Trial record 1 of 1 for:    Randomized Phase III Trial Comparing Everolimus versus Everolimus Plus Bevacizumab
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Everolimus With or Without Bevacizumab in Treating Patients With Advanced Kidney Cancer That Progressed After First-Line Therapy

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01198158
First received: September 8, 2010
Last updated: October 17, 2014
Last verified: July 2014
  Purpose

This randomized phase III trial studies giving everolimus together with bevacizumab to see how well it works compared to everolimus alone in treating patients with advanced kidney cancer that progressed after first-line therapy. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can interfere with tumor growth by blocking the ability of tumor cells to grow and spread. Everolimus and bevacizumab may also stop the growth of kidney cancer by blocking blood flow to the tumor. It is not yet known whether giving everolimus together with bevacizumab is better than everolimus alone in treating patients with advanced kidney cancer that has progressed after first-line therapy.


Condition Intervention Phase
Clear Cell Renal Cell Carcinoma
Recurrent Renal Cell Cancer
Stage III Renal Cell Cancer
Stage IV Renal Cell Cancer
Drug: everolimus
Biological: bevacizumab
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Randomized Phase III Trial Comparing Everolimus Versus Everolimus Plus Bevacizumab for Advanced Renal Cell Carcinoma Progressing After Treatment With Tyrosine Kinase Inhibitors

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Overall survival (OS) [ Time Frame: The time from date of randomization to date of death due to any cause, assessed up to 5.5 years ] [ Designated as safety issue: No ]
    The stratified log-rank statistic will be the primary analysis to compare the two treatment arms on OS adjusting on the stratification factors (number of negative prognostic factors (0, 1, 2-3) and prior VEGFR-TKI therapy (< 12 weeks, >= 12 weeks). The Kaplan-Meier product-limit estimator will be used to estimate the OS distribution. In addition, the proportional hazards model will be used to assess the importance of the treatment arm adjusting on patient characteristics, stratification variables and other important covariates in predicting OS.


Secondary Outcome Measures:
  • Progression-free survival (PFS) [ Time Frame: The time from randomization to disease progression or death from any cause, assessed up to 5.5 years ] [ Designated as safety issue: No ]
    The stratified log-rank statistic will be the primary analysis to compare the two treatment arms on PFS adjusting on the stratification factors (number of negative prognostic factors (0, 1, 2-3) and prior VEGFR-TKI therapy (< 12 weeks, >= 12 weeks). The Kaplan-Meier product-limit estimator will be used to estimate the PFS distribution. In addition, the proportional hazards model will be used to assess the importance of the treatment arm adjusting on patient characteristics, stratification variables and other important covariates in predicting PFS.

  • Objective response rate (defined as confirmed complete response plus partial response) [ Time Frame: Up to 5.5 years ] [ Designated as safety issue: No ]
    Furthermore, the Cochran-Mantel-Haenszel test will be used to compare the two arms on the proportion of patients who experience an objective response (defined as either a confirmed CR or a PR) adjusting on the stratification factors (number of negative prognostic features and prior VEGFR-TKI therapy.

  • Toxicities, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
    The Fisher exact test will be used to compare the two treatment arms on the proportion of patients with unacceptable treatment related grade 3 or higher toxicity.


Other Outcome Measures:
  • Cutpoints for change in biomarker levels [ Time Frame: Baseline to 8 weeks ] [ Designated as safety issue: No ]
    Statistical methods based on exact asymptotic distributions will be used to find a cutpoint (other than the median) for change in each biomarker at 8 weeks from baseline.


Estimated Enrollment: 700
Study Start Date: September 2010
Estimated Primary Completion Date: June 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I (everolimus)
Patients receive everolimus PO QD on days 1-28.
Drug: everolimus
Given PO
Other Names:
  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Experimental: Arm II (everolimus with bevacizumab)
Patients receive everolimus PO QD on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 15.
Drug: everolimus
Given PO
Other Names:
  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

l. To compare the overall survival of patients receiving bevacizumab plus everolimus and everolimus alone among patients with advanced renal cell carcinoma progressing after first line vascular epidermal growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) treatment.

SECONDARY OBJECTIVES:

I. To compare the progression-free survival and proportion who experience an objective response (defined as complete clinical response [cCR] + partial response [PR]) in patients with advanced renal cell carcinoma receiving bevacizumab plus everolimus and everolimus alone.

II. To compare grade 3 or higher toxicity in patients receiving each treatment regimen.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive everolimus orally (PO) once daily (QD) on days 1-28.

ARM II: Patients receive everolimus PO QD on days 1-28 and bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 8 weeks until disease progression and then every 6 months for up to 5.5 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Renal cell carcinoma with some component of clear cell histology
  • Metastatic or unresectable disease
  • Must have been treated with at least 1 prior VEGFR tyrosine kinase inhibitor treatment and have progressed or have been intolerant to treatment
  • No prior systemic therapy with a vascular endothelial growth factor (VEGF) binding agent (e.g., bevacizumab)
  • No prior systemic therapy with any mechanistic target of rapamycin (mTOR) inhibitor (e.g., sirolimus, temsirolimus, everolimus)
  • Prior cytokine therapy is allowed
  • Any systemic therapy must be completed at least 4 weeks prior to registration
  • >= 2 weeks since any prior radiation (including palliative)
  • Patients must not have had a major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to study registration, and must have fully recovered from any such procedure

    • The following are not considered to be major procedures: thoracentesis, paracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional biopsies and routine dental procedures
  • Patients must have measurable disease by RECIST criteria; lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 2 cm with conventional techniques or as >= 1 cm with spiral computed tomography (CT) scan
  • No active brain metastases: patients with treated, stable brain metastases for at least three months are eligible as long as they meet the following criteria:

    • Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 3 months, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or CT) (stable dose of anticonvulsants are allowed); treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or equivalent) or a combination as deemed appropriate by the treating physician; patients with central nervous system (CNS) metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 are not eligible
    • Baseline brain imaging (MRI/CT) is required
  • No serious non-healing wound, ulcer, or bone fracture
  • No arterial thrombotic events within 6 months of registration:

    • Including transient ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial thrombus, unstable angina or angina requiring surgical or medical intervention in the past 6 months, or myocardial infarction (MI); patients with clinically significant peripheral artery disease (i.e., claudication on less than one block), significant vascular disease (i.e., aortic aneurysm, history of aortic dissection), or any other arterial thrombotic event are ineligible
  • Patients who have experienced a deep venous thrombosis or pulmonary embolus within the past 6 months must be on stable therapeutic anticoagulation to be enrolled to this study
  • Patients receiving anti-platelet agents and prophylactic anticoagulation are eligible
  • No inadequately controlled hypertension: (defined as a blood pressure of >= 160 mmHg systolic and/or >= 90 mmHg diastolic on medication), or any prior history of hypertensive crisis or hypertensive encephalopathy
  • No known severe impairment of lung function, defined as >= grade 2 dyspnea or cough, or either:

    • Requirement of supplemental oxygen, or
    • In cases where pulmonary function or pulse oximetry tests have been obtained, forced expiratory volume of the lung in one second (FEV1) or forced vital capacity (FVC) are < 50% of predicted, or single breath diffusing capacity of the lung for carbon monoxide (DLCO) is < 35% of predicted or resting room oxygen saturation is less than 90%
  • No active or severe liver disease (e.g. acute or chronic hepatitis, cirrhosis)
  • No positive serology for anti-hemoglobin C (HBC) or anti-hepatitis C virus (HCV) antibodies; hepatitis B virus (HBV) seropositive patients (hepatitis B surface antigen [HBsAg] positive) are eligible if they are closely monitored for evidence of active HBV infection by HBV deoxryribonucleic acid (DNA) testing and agree to receive suppressive therapy with lamivudine or other HBV-suppressive therapy until at least 4 weeks after the last dose of everolimus
  • No New York Heart Association (NYHA) class >= 2 congestive heart failure
  • No active bleeding or chronic hemorrhagic diathesis or increased risk for bleeding: Including but not limited to history of major bleeding within 6 months (e.g. gastrointestinal, lung, CNS sites; or required transfusion support)
  • No history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to the initiation of treatment
  • No ongoing immunosuppressive therapy: including chronic systemic treatment with corticosteroids (>= 10 mg/day prednisone equivalent)
  • Archival tissue must be available for submission: though it is optional patients to choose to participate in the correlative substudies or not
  • Patients who are pregnant or nursing are not eligible

    • Women of child bearing potential must have a negative serum or urine pregnancy test within 16 days prior to registration
    • Women of child-bearing potential include:

      • Any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >= 12 consecutive months)
      • Women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35m IU/mL
      • Women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy)
  • Performance status Eastern Cooperative Oncology Group (ECOG) 0-2 or Karnofsky score >= 60%
  • Granulocytes >= 1,500/μL
  • Platelet count >= 100,000/μL
  • Calculated creatinine clearance >= 30 mL/minute (modified Cockroft and Gault formula)
  • Bilirubin =< 1.5 x upper limits of normal
  • Aspartate aminotransferase (AST) =< 2.5 x upper limits of normal (ULN)
  • Fasting serum triglycerides =< 200 mg/dL
  • Serum cholesterol =< 300 mg/dL
  • Fasting serum glucose =< 1.5 x ULN
  • Urine protein to creatinine ratio < 1.0 or urine protein =< 1+
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01198158

  Show 531 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: George Philips Alliance for Clinical Trials in Oncology
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01198158     History of Changes
Other Study ID Numbers: NCI-2011-02603, NCI-2011-02603, CDR0000684313, CALGB 90802, CALGB-90802, U10CA180821, U10CA031946
Study First Received: September 8, 2010
Last Updated: October 17, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Bevacizumab
Sirolimus
Everolimus
Carcinoma, Renal Cell
Carcinoma
Adenocarcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Antibodies
Antibodies, Monoclonal
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses
Immunologic Factors
Immunosuppressive Agents
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic

ClinicalTrials.gov processed this record on October 19, 2014