Everolimus and Gefitinib in Treating Patients With Progressive Glioblastoma Multiforme or Progressive Metastatic Prostate Cancer
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Purpose
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).
| Condition | Intervention | Phase |
|---|---|---|
|
Brain and Central Nervous System Tumors Prostate Cancer |
Drug: everolimus Drug: gefitinib |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | 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 |
- Safe and tolerable dose of everolimus (Phase I) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- Tolerability by NCI-CTC Criteria (Phase II) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
- Efficacy by Simon 2-Stage Design, serum prostate-specific antigen (prostate cancer only) (closed to accrual as of 10/19/2006), CT scan, bone scans at week 12 (Phase II) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- Pharmacokinetic interaction between everolimus and gefitinib as measured by a clearance of each drug given alone and together at baseline and weeks 1 and 2 for everolimus, at week 3 for gefitinib, and at week 4 for everolimus and gefitinib [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- Clinical outcomes compared to fludeoxyglucose F 18 positron-emission topography scan results at baseline, and at 3 days and 12 weeks following after completion of study treatment [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- Clinical outcomes compared to immunohistochemical markers related to the EGFR and PTEN-PI3K-AKT pathways at baseline [ Time Frame: 2 years ] [ Designated as safety issue: No ]
| Enrollment: | 61 |
| Study Start Date: | March 2004 |
| Study Completion Date: | February 2008 |
| Primary Completion Date: | February 2008 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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 |
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.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Male |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations| United States, New York | |
| Memorial Sloan-Kettering Cancer Center | |
| New York, New York, United States, 10021 | |
| Spain | |
| Vall d'Hebron University Hospital | |
| Barcelona, Spain, 08035 | |
| Principal Investigator: | Howard I. Scher, MD | Memorial Sloan-Kettering Cancer Center |
| Principal Investigator: | Neal Rosen, MD | Memorial Sloan-Kettering Cancer Center |
| Principal Investigator: | Lauren E. Abrey, MD | Memorial Sloan-Kettering Cancer Center |
More Information
Additional Information:
No publications provided
| Responsible Party: | Memorial Sloan-Kettering Cancer Center |
| ClinicalTrials.gov Identifier: | NCT00085566 History of Changes |
| Other Study ID Numbers: | 04-010, MSKCC-04010 |
| Study First Received: | June 10, 2004 |
| Last Updated: | April 26, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Keywords provided by Memorial Sloan-Kettering Cancer Center:
|
adult glioblastoma recurrent prostate cancer recurrent adult brain tumor |
stage IV prostate cancer adult giant cell glioblastoma adult gliosarcoma |
Additional relevant MeSH terms:
|
Glioblastoma Nervous System Neoplasms Prostatic Neoplasms Central Nervous System Neoplasms Astrocytoma Glioma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue Neoplasms by Site Nervous System Diseases |
Genital Neoplasms, Male Urogenital Neoplasms Genital Diseases, Male Prostatic Diseases Everolimus Sirolimus Gefitinib Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions Antibiotics, Antineoplastic Antineoplastic Agents Therapeutic Uses Antifungal Agents |
ClinicalTrials.gov processed this record on May 16, 2013