Sunitinib and Erlotinib in Treating Patients With Unresectable or Metastatic Kidney Cancer

Study Overview
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Brief Summary
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RATIONALE: Sunitinib and erlotinib may stop the growth of tumor cell by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving sunitinib together with erlotinib may kill more tumor cells. PURPOSE: This phase II trial is studying the best dose of erlotinib when given together with sunitinib and to see how well they work in treating patients with unresectable or metastatic kidney cancer.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose of erlotinib hydrochloride when administered with sunitinib malate in patients with unresectable or metastatic renal cell carcinoma. Determine the 8-month progression-free survival of patients treated with this regimen. Secondary Determine the safety of sunitinib malate and erlotinib hydrochloride in these patients. Determine the duration of response in these patients. Determine the proportion of patients whose best overall response is complete response, partial response, stable disease, or progressive disease. Determine the overall survival of patients treated with this regimen. Determine the maximum percent reduction in tumor measurement in patients treated with this regimen. Collect blood and tissue from these patients for future correlative studies. OUTLINE: This is an open-label, multicenter, dose-escalation study of erlotinib hydrochloride. Patients receive oral sunitinib malate once daily on days 1-28 and oral erlotinib hydrochloride once daily on days 1-42. Treatment repeats every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 33% of patients experience dose-limiting toxicity. Once the MTD is determined, patients are treated with erlotinib hydrochloride at the MTD and sunitinib malate. Patients undergo blood and tumor specimen collection periodically during study for future correlative studies. PROJECTED ACCRUAL: A total of 49 patients will be accrued for this study.

Official Title
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A Dose Escalation Phase II Study of Sunitinib Plus Erlotinib in Advanced Renal Carcinoma

Conditions
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Kidney Cancer

Intervention / Treatment
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* Drug: erlotinib hydrochloride
* Drug: sunitinib malate
* Procedure: biopsy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed renal cell carcinoma with a component of clear cell or papillary carcinoma Unresectable or metastatic disease (radiologically or clinically confirmed) Measurable disease (≥ 1 site) No known brain metastasis that has not been adequately treated with radiotherapy and/or surgery PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ No grade 3 hemorrhage within the past 4 weeks Bilirubin ≤ 1.5 times upper limit of normal (ULN) Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 times ULN (< 5 times ULN if due to underlying disease) No chronic liver disease (i.e., chronic active hepatitis or cirrhosis) Creatinine ≤ 1.5 times ULN None of the following cardiovascular conditions within the past 12 months: Myocardial infarction Severe/unstable angina Coronary/peripheral artery bypass graft Symptomatic congestive heart failure Cerebrovascular accident or transient ischemic attack Pulmonary embolism Ongoing cardiac dysrhythmia ≥ grade 2 Atrial fibrillation of any grade Prolongation of the corrected QT (QTc) interval to > 450 msec for males or to > 470 msec for females Left Ventricular Ejection Fraction (LVEF) normal by Multigated Acquisition (MUGA) or echocardiogram No hypertension uncontrolled with medical therapy No other active malignancy within the past 5 years except basal cell skin cancer or cervical carcinoma in situ No uncontrolled adrenal insufficiency No uncontrolled hypothyroidism Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after completion of study treatment No severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection) No impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drugs No other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would preclude study participation PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 4 weeks since prior major surgery More than 4 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosoureas or mitomycin C) More than 4 weeks since prior radiotherapy No prior radiotherapy to > 25% of the bone marrow More than 28 days since prior investigational agents No prior sunitinib malate No prior anti-epidermal growth factor receptor therapy (e.g., erlotinib hydrochloride, panitumumab, cetuximab, or gefitinib) No concurrent therapeutic warfarin Low-dose oral warfarin ≤ 2 mg daily for deep vein thrombosis prophylaxis is allowed after the maximum tolerated dose of erlotinib hydrochloride is determined No concurrent Hypericum perforatum (St. John's wort) No concurrent chemotherapy or biologic therapy No other concurrent anticancer therapy No other concurrent investigational agents

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erlotinib and Sunitinib<br>Drug: erlotinib hydrochloride Dose Level 0 = 50 mg/day, continuous daily; 0.5= 75 mg/day, continuous daily; 100 mg/day, continuous daily; 1.5= 125 mg/day, continuous daily; 150 mg/day, continuous daily Drug: sunitinib malate Will be administered at 50 mg daily, 4 weeks on, 2 weeks off | Drug: erlotinib hydrochloride<br>* Dose Level 0 = 50 mg/day, continuous daily; 0.5= 75 mg/day, continuous daily; 100 mg/day, continuous daily; 1.5= 125 mg/day, continuous daily; 150 mg/day, continuous daily<br>Drug: sunitinib malate<br>* Will be administered at 50 mg daily, 4 weeks on, 2 weeks off<br>Procedure: biopsy<br>* Paraffin block (or unstained slides) of the primary tumor and/or metastatic lesions (as available) and a plasma sample for future correlative studies will be collected. A paraffin block (or at least 10 unstained slides, each of 10 micromillimeter thickness) from the original paraffin-embedded biopsy material taken at the diagnosis will be stored at 4 degrees Celsius.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Erlotinib Hydrochloride When Used in Combination With Sunitinib. | The MTD is defined as the dose that produces dose limiting toxicity (DLT) in 33% of the patients. | Participants assessed for DLTs weekly during the first cycle of treatment and every 3 weeks in subsequent cycles until at least one DLT occurs in 33% or more of participants at that dose; participants assessed for the duration of the study, up to 7 years | 
| Progression-free Survival at 8 Months | Defined as the proportion of patients who are progression free (CR, PR and SD) at 8 months after initiating treatment with sunitinib in combination with erlotinib in patients with metastatic or unresectable clear cell or papillary carcinoma of the kidney. Complete Response (CR)= disappearance of all target lesions, Partial Response (PR)= At least a 30% decrease in the sum of the longest diameter of target lesions, and Stable Disease (SD)= Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (20% increase in the sum). | 8 months after initiating treatment with sunitinib in combination with erlotinib in patients with metastatic or unresectable clear cell or papillary carcinoma of the kidney | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Determine the Safety of Sunitinib in Combination With Erlotinib |  | For the duration of the study, up to 7 years | 
| Median Time to Progression | The Kaplan-Meier method will be used to estimate the median time to progression. | For the duration of the study, up to 7 years | 
| Proportion of Patients Whose Best Overall Response is Complete Response, Partial Response, Stable Disease, or Progressive Disease |  | From the start of treatment until the criteria for response is met. | 
| Maximum Percent Change in Tumor Measurement | The maximum percent change in Tumor Measurement is the greatest percent change in longest diameter (LD) for the target lesions from the baseline LD. For patients with no change in LD, the maximum percent change is the lowest increase in LD from the baseline LD. | Baseline through end of study, up to 7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III renal cell cancer, stage IV renal cell cancer, clear cell renal cell carcinoma, recurrent renal cell cancer