Vatalanib and Everolimus in Treating Patients With Advanced Solid Tumors (PTK/RAD)

Daniel George, MD

Status and phase

Completed

Phase 1

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Kidney Cancer

Treatments

Drug: RAD001 (everolimus)

Drug: PTK787 (vatalanib)

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT00303732

CDR0000454988 (Other Identifier)

Pro00012347

DUMC-6626-04-12R0 (Other Identifier)

Details and patient eligibility

About

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.

Full description

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.

Enrollment

37 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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