A Phase 3 interventional study of Bevacizumab + FOLFIRI-3 in Metastatic Colorectal Cancer, sponsored by AryoGen Pharmed Co.. Completed at 22 sites in Iran, Islamic Republic of. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2021-01-22.
Sponsored by AryoGen Pharmed Co. · Phase 3, Interventional, and Treatment
This is a Phase III, randomized, two arms, double-blind (patient and assessor blinded), parallel active non inferiority controlled clinical trial with a 2:1 allocation. This trial was conducted to evaluate the efficacy and safety of bevacizumab (produced by AryoGen Pharmed) plus FOLFIRI-3 compared with bevacizumab (Avastin®) plus FOLFIRI-3 in patients with metastatic colorectal cancer (mCRC). Patients who met the following criteria could be recruited to receive the mentioned intervention randomly. Inclusion criteria: male or female aged 18-75 years, mCRC verified histologically, Having one or more bi-dimensionally measurable lesions as defined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria, Was not felt to be amenable to curative resection, With an (ECOG) performance status of ≤ 1, Life expectancy of longer than 3 months, Adequate organ and marrow function, May have received adjuvant therapy for primary colorectal cancer provided that at least 6 months have elapsed from the time the adjuvant therapy was concluded and recurrent disease was documented, Patients with history of hypertension must be well-controlled (blood pressure less than/equal to 150/100), on a stable regimen of anti-hypertensive therapy.
This is a Phase III, randomized, two arms, double-blind (patient and assessor blinded), parallel active non inferiority controlled clinical trial with a 2:1 allocation. This trial was conducted to evaluate the efficacy and safety of bevacizumab (produced by AryoGen) plus FOLFIRI-3 compared with bevacizumab (Avastin®) plus FOLFIRI-3 in patients with metastatic colorectal cancer (mCRC). Patients who met the following criteria could be recruited to receive the mentioned intervention randomly. Inclusion criteria: male or female aged 18-75 years, mCRC verified histologically, Having one or more bi-dimensionally measurable lesions as defined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria, Was not felt to be amenable to curative resection, With an (ECOG) performance status of ≤ 1, Life expectancy of longer than 3 months, Adequate organ and marrow function, May have received adjuvant therapy for primary colorectal cancer provided that at least 6 months have elapsed from the time the adjuvant therapy was concluded and recurrent disease was documented, Patients with history of hypertension must be well-controlled (blood pressure less than/equal to 150/100), on a stable regimen of anti-hypertensive therapy. Exclusion criteria: Prior targeted therapy for mCRC, Radiotherapy or surgery for mCRC less than 4 weeks before random assignment, Undergone major surgical procedures or open biopsy within 28 days before the initiation of study treatment, Experienced significant traumatic injury, within 28 days before study entry, Currently using or had recently used therapeutic anticoagulants, thrombolytic therapy, chronic, daily treatment with aspirin (higher than 325 mg/daily), Proteinuria exceeding 500mg/24 h, History or presence of central nervous system metastases, Female patients who are pregnant or lactating, Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab, irinotecan, 5-FU, or leucovorin, Serious non-healing wound, ulcer, or active bone fracture, Myocardial infarction within 6 months before of study enrollment, History of stroke within 6 months before of study enrollment, Unstable symptomatic arrhythmia requiring medication, Clinically significant peripheral vascular disease, Uncontrolled diabetes; Serious active or uncontrolled infection, Inability to comply with study and/or follow-up procedures. The primary endpoint is progression-free survival and overall survival, Objective Response rate, time of treatment failures, adverse events and immunogenicity will be assessed as secondary outcomes.
Adequate organ and marrow function as defined below:
Exclusion Criteria:
Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.
Drug: Bevacizumab + FOLFIRI-3
Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.
Drug: Bevacizumab + FOLFIRI-3
Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.
Also known as: FOLFIRI-3 = irinotecan + calcium folinate + 5-fluorouracil
Progression Free Survival (PFS)
PFS is defined as the time from the date of randomization to the first date of documentation progression (per investigator assessment) or death as a result of any cause.
Time frame: PFS was measured from the start of chemotherapy to the date of disease progression or to the date of death if no progression whichever came first, assessed up to 12 months
Overall Survival (OS)
Overall survival OS was defined as the time from date of randomization to date of death due to any cause
Time frame: Up to 12 months
Objective Response Rate
Tumor response was defined as partial and complete responses, according to the RECIST criteria ( version 1.1). The definitions were as follows: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), decrease of at least 30% in the lesion that has the largest diameter; Objective Response Rate (ORR) = CR + PR.
Time frame: Up to 12 months
Time to Treatment Failure
Time to treatment failure was defined as the time from the date of randomization to the date of each of the following, * The treatment modalities did not destroy or modify the cancer cells, * The tumor either became larger (disease progression) or stayed the same size after treatment, * Death due to any cause, * Discontinuation of treatment
Time frame: Up to 12 months
Incidence of the Adverse Events
Safety was assessed on the basis of reports of adverse events, laboratory-test results, and vital sign measurements. Adverse events were categorized According to the Common Toxicity Criteria of the National Cancer Institute, version 5.0, in which a grade of 1 indicates mild adverse events, a grade of 2 moderate adverse events, a grade of 3 serious adverse events, and a grade of 4 life-threatening adverse events
Time frame: Up to 12 months
Number of Positive Anti-drug Antibody (ADA) Samples Among Patients (Immunogenicity)
Anti-drug antibody assessment
Time frame: Up to 12 months
| Milestone | Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) |
|---|---|---|
| Started | 82 | 44 |
| Patients receiving medication | 80 | 44 |
| Completed | 72 | 40 |
| Not completed | 10 | 4 |
| Withdrew: Protocol violation | 10 | 4 |
PFS is defined as the time from the date of randomization to the first date of documentation progression (per investigator assessment) or death as a result of any cause.
| Day | Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) |
|---|---|---|
| Progression Free Survival (PFS) | 232 ± NA | 210 ± 12.21 |
Overall survival OS was defined as the time from date of randomization to date of death due to any cause
| Participants | Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) |
|---|---|---|
| Overall Survival (OS) | 30 | 17 |
Tumor response was defined as partial and complete responses, according to the RECIST criteria ( version 1.1). The definitions were as follows: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), decrease of at least 30% in the lesion that has the largest diameter; Objective Response Rate (ORR) = CR + PR.
| Participants | Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) |
|---|---|---|
| Objective Response Rate | 17 | 5 |
Time to treatment failure was defined as the time from the date of randomization to the date of each of the following, * The treatment modalities did not destroy or modify the cancer cells, * The tumor either became larger (disease progression) or stayed the same size after treatment, * Death due to any cause, * Discontinuation of treatment
| Day | Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) |
|---|---|---|
| Time to Treatment Failure | 73 ± 9.39 | 73 ± 9.12 |
Safety was assessed on the basis of reports of adverse events, laboratory-test results, and vital sign measurements. Adverse events were categorized According to the Common Toxicity Criteria of the National Cancer Institute, version 5.0, in which a grade of 1 indicates mild adverse events, a grade of 2 moderate adverse events, a grade of 3 serious adverse events, and a grade of 4 life-threatening adverse events
| Participants | Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) |
|---|---|---|
| Incidence of the Adverse Events | 76 | 44 |
Anti-drug antibody assessment
| Participants | Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) |
|---|---|---|
| Number of Positive Anti-drug Antibody (ADA) Samples Among Patients (Immunogenicity) | 1 | 1 |
Collected over Up to 12 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | 30/82 (36.6%) | 31/80 (38.8%) | 75/80 (93.8%) |
| Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) | 17/44 (38.6%) | 17/44 (38.6%) | 42/44 (95.5%) |
| Event | Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) |
|---|---|---|
| Disease progressionGeneral disorders | 25/80 | 15/44 |
| Myocardial infarctionCardiac disorders | 1/80 | 1/44 |
| SepsisInfections and infestations | 0/80 | 1/44 |
| Abdominal infectionInfections and infestations | 1/80 | 0/44 |
| Acute kidney injuryRenal and urinary disorders | 1/80 | 0/44 |
| Gastrointestinal haemorrhageGastrointestinal disorders | 1/80 | 0/44 |
| Opioid abusePsychiatric disorders | 1/80 | 0/44 |
| PerforationGeneral disorders | 1/80 | 0/44 |
| PeritonitisGastrointestinal disorders | 1/80 | 0/44 |
| PneumoniaInfections and infestations | 1/80 | 0/44 |
| Event | Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) |
|---|---|---|
| AnaemiaBlood and lymphatic system disorders | 62/80 | 37/44 |
| HyperglycaemiaEndocrine disorders | 43/80 | 28/44 |
| LeukopeniaBlood and lymphatic system disorders | 22/80 | 19/44 |
| NeutropeniaBlood and lymphatic system disorders | 25/80 | 15/44 |
| Aspartate aminotransferase increasedInvestigations | 24/80 | 9/44 |
| Alanine aminotransferase increasedInvestigations | 22/80 | 9/44 |
| ProteinuriaRenal and urinary disorders | 18/80 | 12/44 |
| International normalised ratio increasedInvestigations | 20/80 | 11/44 |
| Blood bilirubin increasedInvestigations | 10/80 | 9/44 |
| HyponatraemiaMetabolism and nutrition disorders | 8/80 | 9/44 |
| Age, Continuous(years) | Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) | Total |
|---|---|---|---|
| Mean | 56.26 ± 11.94 | 56.27 ± 13.12 | 56.26 ± 12.31 |
| Sex: Female, Male(Participants) | Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) | Total |
|---|---|---|---|
| Female | 31 | 15 | 46 |
| Male | 51 | 29 | 80 |
| Race (NIH/OMB)(Participants) | Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 |
| White | 82 | 44 | 126 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
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AryoGen Pharmed Co.