZ92 and Avastin®

Bevacizumab proposed 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).

Bevacizumab reference product: 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).

In the Avastin arm there were 3 missing samples at the timepoint required for the specific PK parameters within Cycle 7.

AUC at Steady State (AUCss) of BEVZ92 and Avastin®

Any TEAE (any causality)

Any grade>=3 TEAE

Any TEAE leading to discontinuation

Any treatment-related TEAE

Any grade >=3 treatment-related TEAE

Any serious TEAE

Any bleeding event

Bevacizumab 25 mg/mL (strength: 100 mg/4 mL).

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).

Bevacizumab 25mg/ml (strength: 100mg/4ml)

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).

All patients receiving at least one dose of study medication.

Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Reported With BEVZ92 and Avastin®

Seroconversion

No seroconversion

Bevacizumab 25mg/ml (strength: 100mg/4ml)

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).

Anti-Drug Antibody (ADA) of BEVZ92 and Avastin®

ORR (CR+PR)

Stable disease

Progressive disease

unevaluable

Objective Response Rate (ORR) of BEVZ92 and Avastin®

Bevacizumab reference product:

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).

Cmax,sd of BEVZ92 and Avastin®

Progression-free Survival (PFS) of BEVZ92 and Avastin®

In the Avastin arm there were 3 missing samples at the timepoint required for the specific PK parameter within Cycle 7.

Cmax,ss of BEVZ92 and Avastin®

In the Avastin arm there was 1 missing samples at the timepoint required for the specific PK parameter within Cycle 1.

Ctrough,sd of BEVZ92 and Avastin®

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.

Ctrough,ss of BEVZ92 and Avastin®

In the Avastin arm there were several missing samples at the timepoint required for the specific PK parameter

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Bioequivalence Study Bevacizumab Biosimilar (BEVZ92) Versus Bevacizumab (AVASTIN®) in First-line Treatment mCRC Patients	NCT02069704	Metastatic Colo...	Bevacizumab bio... Avastin® (bevac...	18 Years -	mAbxience Research S.L.
Bioequivalence Study Bevacizumab Biosimilar (BEVZ92) Versus Bevacizumab (AVASTIN®) in First-line Treatment mCRC Patients	NCT02069704	Metastatic Colo...	Bevacizumab bio... Avastin® (bevac...	18 Years -	mAbxience Research S.L.
Bioequivalence Study Bevacizumab Biosimilar (BEVZ92) Versus Bevacizumab (AVASTIN®) in First-line Treatment mCRC Patients	NCT02069704	Metastatic Colo...	Bevacizumab bio... Avastin® (bevac...	18 Years -	mAbxience Research S.L.

Spots Global Cancer Trial Database for avastin® (bevacizumab, reference product)