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Sunitinib Malate or Sorafenib Tosylate in Treating Patients With Kidney Cancer That Was Removed By Surgery (ASSURE)

This study has been completed.
Sponsor:
Collaborators:
ECOG-ACRIN Cancer Research Group
NCIC Clinical Trials Group
Southwest Oncology Group
Cancer and Leukemia Group B
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00326898
First received: May 16, 2006
Last updated: December 15, 2016
Last verified: December 2016
  Purpose
This randomized phase III trial studies sunitinib malate and sorafenib tosylate to see how well they work compared to placebo in treating patients with kidney cancer that has been removed by surgery. Sunitinib malate and sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving sunitinib malate or sorafenib tosylate after surgery may kill any tumor cells that remain after surgery. It is not yet known whether sunitinib malate or sorafenib tosylate is more effective than placebo in treating kidney cancer.

Condition Intervention Phase
Stage I Renal Cell Cancer Stage II Renal Cell Cancer Stage III Renal Cell Cancer Other: Placebo Drug: Sorafenib Drug: Sunitinib Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: ASSURE: Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Disease-free Survival (DFS) [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry ]
    Disease-free survival (DFS) is defined as time from randomization to recurrence, development of second primary cancer (except localized breast or prostate cancer or nonmelanoma skin cancer), or death from any cause. Patients who were alive without recurrence or qualifying second primary cancer were censored at the date of last disease evaluation.


Secondary Outcome Measures:
  • 5-year Overall Survival Rate [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry ]
    Overall survival is defined as the time from randomization to death from any cause. Patients without a date of death were censored at the date of last contact. Kaplan-Meier method was used to estimate 5-year survival rate.

  • Proportion of Patients With Cardiac Events [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry ]
    Cardiac event is defined as left ventricular ejection fraction (LVEF) below the institutional lower limit of normal, where the decrease was >15% absolute percentage points from baseline within 6 months.

  • 5-year Disease-free Survival (DFS) Rate Among Patients With Clear Cell Histology [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry ]
    Disease-free survival (DFS) is defined as time from randomization to recurrence, development of second primary cancer (except localized breast or prostate cancer or nonmelanoma skin cancer), or death from any cause. Patients who were alive without recurrence or qualifying second primary cancer were censored at the date of last disease evaluation. 5-year DFS rate is the proportion of patients who are alive and disease-free at 5 years based on the Kaplan-Meier estimate.


Other Outcome Measures:
  • The Association Between Angiogenesis Markers and Disease-free Survival [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry ]
  • The Association Between Disease-free Survival and the Frequency of Oncogene as Well as Tumor Suppressor Gene Mutations [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry ]
  • The Association Between Tumor and Genetic Polymorphisms and Disease-free Survival [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry ]
  • The Association Between Deoxyribonucleic Acid (DNA) Methylation Profiles and Disease-free Survival [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry ]
  • The Relationship of Polymorphisms in Drug Metabolizing Enzymes With Steady State Concentrations of Sorafenib and Sunitinib in Selected Patients [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry ]
  • The Effect of Vascular Endothelial Growth Factor (VEGF) Targeted Therapy on Circulating Endothelial Cells and Circulating Endothelial Progenitors [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; then annually if patient is 5 - 10 years from study entry ]
  • Patient-reported Fatigue Using Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue Scale [ Time Frame: Assessed at baseline, 10 weeks and 22 weeks ]
  • Patient-reported Fatigue Using the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form [ Time Frame: Assessed at baseline, 10 weeks and 22 weeks ]
    PROMIS Fatigue short form is a newly developed state-of-the-science PROMIS measure for fatigue

  • The Association Between Scan Frequency and Development of Congestive Heart Failure [ Time Frame: Assessed at 3, 6 and 12 months ]
  • Frequency of Clinically Significant Congestive Heart Failure (CHF) Grade 3 or Higher Using the Common Terminology Criteria for Adverse Events Version 4.0 [ Time Frame: Assessed every 6 weeks while on treatment and for 30 days after the end of treatment ]

Enrollment: 1943
Study Start Date: April 2006
Study Completion Date: August 2015
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (sunitinib + sorafenib placebo)
Beginning 4-12 weeks following radical or partial nephrectomy, patients receive sunitinib malate PO QD for 4 weeks and placebo sorafenib tosylate PO QD or BID for 6 weeks.
Other: Placebo
Given PO
Other Name: sham therapy
Drug: Sunitinib
Given PO
Other Names:
  • SU011248
  • SU011248 L- Malate salt
  • Sunitinib Malate
  • Sutent
  • SU010398
  • PHA -290940AD
Experimental: Arm B (sorafenib + sunitinib placebo)
Beginning 4-12 weeks following radical or partial nephrectomy, patients receive sorafenib tosylate PO QD or BID for 6 weeks and placebo sunitinib malate PO QD for 4 weeks followed.
Other: Placebo
Given PO
Other Name: sham therapy
Drug: Sorafenib
Given PO
Other Names:
  • BAY 43-9006 Tosylate
  • BAY 54-9085
  • Nexavar
  • sorafenib tosylate
Placebo Comparator: Arm C (sunitinib placebo + sorafenib placebo)
Beginning 4-12 weeks following radical or partial nephrectomy, patients receive placebo sorafenib tosylate as in Arm A and placebo sunitinib malate as in Arm B.
Other: Placebo
Given PO
Other Name: sham therapy

  Hide Detailed Description

Detailed Description:

PRIMARY OBJECTIVES:

I. To demonstrate an improvement in disease-free survival in locally advanced renal cell carcinoma patients randomly assigned to adjuvant sunitinib (sunitinib malate) (Arm A) or sorafenib (sorafenib tosylate) (Arm B) versus placebo (Arm C) after radical or partial nephrectomy.

SECONDARY OBJECTIVES:

I. To compare overall survival of patients randomized to each of the two regimens with placebo.

II. To further define the toxicity of prolonged administration of sunitinib or sorafenib in this patient population.

III. To evaluate cardiac function in each arm

OTHER PRE-SPECIFIED OBJECTIVES:

I. To prospectively collect tumor and biological specimens to assess their characteristics and associations: novel approaches to assess angiogenesis markers in tissue, blood and urine as predictors of disease-free survival and of therapeutic benefit.

II. To prospectively collect tumor and biological specimens to assess their characteristics and associations: the frequency of oncogene and tumor suppressor gene mutations as predictors of disease-free survival and therapeutic benefit.

III. To prospectively collect tumor and biological specimens to assess their characteristics and associations: tumor and genetic polymorphisms as predictors of disease-free survival and therapeutic benefit.

IV. To prospectively collect tumor and biological specimens to assess their characteristics and associations: deoxyribonucleic acid (DNA) methylation profiles as predictors of outcome and of therapeutic benefit.

V. To prospectively collect tumor and biological specimens to assess their characteristics and associations: The relationship of polymorphisms in drug metabolizing enzymes with steady state concentrations of sorafenib and sunitinib in selected patients.

VI. To study the effect of vascular endothelial growth factor (VEGF) targeted therapy on circulating endothelial cells and circulating endothelial progenitors.

VII. To prospectively assess patient-reported fatigue in order to compare the magnitude and trajectory of fatigue among renal cell carcinoma (RCC) patients randomized to adjuvant sunitinib (Arm A) or sorafenib (Arm B) to placebo (Arm C). (Quality of life objectives) VIII. To evaluate the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue-Short Form (SF)1, a newly developed state-of-the-science PROMIS measure for fatigue and to calibrate the PROMIS Fatigue-SF1 with the established, validated Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue scale. (Quality of life objectives)

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM A: Beginning 4-12 weeks following radical or partial nephrectomy, patients receive sunitinib malate orally (PO) once daily (QD) for 4 weeks and placebo sorafenib tosylate PO QD or twice daily (BID) for 6 weeks.

ARM B: Beginning 4-12 weeks following radical or partial nephrectomy, patients receive sorafenib tosylate PO QD or BID for 6 weeks and placebo sunitinib malate PO QD for 4 weeks followed.

ARM C: Beginning 4-12 weeks following radical or partial nephrectomy, patients receive placebo sorafenib tosylate as in Arm A and placebo sunitinib malate as in Arm B.

In all arms, treatment repeats every 6 weeks for 9 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 5 years.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Pre-Registration Inclusion Criteria:

  • Pre-surgical criteria:

    • Patients must have primary-intact renal cell carcinoma, eligible for nephrectomy with curative intent
    • Tumors >= 4 cm AND/OR macroscopic fully resectable nodes AND/OR surgically resectable renal vein thrombus AND/OR surgically resectable inferior vena caval thrombus by radiologic criteria to be clinically >= pT1bNany (resectable) M0 disease
    • Multifocal ipsilateral renal cell carcinoma is allowed provided fully resectable and does not exceed inclusion criteria
  • Patients must have corrected QT (QTc) interval < 500 msec on baseline electrocardiogram (EKG)
  • Women of child-bearing potential and men must agree to use an accepted and effective method of contraception prior to study entry and for the duration of study participation; should a woman become pregnant while participating in this study, she should inform her treating physician immediately; if a man impregnates a woman while participating in this study, he should inform his treating physician immediately as well
  • The date of randomization must be less than 12 weeks after the date of surgery; patients must have recovered from any surgical related complications

Inclusion Criteria at Randomization:

  • Within 4 weeks prior to randomization, patients must meet preoperative eligibility requirements
  • Patients must complete surgery less than 12 weeks prior to randomization
  • Patients must have histologically or cytologically confirmed renal cell carcinoma. Using 2002 (American Joint Committee on Cancer [AJCC] 6th edition) TNM Staging, patients must be one of the following:

    • pT1b G3-4 N0 (or pNX where clinically N0) M0
    • pT2 G (any) N0 (or pNX where clinically N0) M0
    • pT3 G (any) N0 (or pNX where clinically N0) M0
    • pT4 G (any) N0 (or pNX where clinically N0) M0 or
    • T (any) G (any) N+ (fully resected) M0

      • Patients with microvascular invasion of the renal vein of any grade or stage (as long as M0) are also eligible
      • Patients must have undergone a full surgical resection (radical nephrectomy or partial nephrectomy) by either open or laparoscopic technique; clinical evidence of lymph node positivity requires removal of all clinically positive nodes; surgeons should designate extent of node dissection; all surgical specimens must have negative margins; patients with positive renal vein margins are eligible unless there is invasion of the renal vein wall at the margin (provided no other margins are positive)
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Patients must have an absolute baseline left ventricular ejection fraction (LVEF) of >= 50% by multigated acquisition (MUGA) scan within 4 weeks prior to randomization
  • Patients must have paraffin-embedded tumor specimen available for central core review of tumor histology and other correlative studies; tumor samples will be shipped as specified
  • Patients must have no evidence of residual or metastatic renal cell cancer as documented on computed tomography (CT) scans of the chest, abdomen, and pelvis, all with oral and intravenous (IV) contrast (magnetic resonance imaging [MRI] scans of the abdomen and pelvis with gadolinium and a non-contrast CT of the chest may be substituted if patient is not able to have CT scans with intravenous contrast); patients unable to tolerate either gadolinium or IV contrast should not participate in this study (limitations to a patient's renal function should be taken into consideration when screening for this study)

    • Scans must be obtained within 4 weeks of randomization; changes on these scans that are felt to be post surgical must be documented
    • Patients without reported lymph nodes in the resected surgical specimen and a reported pathologic stage (post-nephrectomy) of pNX MUST undergo a post-operative contrast-enhanced CT scan (or MRI with gadolinium) within 4 weeks of randomization to document that there is no evidence of residual disease
  • Absolute granulocyte count (AGC) >= 1,500/mm^3
  • Platelet count >= 100,000/mm^3
  • Serum creatinine =< 2.0 x upper limit of normal (ULN) or calculated creatinine clearance (CrCl) >= 30 mL/min (neither drug is cleared by the kidney)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) =< 2.5 x ULN
  • Patients must be able to swallow pills

Exclusion Criteria:

  • History of distant metastases
  • Prior anti-cancer therapy for renal cell carcinoma in either the adjuvant or neoadjuvant setting; this includes metastatectomy for renal cell carcinoma, or radiation therapy to the renal bed
  • Other current malignancies, other than basal cell skin cancer, squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in situ of the breast; patients with other malignancies are eligible if they have been continuously disease-free for >= 5 years prior to the time of registration
  • Serious intercurrent illness including, but not limited to, the following: clinically significant cardiovascular disease (e.g. uncontrolled hypertension, myocardial infarction, unstable angina); New York Heart Association grade II or greater congestive heart failure; serious cardiac arrhythmia requiring medication; grade II or greater peripheral vascular disease; or psychiatric illness/social situations that would limit compliance with study requirements
  • Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism
  • Ongoing ventricular cardiac dysrhythmias of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 grade >= 2; history of serious ventricular arrhythmia (ventricular tachycardia [VT] or ventricular fibrillation [VF] >= 3 beats in a row); ongoing atrial fibrillation
  • Hypertension that cannot be controlled by medications (>= diastolic blood pressure 100 mm Hg despite optimal medical therapy)
  • Pre-existing thyroid abnormality with thyroid stimulating hormone that cannot be maintained in the normal range with medication
  • Pregnant or breastfeeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to pre-registration to rule out pregnancy; if pre-registration occurs prior to surgery, the blood or urine study must be repeated within 2 weeks prior to randomization to rule out pregnancy; (note: should a woman become pregnant while participating in this study, she should inform her treating physician immediately)
  • Patients with known human immunodeficiency virus (HIV)
  • Collecting duct carcinomas or medullary carcinomas
  • Patients taking cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine or phenobarbital), St John's Wort, ketoconazole, dexamethasone, the dysrhythmic drugs (terfenadine, quinidine, procainamide, sotalol, probucol, bepridil, indapamide or flecainide), haloperidol, risperidone, rifampin, grapefruit, or grapefruit juice within two weeks of randomization and during the course of therapy; (medications are not prohibited unless listed above); topical and inhaled steroids are permitted
  • Receiving any other investigational anti-cancer agents during the period on study
  • Serious intercurrent illness, including ongoing or active infection requiring parental antibiotics
  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: NCT00326898

  Show 921 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
ECOG-ACRIN Cancer Research Group
NCIC Clinical Trials Group
Southwest Oncology Group
Cancer and Leukemia Group B
Investigators
Study Chair: Naomi Balzer-Haas, M.D. University of Pennsylvania
  More Information

Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00326898     History of Changes
Other Study ID Numbers: NCI-2009-00534
NCI-2009-00534 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
E2805 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
U10CA023318 ( U.S. NIH Grant/Contract )
Study First Received: May 16, 2006
Results First Received: October 18, 2016
Last Updated: December 15, 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.

Keywords provided by National Cancer Institute (NCI):
Sorafenib
Sunitinib
Renal Carcinoma

Additional relevant MeSH terms:
Carcinoma, Renal Cell
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Sorafenib
Sunitinib
Niacinamide
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Inhibitors

ClinicalTrials.gov processed this record on August 22, 2017