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

• Sponsor: Memorial Sloan Kettering Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00085566
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 61
• Locations: 2
• Arm: 1
• Duration (Months): 47
• Patients Per Site: 30.5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors; Prostate Cancer	Drug: everolimus; Drug: gefitinib	Phase 1/Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: Mar 1, 2004
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Feb 1, 2008

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Overall Objective Response [2 years]

   Response will be evaluated in this study using the new international criteria Response Evaluation Criteria in Solid Tumors (RECIST)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes 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

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
2	Vall d'Hebron University Hospital	Barcelona		Spain	08035

Sponsors and Collaborators

• Memorial Sloan Kettering Cancer Center
• National Cancer Institute (NCI)

Investigators

• 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT00085566
• Other Study ID Numbers: 04-010; MSKCC-04010
• First Posted: Jun 11, 2004
• Last Update Posted: Jan 20, 2016
• Last Verified: Dec 1, 2015

• 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: Prostatic Neoplasms; Glioblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Everolimus; Gefitinib

Study Results

Participant Flow

Arm/Group Title	RAD 001 30 mg	RAD 001 50 mg	RAD 001 70 mg
Arm/Group Description	30 mg RAD 001 with Gefitinib in Patients with Glioblastoma Multiforme and Prostate Cancer	50 mg RAD 001 with Gefitinib in Patients with Glioblastoma Multiforme and Prostate Cancer	70 mg RAD 001 with Gefitinib in Patients with Glioblastoma Multiforme and Prostate Cancer
Period Title: Overall Study
STARTED	3	3	57
COMPLETED	3	3	43
NOT COMPLETED	0	0	14

Baseline Characteristics

Arm/Group Title	RAD 001 30 mg	RAD 001 50 mg	RAD 001 70 mg	Total
Arm/Group Description	30 mg RAD 001 with Gefitinib in Patients with Glioblastoma Multiforme and Prostate Cancer	50 mg RAD 001 with Gefitinib in Patients with Glioblastoma Multiforme and Prostate Cancer	70 mg RAD 001 with Gefitinib in Patients with Glioblastoma Multiforme and Prostate Cancer	Total of all reporting groups
Overall Participants	3	3	57	63
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	1 33.3%	1 33.3%	32 56.1%	34 54%
>=65 years	2 66.7%	2 66.7%	25 43.9%	29 46%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	11 19.3%	11 17.5%
Male	3 100%	3 100%	46 80.7%	52 82.5%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RAD 001 30 mg	RAD 001 50 mg	RAD 001 70 mg
Arm/Group Description	30 mg RAD 001 with Gefitinib in Patients with Glioblastoma Multiforme and Prostate Cancer	50 mg RAD 001 with Gefitinib in Patients with Glioblastoma Multiforme and Prostate Cancer	70 mg RAD 001 with Gefitinib in Patients with Glioblastoma Multiforme and Prostate Cancer
Measure Participants	3	3	43
Partial Response (PR)	0 0%	0 0%	2 3.5%
Stable Disease (SD)	0 0%	1 33.3%	15 26.3%
Progression of Disease (POD)	3 100%	2 66.7%	26 45.6%

Adverse Events

Arm/Group Title	RAD 001 30 mg		RAD 001 50 mg		RAD 001 70 mg
Arm/Group Description	30 mg RAD 001 with Gefitinib in Patients with Glioblastoma Multiforme and Prostate Cancer		50 mg RAD 001 with Gefitinib in Patients with Glioblastoma Multiforme and Prostate Cancer		70 mg RAD 001 with Gefitinib in Patients with Glioblastoma Multiforme and Prostate Cancer
All Cause Mortality
	RAD 001 30 mg		RAD 001 50 mg		RAD 001 70 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	RAD 001 30 mg		RAD 001 50 mg		RAD 001 70 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		1/3 (33.3%)		18/57 (31.6%)
Blood and lymphatic system disorders
Hemoglobin	0/3 (0%)	0	1/3 (33.3%)	1	0/57 (0%)	0
ALT, SGPT	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Hemorrhage, Peritoneal cavity	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Leukocytes (total WBC)	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Cardiac disorders
Cardiac General, other	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Eye disorders
Vision-blurred vision	0/3 (0%)	0	1/3 (33.3%)	1	0/57 (0%)	0
Gastrointestinal disorders
Diarrhea	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Nausea	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
General disorders
Death not associated w CTCAE term-Disease progression NOS	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Dehydration	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Extremity-lower (gait/walking)	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Fatigue (asthenia, lethargy, malaise)	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Muscle weakness - Extremity-lower	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Pain - Head/headache	0/3 (0%)	0	0/3 (0%)	0	2/57 (3.5%)	2
Infections and infestations
Infection, other	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Metabolism and nutrition disorders
Creatinine	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Nervous system disorders
Confusion	0/3 (0%)	0	1/3 (33.3%)	1	2/57 (3.5%)	2
Hydrocephalus	0/3 (0%)	0	1/3 (33.3%)	1	0/57 (0%)	0
Mood alteration - Agitation	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Neurology - Other	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Seizure	0/3 (0%)	0	0/3 (0%)	0	3/57 (5.3%)	3
Renal and urinary disorders
Incontinence, urinary	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Renal failure	0/3 (0%)	0	0/3 (0%)	0	2/57 (3.5%)	2
Urinary retention (including neurogenic bladder)	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Pulmonary/upper respiratory - Other	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Thrombosis/embolism (vascular access-related)	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Thrombosis/thrombus/embolism	0/3 (0%)	0	0/3 (0%)	0	2/57 (3.5%)	2
Skin and subcutaneous tissue disorders
Skin infection	0/3 (0%)	0	0/3 (0%)	0	1/57 (1.8%)	1
Other (Not Including Serious) Adverse Events
	RAD 001 30 mg		RAD 001 50 mg		RAD 001 70 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		3/3 (100%)		48/57 (84.2%)
Blood and lymphatic system disorders
Hemoglobin	1/3 (33.3%)	1	2/3 (66.7%)	2	20/57 (35.1%)	20
Prothrombin Time and International Normalized Ratio	0/3 (0%)	0	0/3 (0%)	0	5/57 (8.8%)	5
Leukocytes (total WBC)	0/3 (0%)	0	1/3 (33.3%)	1	10/57 (17.5%)	10
Lymphopenia	0/3 (0%)	0	1/3 (33.3%)	1	17/57 (29.8%)	17
Neutrophils/granulocytes (ANC/AGC)	0/3 (0%)	0	0/3 (0%)	0	5/57 (8.8%)	5
Platelets	0/3 (0%)	0	0/3 (0%)	0	4/57 (7%)	4
Partial Thromboplastin Time (PTT)	0/3 (0%)	0	0/3 (0%)	0	6/57 (10.5%)	6
Gastrointestinal disorders
Nausea	0/3 (0%)	0	0/3 (0%)	0	3/57 (5.3%)	3
General disorders
Edema: limb	0/3 (0%)	0	0/3 (0%)	0	5/57 (8.8%)	5
Fatigue (asthenia, lethargy, malaise)	1/3 (33.3%)	1	1/3 (33.3%)	1	12/57 (21.1%)	12
Mucositis (Clincal exam)- Oral cavity	0/3 (0%)	0	0/3 (0%)	0	4/57 (7%)	4
Pain - Bone	1/3 (33.3%)	1	0/3 (0%)	0	0/57 (0%)	0
Extremity-lower (gait/walking)	0/3 (0%)	0	1/3 (33.3%)	1	0/57 (0%)	0
Metabolism and nutrition disorders
Albumin, low (hypoalbuminemia)	0/3 (0%)	0	0/3 (0%)	0	4/57 (7%)	4
Alkaline phosphatase	2/3 (66.7%)	2	0/3 (0%)	0	8/57 (14%)	8
ALT, SGPT	0/3 (0%)	0	0/3 (0%)	0	8/57 (14%)	8
AST, SGOT	1/3 (33.3%)	1	0/3 (0%)	0	6/57 (10.5%)	6
Calcium, low (hypocalcemia)	0/3 (0%)	0	0/3 (0%)	0	10/57 (17.5%)	10
Cholesterol, high (hypercholestremia)	0/3 (0%)	0	0/3 (0%)	0	3/57 (5.3%)	3
Creatinine	0/3 (0%)	0	0/3 (0%)	0	4/57 (7%)	4
Glucose, high (hyperglycemia)	0/3 (0%)	0	2/3 (66.7%)	2	19/57 (33.3%)	19
Phosphate, low (hypophosphatemia)	0/3 (0%)	0	0/3 (0%)	0	6/57 (10.5%)	6
Sodium, low (hyponatremia)	0/3 (0%)	0	0/3 (0%)	0	4/57 (7%)	4
Nervous system disorders
Seizure	0/3 (0%)	0	0/3 (0%)	0	6/57 (10.5%)	6
Neuropathy: sensory	1/3 (33.3%)	1	1/3 (33.3%)	1	0/57 (0%)	0
Reproductive system and breast disorders
Dyspnea (shortness of breath)	0/3 (0%)	0	0/3 (0%)	0	8/57 (14%)	8
Skin and subcutaneous tissue disorders
Rash: acne/acneiform	0/3 (0%)	0	0/3 (0%)	0	6/57 (10.5%)	6
Pruritus/itching	0/3 (0%)	0	1/3 (33.3%)	1	0/57 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.