A Study of Avastin (Bevacizumab) Added to Interferon Alfa-2a (Roferon) Therapy in Patients With Metastatic Renal Cell Cancer With Nephrectomy

Study Overview
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Brief Summary
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This 2-arm study will evaluate the efficacy and safety of Avastin versus placebo in combination with Roferon as first-line treatment in participants with metastatic renal cell cancer (clear cell type) who have had nephrectomy. The anticipated time of study treatment is 1-2 years, and the target sample size is greater than (>)500 individuals.

Official Title
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A Randomised, Double-blind Study to Evaluate the Efficacy and Safety of Avastin Plus Roferon Compared With Placebo Plus Roferon on Overall Survival and Tumor Assessment in Nephrectomised Patients With Metastatic Clear Cell Renal Cell Carcinoma

Conditions
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Renal Cell Cancer

Intervention / Treatment
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* Drug: Bevacizumab [Avastin]
* Drug: Interferon alfa 2a [Roferon]
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: metastatic renal cell cancer (clear cell type); nephrectomy; absence of proteinuria. Exclusion Criteria: prior systemic treatment for metastatic renal cell cancer; major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to study treatment start; presence of brain metastases or spinal cord compression; ongoing need for full dose anticoagulants; uncontrolled hypertension; clinically significant cardiovascular disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bevacizumab + IFN-Alfa-2A<br>Bevacizumab infusions will be administered every 2 weeks at a dose of 10 milligram per kilogram (mg/kg) for 52 weeks or until disease progression or unacceptable toxicity. Interferon alfa-2a (IFN-Alfa-2A) will be administered 3 times per week as a subcutaneous injection at a dose of 9 million international units (MIU) for 52 weeks or until disease progression or major toxicity. | Drug: Bevacizumab [Avastin]<br>* 10 mg/kg IV every 2 weeks<br>Drug: Interferon alfa 2a [Roferon]<br>* 9 MIU SC 3 times/week<br>|
| Placebo Comparator: Placebo + IFN-Alfa-2A<br>Placebo matched with Bevacizumab infusions will be administered every 2 weeks for 52 weeks or until disease progression or unacceptable toxicity. IFN-Alfa-2A will be administered 3 times per week as a subcutaneous injection at a dose of 9 MIU for 52 weeks or until disease progression or major toxicity. | Drug: Interferon alfa 2a [Roferon]<br>* 9 MIU SC 3 times/week<br>Drug: Placebo<br>* IV every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Died |  | Baseline up to 4.25 years | 
| Overall Survival (OS) Duration | Duration of survival was defined as the time between the date of randomization and date of death due to any cause. Participants still alive at the time of analysis were censored at the date they were last known to be alive. Kaplan-Meier estimates were used for analysis. | Baseline until death (up to 4.25 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Disease Progression or Death | Progressive disease was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. | Baseline until disease progression or death, whichever occurred first (assessed at baseline, Weeks 8, 16, 24, 32, 44, 56, 68 thereafter every 12 weeks up to week 104 and then every 6 months up to 4.25 years) | 
| Progression Free Survival (PFS) According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | Progression-free survival was defined as the time between the date of randomization and the first date of documented progression or date of death due to any cause, whichever occurred first. Tumor assessment was performed using modified RECIST. Progressive disease was defined as at least a 20 percentage(%) increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. Participants without an event were censored at the date of last follow-up for progression or date of last available tumor measurement if no follow-up assessment for progression was performed. Participants who were randomized but not exposed to study drug and had no further follow-up were censored on the day of randomization. | Baseline until disease progression or death, whichever occurred first (assessed at baseline, Weeks 8, 16, 24, 32, 44, 56, 68 thereafter every 12 weeks up to week 104 and then every 6 months up to 4.25 years) | 
| Time to Progression (TTP) According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | Time to progression was defined as the time between date of randomization and date of documented progression. Tumor assessment was performed using mRECIST. Progressive disease was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. Participants without an event (including participants who died before progressive disease) were censored at the date of last follow-up for progression or date of last available tumor measurement if no follow-up assessment for progression was performed. Participants who were randomized but not exposed to study drug and had no further follow-up were censored on the day of randomization. | Baseline until disease progression or death, whichever occurred first (assessed at baseline, Weeks 8, 16, 24, 32, 44, 56, 68 thereafter every 12 weeks up to week 104 and then every 6 months up to 4.25 years) | 
| Percentage of Participants With Treatment Failure | Treatment failure is defined as insufficient therapeutic response (including disease progression), death, withdrawal of treatment due to adverse events or laboratory abnormality, or withdrawal of informed consent. Tumor assessment was performed using mRECIST. Progressive disease was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. | Baseline until disease progression or death, whichever occurred first (assessed at baseline, Weeks 8, 16, 24, 32, 44, 56, 68 thereafter every 12 weeks up to week 104 and then every 6 months up to 4.25 years) | 
| Time to Treatment Failure (TTF) According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | Time to treatment failure was defined as the time between the date of randomization and the date of insufficient therapeutic response (including disease progression), death, withdrawal of treatment due to adverse events or laboratory abnormality, or withdrawal of informed consent. Tumor assessment was performed using mRECIST. Progressive disease was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. Participants without an event were censored at the date of last tumor assessment or last treatment administration, whichever occurred last. Participants who were randomized but not exposed to study drug and had no further follow-up were censored on the day of randomization. | Baseline until disease progression or death, whichever occurred first (assessed at baseline, Weeks 8, 16, 24, 32, 44, 56, 68 thereafter every 12 weeks up to week 104 and then every 6 months up to 4.25 years) | 
| Percentage of Participants With Objective Response According to mRECIST | Objective response referred to participants with complete response (CR) or partial response (PR). CR: disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. PR: greater than or equal to (>=) 30% decrease in sum of the longest diameter (LD) of all target lesions taking as reference the screening sum LD. To be assigned a status of PR or CR, changes in tumor measurements had to be confirmed by repeat assessments that should have been performed no less than 4 weeks after the criteria for response were first met. Longer intervals as determined by the study protocol were also appropriate. | Baseline until disease progression or death, whichever occurred first (assessed at baseline, Weeks 8, 16, 24, 32, 44, 56, 68 thereafter every 12 weeks up to week 104 and then every 6 months up to 4.25 years) | 
| Percentage of Participants With Best Overall Response According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) | Best response recorded from the start of treatment until disease progression. Based on assessment of CR, PR, stable disease (SD), or progressive disease (PD), according to mRECIST. CR: disappearance of all target lesions, non-target lesions, and normalization of tumor marker level. PR: >=30% decrease under baseline of the sum of the LD of all target lesions. CR and PR persist on repeat imaging study at least 4 weeks after initial documentation. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Reference is the smallest sum LD. PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions and/or the unequivocal progression of existing non-target lesions. | Baseline until disease progression or death, whichever occurred first (assessed at baseline, Weeks 8, 16, 24, 32, 44, 56, 68 thereafter every 12 weeks up to week 104 and then every 6 months up to 4.25 years) | 
| Change From Baseline in Karnofsky Performance Status | Karnofsky performance score is used to quantify participant's general well-being and activities of daily life and participants were classified based on their functional impairment. Karnofsky performance score is 11 level score which ranges between 0 (death) to 100 (no evidence of disease). Higher score means higher ability to perform daily tasks. | Baseline, Week 7, 15, 23, 31, 43 |