Metastatic Colorectal Cancer
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGBevacizumab + 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.
Sponsors
AryoGen Pharmed Co.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Are male or female aged 18-75 years at the time of signing the informed consent form. * Have been diagnosed as 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 Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 * Life expectancy of longer than 3 months ( clinical assessment) * Adequate organ and marrow function as defined below: * Absolute neutrophil count (ANC) greater than/equal to 1,500/mm3; * Platelets greater than/equal to 100,000/ mm3; * Hemoglobin greater than/equal to 9 gm/dl (may be transfused to maintain or exceed this level); * Total bilirubin less than/equal to 1.5 within institutional upper limit of normal (IULN); * Aspartate aminotransferase (AST or SGOT)/alanine aminotransferase (ALT or SGPT) less than/equal to 2.5 times IULN, or less than/equal to 5 times IULN if known liver metastases; * 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). (Patients may have prophylactic use of low molecular weight heparin, however therapeutic use of heparin or low molecular weight heparin is not acceptable) * 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; * Clinically significant peripheral vascular disease; * Uncontrolled diabetes; Serious active or uncontrolled infection * Inability to comply with study and/or follow-up procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 12 months | Overall survival OS was defined as the time from date of randomization to date of death due to any cause |
| Objective Response Rate | Up to 12 months | 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 to Treatment Failure | Up to 12 months | 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 |
| Incidence of the Adverse Events | Up to 12 months | 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 |
| Number of Positive Anti-drug Antibody (ADA) Samples Among Patients (Immunogenicity) | Up to 12 months | Anti-drug antibody assessment |
Countries
Iran
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.
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. | 82 |
| Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.
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. | 44 |
| Total | 126 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 10 | 4 |
Baseline characteristics
| Characteristic | Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) | Total | Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) |
|---|---|---|---|
| Age, Continuous | 56.27 years STANDARD_DEVIATION 13.12 | 56.26 years STANDARD_DEVIATION 12.31 | 56.26 years STANDARD_DEVIATION 11.94 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 44 Participants | 126 Participants | 82 Participants |
| Sex: Female, Male Female | 15 Participants | 46 Participants | 31 Participants |
| Sex: Female, Male Male | 29 Participants | 80 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 30 / 82 | 17 / 44 |
| other Total, other adverse events | 75 / 80 | 42 / 44 |
| serious Total, serious adverse events | 31 / 80 | 17 / 44 |
Outcome results
Primary
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
Population: The population assessable for PFS was per protocol.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Progression Free Survival (PFS) | 232 Day | — |
| Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) | Progression Free Survival (PFS) | 210 Day | Standard Error 12.21 |
p-value: 0.4790% CI: [0.46, 1.35]Regression, Cox
Secondary
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
Population: A total of 124 patients were analyzed for AEs. since two patients did not receive study medication and were not included in the safety population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Incidence of the Adverse Events | 76 Participants |
| Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) | Incidence of the Adverse Events | 44 Participants |
p-value: >0.05Fisher's Exact Test
Secondary
Number of Positive Anti-drug Antibody (ADA) Samples Among Patients (Immunogenicity)
Anti-drug antibody assessment
Time frame: Up to 12 months
Population: Positive ADA was reported in two patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Number of Positive Anti-drug Antibody (ADA) Samples Among Patients (Immunogenicity) | 1 Participants |
| Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) | Number of Positive Anti-drug Antibody (ADA) Samples Among Patients (Immunogenicity) | 1 Participants |
Secondary
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
Population: Both baseline imaging and imaging at the time of withdrawal, could not be gathered in all patients. So ORR could be reported in the mentioned population in each treatment group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Objective Response Rate | 17 Participants |
| Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) | Objective Response Rate | 5 Participants |
p-value: 0.17Fisher's Exact Test
Secondary
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
Population: ITT population was used in this outcome analysis. The probability of overall survival in this study was higher than 50% in one year, so the calculation of median was not applicant.~The number of death in both arms is reported.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Overall Survival (OS) | 30 Participants |
| Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) | Overall Survival (OS) | 17 Participants |
p-value: 0.9995% CI: [0.55, 1.8]Regression, Cox
Secondary
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
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab) | Time to Treatment Failure | 73 Day | Standard Error 9.39 |
| Bevacizumab + FOLFIRI-3 (Roche Bevacizumab) | Time to Treatment Failure | 73 Day | Standard Error 9.12 |
p-value: 0.5995% CI: [0.76, 1.61]Regression, Cox