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Safety and Efficacy of Bevacizumab Plus RAD001 Versus Interferon Alfa-2a and Bevacizumab for the First-line Treatment in Adult Patients With Kidney Cancer

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ClinicalTrials.gov Identifier: NCT00719264
Recruitment Status : Completed
First Posted : July 21, 2008
Results First Posted : May 7, 2014
Last Update Posted : March 20, 2017
Sponsor:
Collaborator:
Roche Pharma AG
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE July 15, 2008
First Posted Date  ICMJE July 21, 2008
Results First Submitted Date  ICMJE April 4, 2014
Results First Posted Date  ICMJE May 7, 2014
Last Update Posted Date March 20, 2017
Actual Study Start Date  ICMJE November 12, 2008
Actual Primary Completion Date December 31, 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 4, 2014)
Progression-free Survival (PFS) of Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab [ Time Frame: Time from randomization to the date of radiological progressive disease as per independent central review, death from any cause, or last tumor assessment, reported between date of first participant randomized until 31Dec2011, cutoff date. ]
Tumor response and disease progression were assessed using response evaluation criteria in solid tumors (RECIST), version 1.0. All target and non-target lesions identified at baseline were assessed using the same method, CT scan with contrast or MRI with contrast, throughout the trial. All scans were reviewed by independent, central radiology. Disease progression was defined as: 1) a 20% increase in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameters of all target lesions recorded at or after baseline or 2) the appearance of a new lesions or 3) the unequivocal progression of non-target lesions overall.
Original Primary Outcome Measures  ICMJE
 (submitted: July 18, 2008)
CT/MRI scans
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 4, 2014)
  • Overall Survival (OS) Treatment Effect in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab [ Time Frame: Time from randomization to the date of death from any cause, reported between date of first participant randomized and up to 2 years after the last participant randomized (data cutoff: 30Aug2012) ]
    Overall survival (OS) was defined as the time of randomization to the date of death due to any cause.
  • Best Overall Response in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab [ Time Frame: Time from first participant randomized until 31Dec2011, cutoff date. ]
    Overall response is defined as the number of participants having achieved confirmed Complete Response (CR) + Partial Response (PR). Confirmed CR = at least two determinations of CR at least 4 weeks apart before progression. Confirmed PR = at least two determinations of PR or better at least 4 weeks apart before progression. CR required a disappearance of all target and non-target lesions. PR required at least a 30% decrease in the sum of the longest diameters of all target lesions, taking as a reference the baseline sum of the longest diameters. Disease progression was defined as: 1) a 20% increase in the sum of the longest diameter of all target lesions, taking as reference the smallest sum of the longest diameters of all target lesions recorded at or after baseline or 2) the appearance of a new lesions or 3) the unequivocal progression of non-target lesions overall.
  • Response Duration Differences in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab [ Time Frame: Time from first documented response date of radiological progressive disease as per independent central review, death due to underlying cancer, or last tumor assessment, reported between date of first participant randomized until 31Dec2011, cut-off date. ]
    The duration of response, applied only to participants with best overall response at CR or PR, is defined as the number of days between the date of first documented response (CR or PR) and the date of the event: radiological progression as per central review or death due to underlying cancer, whichever occurs first. If no event, participant is censored at the last adequate assessment.
  • Number of Participants Who Experienced Adverse Events (AEs), Serious Adverse Events and Deaths [ Time Frame: From the first participant randomized until the last patient discontinued the study treatment + 28 days ]
    Participants were monitored for adverse events, serious adverse events and deaths throughout the study. Participants were assessed continuously at each 28-day cycle.
  • Time to Definitive Deterioration of the Functional Assessment of Cancer Therapy Kidney Symptom Index, Disease Related Symptoms (FKSI-DRS) Risk Score by at Least 2 Score Units [ Time Frame: Time from randomization to the date of definitive deterioration (defined as no later increase above the threshold observed during the study), or date of last assessment, reported between date of first patient randomized until 31Dec2011 ]
    The analysis of this outcome measure was based on the FKSI-DRS scale which is a validated disease-related symptom index containing 9 items that measure symptoms predominantly related to kidney cancer. Each item is scored on a 5-point scale (0 = not at all; 4 = very much). If at least 5 of the 9 questions have been answered, the FKSI-DRS total score is calculated by subtracting nine times the mean of the scores of the answered items from 36. Participants with less than 5 out of the 9 questions answered will have a missing FKSI-DRS total score. The FKSI-DRS total score ranges from 0 (most severe symptoms) to 36 (no symptoms). Definitive deterioration is defined as a decrease by at least 2 units compared to baseline, with no later increase above this threshold observed during the study. A single measure reporting a decrease of at least 2 units was considered definitive only if it is the last one available for the participant.
  • Time to Definitive Deterioration of the Global Health Status and the Physical Functioning (PF) Subscale Scores of the European Organization for the Research and Treatment of Cancer (EORTC)-Core Quality of Life Questionnaire (QLQ-C30) by at Least 10% [ Time Frame: Time from randomization to the date of definitive deterioration (defined as no later increase above the threshold observed during the study), or date of last assessment, reported between date of first participant randomized until 31Dec2011 ]
    The EORTC QLQ-C30 contains 30 items. These include five functional scales (physical, role, emotional, social and cognitive functioning), three symptom scales (fatigue, pain, nausea, and vomiting), a global health status/QoL scale, and six single items (dyspnea, diarrhea, constipation, anorexia, insomnia and financial impact). The PF subscale consists of 5 questions each scored from 1 (not at all) to 4 (very much). The score for the PF subscale and global health status range from 0 to 100, with a higher score representing a high level of functioning/high quality of life. Definitive deterioration by at least 10% is defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study. A single measure reporting a decrease of at least 10% is considered definitive only if it is the last one available for the participant.
  • Duration of Exposure of RAD001 in Participants Randomized to the Treatment Combination of RAD001 and Bevacizumab [ Time Frame: From the date of the first participant treated until the last patient discontinued the study treatment + 28 days ]
    This outcome measure was assessed continuously.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 18, 2008)
PRO
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of Bevacizumab Plus RAD001 Versus Interferon Alfa-2a and Bevacizumab for the First-line Treatment in Adult Patients With Kidney Cancer
Official Title  ICMJE A Randomized, Open-label, Multi-center Phase II Study to Compare Bevacizumab Plus RAD001 Versus Interferon Alfa-2a Plus Bevacizumab for the First-line Treatment of Patients With Metastatic Clear Cell Carcinoma of the Kidney
Brief Summary To estimate the difference in efficacy and safety of bevacizumab and RAD001 compared to bevacizumab and interferon alfa-2a for first-line treatment of patients with metastatic carcinoma of the kidney.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Carcinoma
  • Adenocarcinoma
  • Renal Cell
  • Nephroid Carcinoma
  • Hypernephroid
Intervention  ICMJE
  • Drug: RAD001(everolimus)
    10 mg qd
    Other Name: Afinitor
  • Drug: interferon alfa-2a
    dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3
  • Drug: bevacizumab
    10 mg/kg every 2 weeks
Study Arms  ICMJE
  • Experimental: bevacizumab, RAD001 (everolimus)
    Participants received oral everolimus 10 mg qd plus intravenous bevacizumab 10mg/kg every 2 weeks
    Interventions:
    • Drug: RAD001(everolimus)
    • Drug: bevacizumab
  • Active Comparator: bevacizumab, interferon alfa-2a (IFN)
    Participants received subcutaneous IFN dose escalated from 3 MIU (million international unit) during week 1, 6 MIU during week 2, and 9 MIU during week 3 of treatment and subsequently (if tolerated), 3 times per week plus intravenous bevacizumab 10 mg/kg every 2 weeks
    Interventions:
    • Drug: interferon alfa-2a
    • Drug: bevacizumab
Publications * Ravaud A, Barrios CH, Alekseev B, Tay MH, Agarwala SS, Yalcin S, Lin CC, Roman L, Shkolnik M, Anak O, Gogov S, Pelov D, Louveau AL, Melichar B. RECORD-2: phase II randomized study of everolimus and bevacizumab versus interferon α-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma. Ann Oncol. 2015 Jul;26(7):1378-84. doi: 10.1093/annonc/mdv170. Epub 2015 Apr 7.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 4, 2014)
365
Original Estimated Enrollment  ICMJE
 (submitted: July 18, 2008)
360
Actual Study Completion Date  ICMJE April 15, 2013
Actual Primary Completion Date December 31, 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients with metastatic renal cell carcinoma
  2. Patients with at least one measurable lesion
  3. Patients with progressive metastatic renal cell carcinoma
  4. Patients who had a prior partial or complete nephrectomy
  5. Patients with a Karnofsky Performance Status ≥70%.
  6. Adequate bone marrow function
  7. Adequate liver function
  8. Adequate renal function
  9. Adequate coagulation profile

Exclusion Criteria:

  1. 4 weeks post-major surgery
  2. Patients who had radiation therapy within 28 days prior to start of study
  3. Patients in need for major surgical procedure during the course of the study.
  4. Patients with a serious non-healing wound, ulcer, or bone fracture.
  5. Patients with a history of seizure(s) not controlled with standard medical therapy.
  6. Patients who have received prior systemic treatment for their metastatic RCC.
  7. Patients who received prior therapy with VEGF pathway inhibitor
  8. Patients who have previously received systemic mTOR inhibitors
  9. Patients with a known hypersensitivity RAD001 (everolimus) or other rapamycins or to its excipients.
  10. Patients with history or current central nervous system (CNS) metastases or spinal cord compression.
  11. Patients with a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment.
  12. Patients with proteinuria at screening.
  13. Patients with inadequately controlled hypertension
  14. Patients receiving ongoing or with recent need for full therapeutic dose of oral or parenteral anticoagulants or chronic daily treatment with aspirin
  15. Patients receiving chronic systemic treatment with corticosteroids or another immunosuppressive agent.
  16. Patients with a known history of HIV
  17. Patients with hypersensitivity to interferon alfa-2a or any component of the product.
  18. Patients with an active, bleeding diathesis or coagulopathy or recurrent thromboembolism
  19. Patients who have any severe and/or uncontrolled medical conditions or other conditions
  20. Left Ventricular Ejection Fraction < lower limit of institutional normal assessed by ECHO or MUGA
  21. Patients who have a history of another primary malignancy ≤ 3 years
  22. Female patients who are pregnant or breast feeding
  23. Patients who are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to study treatment start.
  24. Patients unwilling to or unable to comply with the protocol

Other protocol-defined inclusion/exclusion criteria may apply

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Brazil,   Czech Republic,   Egypt,   France,   Germany,   Hong Kong,   Hungary,   Italy,   Korea, Republic of,   Netherlands,   Russian Federation,   Singapore,   South Africa,   Spain,   Switzerland,   Taiwan,   Thailand,   Turkey,   United Kingdom,   United States
Removed Location Countries Slovakia
 
Administrative Information
NCT Number  ICMJE NCT00719264
Other Study ID Numbers  ICMJE CRAD001L2201
2008-000077-38 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Roche Pharma AG
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date February 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP