Clinical trial NCT00303732: Vatalanib and Everolimus in Treating Patients With Advanced Solid Tumors
Official title: PTK787/ZK222584 and RAD001 for Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Kidney Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Keywords: unspecified adult solid tumor, protocol specific
recurrent renal cell cancer
stage IV renal cell cancer
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2006-03-17
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility 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

Primary outcomes:
measure: Maximum tolerated dose (MTD) of vatalanib and everolimus
timeFrame: Day 1 - 28
measure: Safety and tolerability
timeFrame: Duration of study treatment
measure: Safety and tolerability at the MTD in patients with metastatic renal cell carcinoma (RCC)
timeFrame: Duration of study treatment
Secondary outcomes:
measure: Non dose-limiting toxicity
timeFrame: Duration of study treatment
measure: Pharmacokinetics
timeFrame: Day 14 Cycle 1, Day 1 Cycle 2
measure: Changes in the phosphorylation status of S6K protein in peripheral blood mononuclear cells
timeFrame: Day 1 and 28
measure: Clinical response in patients with metastatic RCC
timeFrame: Duration of treatment
measure: Overall survival of patients with RCC
timeFrame: Until death
measure: Time to progression of patients with RCC
timeFrame: Duration of study treatment
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
Study officials:
affiliation: Duke Cancer Institute
name: Daniel J. George, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Speca JC, Mears AL, Creel PA, et al.: Phase I study of PTK787/ZK222584 (PTK/ZK) and RAD001 for patients with advanced solid tumors and dose expansion in renal cell carcinoma patients. [Abstract] J Clin Oncol 25 (Suppl 18): A-5039, 244s, 2007.