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

PTK787/ZK222584 and RAD001 for Patients With Advanced Solid Tumors

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.

Study Overview

• Status: Completed
• Conditions: Kidney Cancer; Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Drug: RAD001 (everolimus); Drug: PTK787 (vatalanib)

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.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: PTK787, RAD001; PTK787 (vatalinib) 1000 mg daily, RAD001 (everolimus) 5 mg daily	Drug: RAD001 (everolimus); Other Names: Afinitor; Drug: PTK787 (vatalanib)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Daniel George, MD
• Collaborators: Novartis

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2004
• Primary Completion (ACTUAL): August 1, 2010
• Study Completion (ACTUAL): August 1, 2012

Study Registration Dates

• First Submitted: March 15, 2006
• First Submitted That Met QC Criteria: March 15, 2006
• First Posted (ESTIMATE): March 17, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): March 3, 2016
• Last Update Submitted That Met QC Criteria: March 1, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: stage IV renal cell cancer; recurrent renal cell cancer; unspecified adult solid tumor, protocol specific
• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Kidney Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Everolimus; Vatalanib
• Other Study ID Numbers: Pro00012347; DUMC-6626-04-12R0 (OTHER: Duke IRB legacy number); CDR0000454988 (OTHER: National Cancer Institute)