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

• ClinicalTrials.gov Identifier: NCT00326898
• Recruitment Status: Completed
• First Posted: May 17, 2006
• Results First Posted: December 12, 2016
• Last Update Posted: July 7, 2020
• Sponsor: National Cancer Institute (NCI)
• Collaborators: Cancer and Leukemia Group B; NCIC Clinical Trials Group; Southwest Oncology Group
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: May 16, 2006
• First Posted Date: May 17, 2006
• Results First Submitted Date: October 18, 2016
• Results First Posted Date: December 12, 2016
• Last Update Posted Date: July 7, 2020
• Actual Study Start Date: April 24, 2006
• Actual Primary Completion Date: December 29, 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 18, 2016)

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.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: December 15, 2016)

• 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.

• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: December 15, 2016)

• 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 ]

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Sunitinib Malate or Sorafenib Tosylate in Treating Patients With Kidney Cancer That Was Removed By Surgery
• Official Title: ASSURE: Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma
• Brief Summary: This randomized phase III trial studies sunitinib malate to see how well it works compared to sorafenib tosylate or 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 is more effective than sorafenib tosylate or placebo in treating kidney cancer.

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 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.

IV. 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.

V. 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.

VI. 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.

VII. 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.

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

IX. 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) X. 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 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Clear Cell Renal Cell Carcinoma
• Stage I Renal Cell Cancer AJCC v6 and v7
• Stage II Renal Cell Cancer AJCC v7
• Stage III Renal Cell Cancer AJCC v7

Intervention

• Other: Laboratory Biomarker Analysis
  Correlative studies
• Other: Placebo
  Given PO
  Other Names:

  • placebo therapy
  • PLCB
  • sham therapy
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Drug: Sorafenib Tosylate
  Given PO
  Other Names:

  • BAY 43-9006 Tosylate
  • BAY 54-9085
  • Nexavar
  • sorafenib
• Drug: Sunitinib Malate
  Given PO
  Other Names:

  • SU011248
  • SU11248
  • sunitinib
  • Sutent

Study Arms

• Experimental: Arm A (sunitinib malate, 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.
  Interventions:

  • Other: Laboratory Biomarker Analysis
  • Other: Placebo
  • Other: Quality-of-Life Assessment
  • Drug: Sunitinib Malate
• Experimental: Arm B (sorafenib tosylate, 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.
  Interventions:

  • Other: Laboratory Biomarker Analysis
  • Other: Placebo
  • Other: Quality-of-Life Assessment
  • Drug: Sorafenib Tosylate
• Placebo Comparator: Arm C (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.
  Interventions:

  • Other: Laboratory Biomarker Analysis
  • Other: Placebo
  • Other: Quality-of-Life Assessment

Publications *

• Jamil ML, Keeley J, Sood A, Dalela D, Arora S, Peabody JO, Trinh QD, Menon M, Rogers CG, Abdollah F. Long-term Risk of Recurrence in Surgically Treated Renal Cell Carcinoma: A Post Hoc Analysis of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network E2805 Trial Cohort. Eur Urol. 2020 Feb;77(2):277-281. doi: 10.1016/j.eururo.2019.10.028. Epub 2019 Nov 6.
• Buti S, Puligandla M, Bersanelli M, DiPaola RS, Manola J, Taguchi S, Haas NB. Validation of a new prognostic model to easily predict outcome in renal cell carcinoma: the GRANT score applied to the ASSURE trial population. Ann Oncol. 2017 Nov 1;28(11):2747-2753. doi: 10.1093/annonc/mdx492. Erratum in: Ann Oncol. 2018 Jul 1;29(7):1604.
• Haas NB, Manola J, Dutcher JP, Flaherty KT, Uzzo RG, Atkins MB, DiPaola RS, Choueiri TK. Adjuvant Treatment for High-Risk Clear Cell Renal Cancer: Updated Results of a High-Risk Subset of the ASSURE Randomized Trial. JAMA Oncol. 2017 Sep 1;3(9):1249-1252. doi: 10.1001/jamaoncol.2017.0076.
• Haas NB, Manola J, Uzzo RG, Flaherty KT, Wood CG, Kane C, Jewett M, Dutcher JP, Atkins MB, Pins M, Wilding G, Cella D, Wagner L, Matin S, Kuzel TM, Sexton WJ, Wong YN, Choueiri TK, Pili R, Puzanov I, Kohli M, Stadler W, Carducci M, Coomes R, DiPaola RS. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016 May 14;387(10032):2008-16. doi: 10.1016/S0140-6736(16)00559-6. Epub 2016 Mar 9. Erratum in: Lancet. 2016 May 14;387(10032):1998.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 18, 2016): 1943
• Original Enrollment: Not Provided
• Actual Study Completion Date: August 27, 2015
• Actual Primary Completion Date: December 29, 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 no history of distant metastases
• No prior anti-cancer therapy for renal cell carcinoma is permitted in either the adjuvant or neoadjuvant setting; this includes metastectomy for renal cell carcinoma, or radiation therapy to the renal bed
• Patients must not have 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
• Patients must have no 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
• Patients must not have 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
• Patient must not have ongoing ventricular cardiac dysrhythmias of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 grade >= 2; patients with a history of serious ventricular arrhythmia (ventricular tachycardia [VT] or ventricular fibrillation [VF] >= 3 beats in a row) are also excluded; additionally, patients with ongoing atrial fibrillation are not eligible
• Patients must have corrected QT (QTc) interval < 500 msec on baseline electrocardiogram (EKG)
• Patient must not have hypertension that cannot be controlled by medications (>= diastolic blood pressure 100 mm Hg despite optimal medical therapy)
• Patient must not have pre-existing thyroid abnormality with thyroid stimulating hormone that cannot be maintained in the normal range with medication
• If female, patient must not be 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)
• 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
• Patients with known human immunodeficiency virus (HIV) are excluded
• ELIGIBILITY CRITERIA FOLLOWING RADICAL OR PARTIAL NEPHRECTOMY
• The date of randomization must be less than 12 weeks after the date of surgery; patients must have recovered from any surgical related complications
• Within 4 weeks prior to randomization, patients must meet preoperative eligibility requirements

• 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 not have collecting duct carcinomas or medullary carcinomas
• 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
• Patients must not be 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
• Patients must not receive any other investigational anti-cancer agents during the period on study
• Patients must not have a serious intercurrent illness, including ongoing or active infection requiring parental antibiotics
• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Puerto Rico, United States

Administrative Information

• NCT Number: NCT00326898
• Other Study ID Numbers: NCI-2009-00534; NCI-2009-00534 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CAN-NCIC-E2805; SWOG-E2805; ECOG-E2805; CDR0000478976; CALGB-E2805; E2805 ( Other Identifier: ECOG-ACRIN Cancer Research Group ); E2805 ( Other Identifier: CTEP ); U10CA180820 ( U.S. NIH Grant/Contract ); U10CA021115 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Cancer Institute (NCI)
• Study Sponsor: National Cancer Institute (NCI)

Collaborators

• Cancer and Leukemia Group B
• NCIC Clinical Trials Group
• Southwest Oncology Group

Investigators

• Principal Investigator: Naomi S Balzer-Haas; ECOG-ACRIN Cancer Research Group

• PRS Account: National Cancer Institute (NCI)
• Verification Date: June 2020