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NCT00719264

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

Completed Phase 2 Results posted Last updated 20 March 2017
What this trial tests

Phase 2 trial testing RAD001(everolimus) in Carcinoma in 365 participants. Completed in 15 April 2013.

Timeline
12 November 2008
Primary endpoint
31 December 2011
15 April 2013

Quick facts

Lead sponsorNovartis Pharmaceuticals
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment365
Start date12 November 2008
Primary completion31 December 2011
Estimated completion15 April 2013
Sites109 locations across Hong Kong, Italy, Taiwan, South Korea, Netherlands, Russia, Turkey (Türkiye), Belgium

Drugs / interventions tested

Conditions studied

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

18 and older, any sex, with Carcinoma or Adenocarcinoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Progression-free Survival (PFS) of Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab Primary · 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 ne

GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)9.38.1 – 11.2
Bevacizumab, Interferon Alfa-2a (IFN)10.08.3 – 12.9
Overall Survival (OS) Treatment Effect in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab Secondary · 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.

GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)27.119.9 – 35.3
Bevacizumab, Interferon Alfa-2a (IFN)27.120.4 – 30.8
Best Overall Response in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab Secondary · 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% inc

Complete response (CR)
GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)0
Bevacizumab, Interferon Alfa-2a (IFN)1
Partial response (PR)
GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)49
Bevacizumab, Interferon Alfa-2a (IFN)50
Stable disease (SD)
GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)90
Bevacizumab, Interferon Alfa-2a (IFN)84
Progressive disease (PD)
GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)25
Bevacizumab, Interferon Alfa-2a (IFN)26
Unknown response
GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)18
Bevacizumab, Interferon Alfa-2a (IFN)22
Overall objective response (CR+PR)
GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)49
Bevacizumab, Interferon Alfa-2a (IFN)51
Response Duration Differences in Participants Who Received RAD001 Plus Bevacizumab Versus Participants Who Received IFN Plus Bevacizumab Secondary · 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.

GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)13.310.7 – 16.7
Bevacizumab, Interferon Alfa-2a (IFN)11.310.4 – NA
Number of Participants Who Experienced Adverse Events (AEs), Serious Adverse Events and Deaths Secondary · 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.

Adverse events (serious and non-serious)
GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)179
Bevacizumab, Interferon Alfa-2a (IFN)180
Serious adverse events
GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)79
Bevacizumab, Interferon Alfa-2a (IFN)76
Deaths
GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)93
Bevacizumab, Interferon Alfa-2a (IFN)95
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 Secondary · 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

GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)7.44.7 – 10.8
Bevacizumab, Interferon Alfa-2a (IFN)8.03.7 – 11.5
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% Secondary · 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 deterioratio

Global health status/QoL
GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)7.45.3 – 12.0
Bevacizumab, Interferon Alfa-2a (IFN)7.85.6 – 10.2
Physical functioning
GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)8.55.6 – 13.8
Bevacizumab, Interferon Alfa-2a (IFN)9.06.5 – 12.9
Duration of Exposure of RAD001 in Participants Randomized to the Treatment Combination of RAD001 and Bevacizumab Secondary · From the date of the first participant treated until the last patient discontinued the study treatment + 28 days

This outcome measure was assessed continuously.

GroupValue95% CI
Bevacizumab, RAD001 (Everolimus)37.02 – 190

Adverse events — posted to ClinicalTrials.gov

Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Bevacizumab, RAD001 (Everolimus)
Serious: 79/180 (44%)
Deaths:
Bevacizumab, Interferon Alfa-2a (IFN)
Serious: 76/181 (42%)
Deaths:

Serious adverse events (187 terms)

ReactionSystemBevacizumab, RAD001 (Evero…Bevacizumab, Interferon Al…
ANAEMIABlood and lymphatic system disorders
ABDOMINAL PAINGastrointestinal disorders
PNEUMONIAInfections and infestations
DYSPNOEARespiratory, thoracic and mediastinal disorders
DIARRHOEAGastrointestinal disorders
BACK PAINMusculoskeletal and connective tissue disorders
RENAL FAILURERenal and urinary disorders
EPISTAXISRespiratory, thoracic and mediastinal disorders
NAUSEAGastrointestinal disorders
VOMITINGGastrointestinal disorders
GENERAL PHYSICAL HEALTH DETERIORATIONGeneral disorders
SEPSISInfections and infestations
DECREASED APPETITEMetabolism and nutrition disorders
ARTHRALGIAMusculoskeletal and connective tissue disorders
HYPERTENSIONVascular disorders
CARDIAC FAILURECardiac disorders
CARDIAC FAILURE CONGESTIVECardiac disorders
INTESTINAL OBSTRUCTIONGastrointestinal disorders
STOMATITISGastrointestinal disorders
DISEASE PROGRESSIONGeneral disorders
FATIGUEGeneral disorders
PYREXIAGeneral disorders
ANAL ABSCESSInfections and infestations
URINARY TRACT INFECTIONInfections and infestations
BLOOD CREATININE INCREASEDInvestigations
Other adverse events (67 terms — click to expand)

ReactionSystemBevacizumab, RAD001 (Evero…Bevacizumab, Interferon Al…
STOMATITISGastrointestinal disorders
PROTEINURIARenal and urinary disorders
DECREASED APPETITEMetabolism and nutrition disorders
FATIGUEGeneral disorders
DIARRHOEAGastrointestinal disorders
HYPERTENSIONVascular disorders
PYREXIAGeneral disorders
ASTHENIAGeneral disorders
EPISTAXISRespiratory, thoracic and mediastinal disorders
WEIGHT DECREASEDInvestigations
COUGHRespiratory, thoracic and mediastinal disorders
NAUSEAGastrointestinal disorders
OEDEMA PERIPHERALGeneral disorders
RASHSkin and subcutaneous tissue disorders
HYPERCHOLESTEROLAEMIAMetabolism and nutrition disorders
HEADACHENervous system disorders
ARTHRALGIAMusculoskeletal and connective tissue disorders
ANAEMIABlood and lymphatic system disorders
MYALGIAMusculoskeletal and connective tissue disorders
INFLUENZA LIKE ILLNESSGeneral disorders
DYSPNOEARespiratory, thoracic and mediastinal disorders
PRURITUSSkin and subcutaneous tissue disorders
CONSTIPATIONGastrointestinal disorders
THROMBOCYTOPENIABlood and lymphatic system disorders
VOMITINGGastrointestinal disorders
BACK PAINMusculoskeletal and connective tissue disorders
PAIN IN EXTREMITYMusculoskeletal and connective tissue disorders
DEPRESSIONPsychiatric disorders
INSOMNIAPsychiatric disorders
HYPERTRIGLYCERIDAEMIAMetabolism and nutrition disorders
DRY SKINSkin and subcutaneous tissue disorders
NEUTROPENIABlood and lymphatic system disorders
CHILLSGeneral disorders
DYSGEUSIANervous system disorders
BLOOD CREATININE INCREASEDInvestigations
ABDOMINAL PAINGastrointestinal disorders
UPPER RESPIRATORY TRACT INFECTIONInfections and infestations
HYPERGLYCAEMIAMetabolism and nutrition disorders
OROPHARYNGEAL PAINRespiratory, thoracic and mediastinal disorders
TOOTHACHEGastrointestinal disorders

Most-reported serious reactions: ANAEMIA, ABDOMINAL PAIN, PNEUMONIA, DYSPNOEA, DIARRHOEA, BACK PAIN, RENAL FAILURE, EPISTAXIS.

Data from ClinicalTrials.gov NCT00719264 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Trial Watch: Immunostimulatory cytokines.
    Vacchelli E, Galluzzi L, Eggermont A, Galon J, et al · · 2012 · cited 70× · PMID 22754768 · DOI 10.4161/onci.20459
  2. 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.
    Ravaud A, Barrios CH, Alekseev B, Tay MH, et al · · 2015 · cited 60× · PMID 25851632 · DOI 10.1093/annonc/mdv170
  3. Trial watch: Immunostimulatory cytokines in cancer therapy.
    Vacchelli E, Aranda F, Obrist F, Eggermont A, et al · · 2014 · cited 47× · PMID 25083328 · DOI 10.4161/onci.29030
  4. Trial Watch-Immunostimulation with cytokines in cancer therapy.
    Vacchelli E, Aranda F, Bloy N, Buqué A, et al · · 2016 · cited 43× · PMID 27057468 · DOI 10.1080/2162402x.2015.1115942
  5. A method for predicting target drug efficiency in cancer based on the analysis of signaling pathway activation.
    Artemov A, Aliper A, Korzinkin M, Lezhnina K, et al · · 2015 · cited 36× · PMID 26320181 · DOI 10.18632/oncotarget.5119
  6. Targeted therapy for metastatic renal cell carcinoma.
    Hofmann F, Hwang EC, Lam TB, Bex A, et al · · 2020 · cited 29× · PMID 33058158 · DOI 10.1002/14651858.cd012796.pub2
  7. Interferon therapy and its association with depressive disorders - A review.
    Lai JY, Ho JX, Kow ASF, Liang G, et al · · 2023 · cited 28× · PMID 36911685 · DOI 10.3389/fimmu.2023.1048592
  8. First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis.
    Aldin A, Besiroglu B, Adams A, Monsef I, et al · · 2023 · cited 20× · PMID 37146227 · DOI 10.1002/14651858.cd013798.pub2

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing