Sorafenib Tosylate With or Without Recombinant Interferon Alfa-2b in Treating Patients With Metastatic Kidney Cancer

Study Overview
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Brief Summary
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This randomized phase II trial is studying sorafenib and interferon alfa-2b to see how well they work compared to sorafenib alone in treating patients with metastatic kidney cancer. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Interferon alfa-2b may interfere with the growth of tumor cells. Sorafenib and interferon alfa-2b may also block blood flow to the tumor. Giving sorafenib together with interferon alfa-2b may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Efficacy of Bay 43-9006 with or without low dose interferon by evaluating response rate in MRCC. II. Toxicities of Bay 43-9006 with or without low dose interferon in MRCC. SECONDARY OBJECTIVES: I. Progression free survival. II. Duration of response. III. Overall Survival. OUTLINE: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral sorafenib twice daily on days 1-28. Arm II: Patients receive sorafenib as in arm I and low-dose interferon alfa-2b subcutaneously twice daily on days 1-28. In both arms, courses repeat every 28 days in the absence of progressive disease or unacceptable toxicity. Tissue samples are analyzed for single nucleotide polymorphisms (SNP) patterns via genotyping. After completion of study treatment, patients are followed every 3 months.

Official Title
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A Phase II Clinical Trial to Evaluate the Efficacy of BAY 43-9006 With or Without Low Dose Interferon in Metastatic Renal Cell Carcinoma

Conditions
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Clear Cell Renal Cell Carcinoma, Recurrent Renal Cell Carcinoma, Stage IV Renal Cell Cancer

Intervention / Treatment
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* Drug: Sorafenib Tosylate
* Biological: Recombinant Interferon Alfa-2b
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically or cytologically confirmed metastatic clear cell RCC Patients must have measurable disease, defined as a lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) and measures >= 20 mm with conventional techniques or >= 10 mm with spiral CT scan ECOG performance status =< 1 Absolute neutrophil count >= 1,500/μL Platelets >= 100,000/μL Hgb > 9.0 g/dL (may be transfused or receive epoetin alfa [e.g., Epogen®] to maintain or exceed this level) Total bilirubin =< 2.0 mg/dl Albumin > 3.0 g/dL Serum creatinine =< 2.0 mg/dl AST(SGOT) and/or ALT (SGPT) =< 2.5 X institutional upper limit of normal for subjects without evidence of liver metastases AST(SGOT) and/or ALT (SGPT) =< 5 X institutional upper limit of normal for subjects with documented liver metastases Female patients of childbearing potential must have a normal plasma beta human chorionic gonadotropin (βHCG) within 24 hours prior to enrolling in the study due to the possible teratogenic effect; however, patients will be eligible if their βHCG elevation is consistent with malignancy rather than pregnancy Patients of child fathering or childbearing potential must agree to practice a form of medically acceptable birth control while on study Patients must give written informed consent prior to initiation of therapy, in keeping with the policies of the institution; patients with a history of major psychiatric illness must be judged able to fully understand the investigational nature of the study and the risks associated with the therapy; the only approved consent is attached to this protocol Patients must have ability to comply with study and/or follow-up procedures Patients must be able to swallow pills Exclusion Criteria: No prior malignancy is allowed, except for non-melanoma skin cancer, in situ carcinoma of any site, or other cancers for which the patient has been adequately treated and disease free for 5 years Patients must not have received any systemic anticancer therapy for renal cell carcinoma; patients must not have received any radiotherapy for renal cell carcinoma within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier Patients must not be scheduled to receive another experimental drug while on this study; patients are permitted to be on concomitant bisphosphonates Patients must not have a primary brain tumor, any brain metastases, leptomeningeal disease, seizure disorders not controlled with standard medical therapy, or history of stroke Patients must not have active acute infections that could be worsened by anticancer therapy or interfere with this study Patients must not have clinically significant cardiovascular disease, myocardial infarction within the past year (unstable angina), New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac dysrhythmia refractory to medical management, or peripheral vascular disease (Grade II or greater) Patients must not have uncontrolled hypertension Patients must not have history of other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications Pregnant women are excluded from this study because BAY 43-9006 is a kinase inhibitor agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with BAY 43-9006, breastfeeding should be discontinued if the mother is treated with BAY 43-9006 Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy; therefore, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with BAY 43-9006; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated Patients must not have a clinical history of coagulopathy, bleeding diathesis or thrombosis; patients must not be on therapeutic anticoagulation; prophylactic anticoagulation (ie low dose warfarin) of venous access devices is allowed provided that INR >= 1.5 is due to warfarin therapy; other patients with an INR >= 1.5 are excluded Patients must not have a history of severe depression Concomitant treatment with rifampin, St. John's wort, and the cytochrome p450 enzyme-inducin antiepileptic drugs (phenytoin, carbamazepine or Phenobarbital)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib Tosylate<br>Arm I: Oral Sorafenib 400 mg twice daily on days 1-28. | Drug: Sorafenib Tosylate<br>* Given orally 400 mg orally (PO) every 12 hours<br>* Other names: BAY 43-9006;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Sorafenib Tosylate, Recombinant interferon alfa-2b<br>Arm II: Sorafenib as in Arm I and low-dose Interferon alfa-2b 0.5 million units subcutaneously twice daily on days 1-28. | Drug: Sorafenib Tosylate<br>* Given orally 400 mg orally (PO) every 12 hours<br>* Other names: BAY 43-9006;Biological: Recombinant Interferon Alfa-2b<br>* Given subcutaneously (SC) 0.5 million with +/- 5 % variance (0.475 MU - 0.525 MU); Dose level 0: 0.5 X 10^6 international units twice daily<br>* Other names: IFN;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) | ORR defined as participants with Complete Response (CR) and Partial Response (PR) as defined by RECIST criteria: Complete Response (CR): Disappearance all target lesions. Partial Response (PR): >30% decrease in sum of longest diameter (LD) of target lesions, reference baseline sum LD. Progressive Disease (PD): >20% increase in sum of LD of target lesions, reference smallest sum LD recorded since treatment started or appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum LD since treatment started. Radiologic testing for progressive disease repeated every 8 weeks. | Tumor restaging performed at 8 weeks following baseline, responding or stable participants restaged at 8 week intervals, up to 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Selected Grade 3-4 Adverse Events Using NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 | Adverse events graded using the CTCAE version 4.0 tabulated by treatment arm within either toxicity grade for the treatment period. Treatment-related toxicity (acute and cumulative) performed every 8 weeks during the first year. | Up to 12 months of treatment | 
| Progression-free Survival | Progression free survival (PFS) is defined as the time interval from the start of protocol therapy to death or disease progression. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months | 
| Median Overall Survival (OS) | Overall survival defined as the time interval from the start of protocol therapy to death or date of last follow-up if alive. | From the start of protocol therapy to death or date of last follow-up, up to 36 months | 
| Duration of Response for Participants With Stable Disease (N=37) Following Treatment | Duration of response for participants with disease stabilization following treatment as measured from the date response is confirmed to the date of disease progression, first assessed up to 8 weeks (2 cycles) following start of treatment. The duration of a Stable Disease (SD) response is measured from the time measurement criteria are met for that specific SD response until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Repeat radiologic studies (CT, MRI, Chest x-ray and bone scan as indicated) to evaluate disease progression or response every 8 weeks. | From the date response is confirmed to the date of disease progression, up to 12 months |