Vatalanib and Everolimus in Treating Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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RATIONALE: Vatalanib and everolimus may stop the growth of tumor cells by blocking blood flow to the tumor and by blocking some of the enzymes needed for cell growth. PURPOSE: This phase I trial is studying the side effects and best dose of vatalanib and everolimus and to see how well they work in treating patients with advanced solid tumors.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose (MTD) of vatalanib and everolimus in patients with advanced solid tumors. Determine the safety and tolerability of vatalanib and everolimus in patients with advanced solid tumors. Evaluate the safety and tolerability of vatalanib and everolimus at the MTD in patients with metastatic renal cell carcinoma (RCC). Secondary Describe the non dose-limiting toxic effects associated with vatalanib and everolimus. Describe the pharmacokinetics of vatalanib and everolimus in patients with advanced solid tumors. Determine the functional extent of mTOR inhibition by changes in the phosphorylation status of S6K protein in peripheral blood mononuclear cells in patients treated with vatalanib and everolimus. Describe any clinical responses seen in patients with metastatic RCC in a dose-expansion cohort treated at the MTD. Observe overall survival of RCC patients treated with vatalanib and everolimus. Determine the time to progression of patients with RCC treated with vatalanib and everolimus. OUTLINE: This is a phase I dose-escalation study followed by a phase Ib study. Phase I (solid tumors): Patients receive oral vatalanib on days 1-28 and oral everolimus on days 15-28 during course 1 and on days 1-28 during all subsequent courses. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of vatalanib and everolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase Ib (renal cell carcinoma only): Patients receive oral vatalanib and oral everolimus at the MTD on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 6 months. PROJECTED ACCRUAL: A total of 44 patients will be accrued for this study.

Official Title
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PTK787/ZK222584 and RAD001 for Patients With Advanced Solid Tumors

Conditions
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Kidney Cancer, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: RAD001 (everolimus)
* Drug: PTK787 (vatalanib)


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed solid tumor with radiographic evidence of metastatic disease No standard therapy exists (phase I) Unresectable or metastatic renal cell carcinoma (phase Ib) PATIENT CHARACTERISTICS: Karnofsky performance status 70-100% Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 9 g/dL AST or ALT ≤ 2.5 times upper limit of normal (ULN) Total cholesterol < 300 mg/dL Triglycerides < 350 mg/dL Bilirubin ≤ 1.5 times ULN Creatinine ≤ 1.5 times ULN OR creatinine clearance > 40 mL/min Negative proteinuria by dip stick OR total urinary protein ≤ 500 mg No uncontrolled high blood pressure, history of labile hypertension, or history of poor compliance with antihypertensive regimen No unstable angina pectoris No symptomatic congestive heart failure (New York Heart Association class III or IV heart disease) No uncontrolled serious cardiac arrhythmia (symptomatic supraventricular tachycardia or any ventricular tachycardia/fibrillation) No myocardial infarction in the past 6 months No uncontrolled diabetes No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung No active or uncontrolled infection No uncontrolled hyperlipidemia No chronic renal disease No acute or chronic liver disease (e.g., hepatitis or cirrhosis) No impaired gastrointestinal (GI) function OR GI disease that may significantly alter the absorption of vatalanib or everolimus, including any of the following: Ulcerative disease Uncontrolled nausea and vomiting with solid food Watery diarrhea > 5 times daily Malabsorption syndrome Bowel obstruction Inability to swallow the tablets No confirmed HIV infection Not pregnant Negative pregnancy test Fertile patients must use effective contraception No other concurrent severe and/or uncontrolled medical condition that would preclude study participation PRIOR CONCURRENT THERAPY: Recovered from prior therapy No prior antivascular endothelial growth factor therapy More than 4 weeks since prior major surgery* (laparotomy) More than 2 weeks since prior minor surgery* More than 4 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas) More than 6 weeks since prior antibody therapy More than 2 weeks since prior biologic/immunotherapy More than 2 weeks since prior limited-field radiotherapy More than 4 weeks since prior full-field radiotherapy More than 4 weeks since prior investigational agents Prior transfusions allowed provided blood counts are stable for > 2 weeks Concurrent epoetin alfa allowed No concurrent warfarin or similar oral anticoagulants that are metabolized by the cytochrome P450 system Heparin and low molecular weight heparin allowed NOTE: *Insertion of a vascular access device is not considered major or minor surgery

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: PTK787, RAD001<br>PTK787 (vatalinib) 1000 mg daily, RAD001 (everolimus) 5 mg daily | Drug: RAD001 (everolimus)<br> <br> * Other names: Afinitor;Drug: PTK787 (vatalanib)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of vatalanib and everolimus | Patients were evaluated on Day 1,14 and 28 for dose limiting toxicities | Day 1 - 28 | 
| Safety and tolerability | Adverse events were assessed every 14 days for the length of the treatment period. | Duration of study treatment | 
| Safety and tolerability at the MTD in patients with metastatic renal cell carcinoma (RCC) | Patients were assessed for adverse events every 14 days while on study treatment | Duration of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non dose-limiting toxicity | Patients were assessed every 14 days for non dose-limiting toxicity while on study treatment | Duration of study treatment | 
| Pharmacokinetics | Blood was drawn for PK assessment on Day 14 of Cycle 1 and Day 1 of Cycle 2 | Day 14 Cycle 1, Day 1 Cycle 2 | 
| Changes in the phosphorylation status of S6K protein in peripheral blood mononuclear cells | Samples were collected on Day 1 and at Day 28 of Cycle 1 | Day 1 and 28 | 
| Clinical response in patients with metastatic RCC | patients underwent restaging studies every 2 cycles while on treatment for evidence of disease response | Duration of treatment | 
| Overall survival of patients with RCC |  | Until death | 
| Time to progression of patients with RCC | Patients were followed for evidence of disease progression as long as they remained on study drug. | Duration of study treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified adult solid tumor, protocol specific, recurrent renal cell cancer, stage IV renal cell cancer