Everolimus and Gefitinib in Treating Patients With Progressive Glioblastoma Multiforme or Progressive Metastatic Prostate Cancer

A Phase I/II Trial to Assess the Tolerability of RAD 001 With Gefitinib in Patients With Glioblastoma Multiforme and Prostate Cancer and Efficacy in Patients With Castrate Metastatic Prostate Cancer

RATIONALE: Everolimus may stop the growth of tumor cells by stopping blood flow to the tumor. Gefitinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Combining everolimus with gefitinib may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of everolimus when given together with gefitinib and to see how well they work in treating patients with progressive glioblastoma multiforme or (progressive metastatic prostate cancer closed to accrual 10/19/06).

Study Overview

• Status: Completed
• Conditions: Prostate Cancer; Brain and Central Nervous System Tumors
• Intervention / Treatment: Drug: everolimus; Drug: gefitinib

Detailed Description

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of everolimus when given in combination with gefitinib in patients with progressive glioblastoma multiforme or (progressive castrate metastatic prostate cancer -closed to accrual as of 10/19/2006). (Phase I)
• Determine the safety and efficacy of this regimen in patients with progressive glioblastoma multiforme or (progressive castrate metastatic prostate cancer - closed to accrual as of 10/19/2006). (Phase II)

Secondary

• Determine whether a pharmacokinetic interaction exists between everolimus and gefitinib in patients treated with this regimen.
• Determine the association between clinical outcomes and markers that may predict sensitivity of a tumor in patients treated with this regimen.
• Determine the pharmacodynamic effects of this regimen on post-therapy tumor specimens and peripheral blood mononuclear cells from these patients.

OUTLINE: This is a phase I, open-label, non-randomized, dose-escalation study of everolimus followed by a phase II study.

• Phase I: Patients receive oral everolimus on day 1 and oral gefitinib once daily on days 8-21. Beginning on day 22, patients receive oral everolimus once weekly and oral gefitinib once daily. Treatment with the combination continues in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of 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 II (prostate cancer patients only) (closed to accrual as of 10/19/2006): Patients receive oral everolimus (at the MTD determined in phase I) once weekly and oral gefitinib once daily. Treatment continues in the absence of disease progression or unacceptable toxicity.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08035
    • Vall d'Hebron University Hospital
• United States
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following:

  • Glioblastoma multiforme (GBM) (phase I only)

    • Progressive disease despite standard therapy

    • Progressive disease based on 1 of the following:

      • New or progressive (25% bidimensional increase) soft tissue masses on CT scan or MRI
      • New or prior lesions that have increased in size by physical examination
    • Patients who had prior interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true disease progression (rather than radiation necrosis) by positron-emission tomography scan, thallium scanning, magnetic resonance spectroscopy, or surgical documentation

  • Castrate metastatic prostate cancer (closed to accrual as of 10/19/2006) (phase I and II)

    • Progressive disease despite standard therapy AND castrate levels < 50 ng/dL of testosterone

    • Progressive disease based on 1 or more of the following:

      • A minimum of 3 rising levels of prostate-specific antigen (PSA) that are obtained 1 or more weeks apart OR 2 rising PSA values obtained more than 1 month apart with at least a 25% increase over the range of values
      • New or progressive (25% bidimensional increase) soft tissue masses on CT scan or MRI
      • New metastatic lesions
    • Patients on an antiandrogen as part of initial therapy must show disease progression after discontinuation of the antiandrogen
    • Patients who have not undergone surgical orchiectomy must continue with medical therapy (e.g., gonadotropin-releasing hormone analogs) to maintain castrate levels of serum testosterone
• No brain metastases

PATIENT CHARACTERISTICS:

Age

• Over 18

Performance status

• Karnofsky 70-100%

Life expectancy

• More than 3 months

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• WBC ≥ 3,000/mm^3

Hepatic

• ALT and AST ≤ 2.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 mg/dL

Renal

• Creatinine within 1.5 times ULN (< 1.95 mg/dL at MSKCC)

Cardiovascular

• No significant cardiovascular disease
• No congestive heart failure
• No New York Heart Association class III or IV cardiac disease
• No active angina pectoris
• No myocardial infarction within the past 6 months

Other

• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception
• No serious medical illness
• No severe infection
• No severe malnutrition

• No other active malignancy except non-melanoma skin cancer

  • Patients are not considered to have an active malignancy if they have completed prior therapy and currently have a < 30% risk for relapse

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent biological therapy
• No concurrent immunotherapy

Chemotherapy

• No concurrent chemotherapy

Endocrine therapy

• See Disease Characteristics

Radiotherapy

• See Disease Characteristics
• More than 4 weeks since prior radiotherapy
• No concurrent radiotherapy

Surgery

• See Disease Characteristics
• Prior recent resection of recurrent or progressive GBM allowed provided patient has recovered
• More than 4 weeks since prior major surgery

Other

• Recovered from all prior therapy
• More than 4 weeks since prior investigational anticancer drugs
• No concurrent anticonvulsant that interacts with CYP3A4 (e.g., phenytoin, carbamazepine, or phenobarbital)
• No other concurrent cytotoxic therapy
• No other concurrent investigational or commercial agents or therapies for the malignancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Everolimus (RAD-001) and Gefitinib; •Phase I: Patients receive oral everolimus on day 1 and oral gefitinib once daily on days 8-21. Beginning on day 22, patients receive oral everolimus once weekly and oral gefitinib once daily. Treatment with the combination continues in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of 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 II (prostate cancer patients only) (closed to accrual as of 10/19/2006): Patients receive oral everolimus (at the MTD determined in phase I) once weekly and oral gefitinib once daily. Treatment continues in the absence of disease progression or unacceptable toxicity.

Drug: everolimus; Drug: gefitinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Objective Response	Response will be evaluated in this study using the new international criteria Response Evaluation Criteria in Solid Tumors (RECIST)	2 years

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Lauren E. Abrey, MD, Memorial Sloan Kettering Cancer Center; Principal Investigator: Howard I. Scher, MD, Memorial Sloan Kettering Cancer Center; Principal Investigator: Neal Rosen, MD, Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start: March 1, 2004
• Primary Completion (Actual): February 1, 2008
• Study Completion (Actual): February 1, 2008

Study Registration Dates

• First Submitted: June 10, 2004
• First Submitted That Met QC Criteria: June 10, 2004
• First Posted (Estimate): June 11, 2004

Study Record Updates

• Last Update Posted (Estimate): January 20, 2016
• Last Update Submitted That Met QC Criteria: December 15, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: stage IV prostate cancer; recurrent prostate cancer; adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma; recurrent adult brain tumor
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Male; Prostatic Diseases; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Prostatic Neoplasms; Glioblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Gefitinib; Everolimus
• Other Study ID Numbers: 04-010; MSKCC-04010