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

• Overall survival [ Time Frame: From the date of registration to up to 8.08 years ] [ Designated as safety issue: No ]
• DFS among patients with clear cell histology [ Time Frame: Up to 13 years ] [ Designated as safety issue: No ]
  The sequentially rejective method will be used for this analysis.
• Decreases in left ventricular ejection fraction (LVEF) in patients treated with sunitinib or sorafenib [ Time Frame: From baseline to 6 months ] [ Designated as safety issue: No ]
  LVEF decline defined as LVEF below the institutional lower limit of normal, where the drop is at least 16% from baseline.
• 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: From baseline to up to 8 weeks after final treatment ] [ Designated as safety issue: Yes ]
• Scan frequency in preventing CHF [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
  The incidence of CHF after MUGA scan intervals of 3 months and 6 months will be described along with changes in LVEF over these intervals.
• Quality of life (QOL) assessed by Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Subscale the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue-SF1 measure [ Time Frame: From baseline to up to 22 weeks ] [ Designated as safety issue: No ]
  For each of the two instruments, descriptive statistics at each timepoint, including Cronbach‟s alpha, will be provided. Repeated measures analyses will be used to examine the treatment and time effects on scores.

This randomized phase III trial is studying 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.

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:

IV. Novel approaches to assess angiogenesis markers in tissue, blood and urine as predictors of disease-free survival and of therapeutic benefit.

V. The frequency of oncogene and tumor suppressor gene mutations as predictors of disease-free survival and therapeutic benefit.

VI. Tumor and genetic polymorphisms as predictors of disease-free survival and therapeutic benefit.

VII. Deoxyribonucleic acid (DNA) methylation profiles as predictors of outcome and of therapeutic benefit.

VIII. The relationship of polymorphisms in drug metabolizing enzymes with steady state concentrations of sorafenib and sunitinib in selected patients.

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

X. 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).

XI. 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.

OUTLINE: This is a randomized, double-blind, multicenter study. Patients who have not had surgical resection undergo radical or partial nephrectomy first. Patients are then randomized to 1 of 3 treatment arms.

ARM A: Patients receive oral sunitinib malate once daily for 4 weeks followed by rest for 2 weeks and oral placebo for sorafenib tosylate twice daily for 6 weeks.

ARM B: Patients receive oral sorafenib tosylate twice daily for 6 weeks and oral placebo for sunitinib malate once daily for 4 weeks followed by rest for 2 weeks.

ARM C: Patients receive oral placebo for sorafenib tosylate as in arm A and oral placebo for sunitinib malate as in arm B.

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

Tumor tissue is collected prior to or during nephrectomy. Blood and urine samples are collected at baseline and periodically during study for biomarker correlative studies.

Patients complete quality of life questionnaires, the FACIT-fatigue scale and the PROMIS fatigue form, at baseline, and after courses 2 and 4 of treatment.

After completion of study treatment, patients are followed periodically for 9 years.

• Clear Cell Renal Cell Carcinoma
• Papillary Renal Cell Carcinoma
• Stage I Renal Cell Cancer
• Stage II Renal Cell Cancer
• Stage III Renal Cell Cancer
• Stage IV Renal Cell Cancer

• Drug: sorafenib tosylate
  Given orally
  Other Names:

  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
• Drug: sunitinib malate
  Given orally
  Other Names:

  • SU11248
  • sunitinib
  • Sutent
• Other: placebo
  Given orally
  Other Name: PLCB
• Other: laboratory biomarker analysis
  Correlative studies
• Procedure: quality-of-life assessment
  Ancillary studies
  Other Name: quality of life assessment

• Experimental: Arm A (sunitinib malate, placebo)
  Patients receive oral sunitinib malate once daily for 4 weeks followed by rest for 2 weeks and oral placebo for sorafenib tosylate twice daily for 6 weeks.
  Interventions:

  • Drug: sunitinib malate
  • Other: placebo
  • Other: laboratory biomarker analysis
  • Procedure: quality-of-life assessment
• Experimental: Arm B (sorafenib tosylate, placebo)
  Patients receive oral sorafenib tosylate twice daily for 6 weeks and oral placebo for sunitinib malate once daily for 4 weeks followed by rest for 2 weeks..
  Interventions:

  • Drug: sorafenib tosylate
  • Other: placebo
  • Other: laboratory biomarker analysis
  • Procedure: quality-of-life assessment
• Placebo Comparator: Arm C (placebo)
  Patients receive oral placebo for sorafenib tosylate as in arm A and oral placebo for sunitinib malate as in arm B.
  Interventions:

  • Other: placebo
  • Other: laboratory biomarker analysis
  • Procedure: quality-of-life assessment

Inclusion Criteria:

• Histologically or cytologically confirmed renal cell carcinoma, including any of the following subtypes:

  • Clear cell carcinoma

  • Nonclear cell carcinoma

    • No collecting duct or medullary carcinomas

• Meets 1 of the following risk categories:

  • Intermediate high-risk disease

    • pT1b, G3-4 N0 (or pNX where clinically N0) M0
    • pT2, G1-2 N0 (or pNX where clinically N0) M0
    • pT2, G3-4 N0 (or pNX where clinically N0) M0
    • pT3a, G1-2 (as long as pT3a is not due to adrenal involvement) N0 (or pNX where clinically N0) M0
    • Patients with microvascular invasion of the renal vein of pT1a-pT3a (as long as pT3a is not due to adrenal involvement and grade 1-2) N0 (or pNX where clinically N0) M0

  • Very high-risk disease

    • pT3a, G3-4 (or any grade pT3a if due to adrenal involvement) N0 (or pNX where clinically N0) M0
    • pT3b-c G any N0 (or pNX where clinically N0) M0
    • pT4 G N0 (or pNX where clinically N0) M0 any
    • pT any G any N+
    • Patients with microvascular invasion of the renal vein with above other characteristics

• Planning to start study treatment between 4-12 weeks after radical or partial nephrectomy

  • Underwent full surgical resection (i.e., radical or partial nephrectomy) by either open or laparoscopic technique within the past 3-10 weeks

    • Clinical evidence of lymph node positivity requires complete regional lymphadenectomy
    • All surgical specimens must have negative margins

  • Planning to undergo the above surgical resection AND meets all of the following criteria:

    • Primary intact renal cell carcinoma, eligible for nephrectomy with curative intent

    • pT1b-4, N0 or any fully resectable N (i.e., N1-2), M0 disease by radiologic criteria, meeting any of the following criteria:

      • Tumors ≥ 4 cm
      • Macroscopic fully resectable nodes
      • Surgically resectable renal vein thrombus
      • Surgically resectable inferior vena caval thrombus by radiologic criteria
    • Multifocal ipsilateral renal cell carcinoma allowed provided fully resectable and does not exceed inclusion criteria

• No evidence of residual or metastatic renal cell cancer by chest, abdomen, and pelvic CT scan with oral and IV contrast (or MRI scan of the abdomen and pelvis with gadolinium and a CT scan of the chest with or without IV contrast) within 4 weeks of randomization (after radical or partial nephrectomy)

  • Patients unable to tolerate either gadolinium or IV contrast should not participate in this study
• No history of distant metastases
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Absolute granulocyte count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Creatinine ≤ 2.0 times upper limit of normal (ULN) OR creatinine clearance ≥ 30 mL/min
• Bilirubin ≤ 1.5 times ULN
• SGOT and SGPT ≤ 2.5 times ULN
• Absolute baseline LVEF ≥ 50% by MUGA within 4 weeks of randomization
• No other malignancy within the past 5 years except basal cell or squamous cell skin cancer, in situ cervical cancer, or ductal or lobular carcinoma in situ of the breast

• No serious intercurrent illness, including, but not limited to, any of the following:

  • Clinically significant cardiovascular disease(e.g., uncontrolled hypertension, myocardial infraction, or unstable angina)
  • New York Heart Association class II-IV congestive heart failure
  • Peripheral vascular disease ≥ grade 2
  • Psychiatric illness or social situation that would preclude study compliance

• At least 6 months since any of the following:

  • Myocardial infarction
  • Severe or unstable angina
  • Coronary or peripheral artery bypass graft
  • Symptomatic congestive heart failure
  • Cerebrovascular accident
  • Transient ischemic attack
  • Pulmonary embolism
• No ongoing ventricular cardiac dysrhythmias ≥ grade 2
• No ongoing atrial fibrillation
• No history of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)
• QTc interval < 500 msec by baseline EKG
• No uncontrolled hypertension (i.e., diastolic blood pressure ≥ 100 mm Hg despite optimal medical therapy)
• No pre-existing thyroid abnormality with thyroid stimulating hormone that cannot be maintained in the normal range with medication
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No known HIV infection
• Able to swallow pills
• Recovered from prior surgery

• No prior anticancer therapy for renal cell carcinoma in either the adjuvant or neoadjuvant setting, including any of the following:

  • Metastectomy
  • Radiotherapy to the renal bed

• At least 2 weeks since prior and no concurrent treatment with any of the following*:

  • Cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine, or phenobarbital)
  • Hypericum perforatum (St. John's wort)
  • Ketoconazole
  • Dexamethasone
  • Dysrhythmic drugs (i.e., terfenadine, quinidine, procainamide, sotalol, probucol, bepridil, indapamide, or flecainide)
  • Haloperidol
  • Risperidone
  • Rifampin
  • Grapefruit juice or grapefruit
• Concurrent participation in protocol ECOG-E1Y03 allowed
• No other concurrent investigational anticancer agents

• Southwestern Oncology Group (SWOG)
• Cancer and Leukemia Group B
• NCIC Clinical Trials Group