Imatinib Mesylate and Hydroxyurea in Treating Patients With Recurrent or Progressive Meningioma

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00354913
• Collaborator: National Cancer Institute (NCI) (NIH), Novartis Pharmaceuticals (Industry)
• Enrollment: 21
• Location: 1
• Arm: 1
• Duration (Months): 65
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

RATIONALE: Imatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as hydroxyurea, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving imatinib mesylate together with hydroxyurea may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving imatinib mesylate together with hydroxyurea works in treating patients with recurrent or progressive meningioma.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma; Gliosarcoma	Drug: hydroxyurea; Drug: imatinib mesylate	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Evaluate the activity of imatinib mesylate and hydroxyurea, as measured by 6-month progression-free survival, in patients with recurrent or progressive meningioma.

Secondary

• Evaluate the progression-free survival (PFS)

• Overall survival (OS),

• Objective response rate among patients treated with this regimen.

OUTLINE: This is an open-label study.

Patients receive oral imatinib mesylate once or twice daily and oral hydroxyurea twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PROJECTED ACCRUAL: A total of 21 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Imatinib Mesylate Plus Hydroxyurea in the Treatment of Patients With Recurrent/Progressive Meningioma
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Imatinib mesylate+hydroxyurea All patients receive imatinib mesylate and hydroxyurea orally on a daily, continuous basis. Dosing of imatinib mesylate is adjusted for patients who are also receiving p450-inducing anti-epileptic drugs.

Drug: hydroxyurea; Hydroxyurea is administered orally twice a day. The dose will be set at 500 mg twice a day for all patients. If vomiting occurs not additional trial medication should be taken that day in an effort to replace the material that has been vomited. It is recommended that patients take their prescribed hydroxyurea at the same time that they take their prescribed imatinib mesylate, however, a 30-60 minute interval between agents is acceptable, if required for practical or other compliance issues.; Other Names: Droxia Hydrea Hydroxycarbamide ; Drug: imatinib mesylate; Imatinib administered orally on daily, continuous basis. Imatinib doses of 400mg/600mg administered once daily, whereas daily doses of 800mg/greater administered as equally divided dose taken twice day. Dose for Imatinib: Patients receiving p450-inducing antiepileptic drugs:500mg twice day Patients not receiving p450-inducing antiepileptic drugs:400mg/day. If patients who were not on Cytochrome P450, family 3, subfamily A (CYP3A) enzyme-reducing anti-epileptic drug (EIAED) when originally enrolled must initiate CYP3A enzyme-inducing anti-epileptic drug while on study, study regimen will remain same for minimum of 2 wks before pt transitions to dosing as specified for patients on anti-epileptic drug. If patients originally enrolled must discontinue all EIAEDs while on study, in interest of patient safety, dosing of study regimen will transition to that of patients not on anti-epileptics immediately.; Other Names: Gleevec

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival at 6 Months [From the date of study treatment initiation to the date of the first documented progression or death from any cause, whichever came first, assessed up to 69 months. For each participant, PFS was assessed at 6 months after treatment initiation.]

   Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or death due to any cause.

Secondary Outcome Measures

1. Median Progression-free Survival (PFS) [From the date of study treatment initiation to the date of the first documented progression or death from any cause, whichever came first, assessed up to 69 months.]

   Time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.

2. Median Overall Survival (OS) [From the date of study treatment initiation to the date of death from any cause, assessed up to 69 months.]

   Time in months from the start of study treatment to date of death due to any cause. Patients alive at last follow-up are censored as of that follow-up date. Median OS was estimated using a Kaplan-Meier curve.

3. Objective Response Rate [69 Months]

   Percentage of participants with an objective response (complete response or partial response). Per modified Macdonald criteria and assessed by MRI, complete response (CR) was the disappearance of all target lesions and partial response (PR) was a ≥50% decrease in the sum of the longest diameter of target lesions. Objective response = CR+PR.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed meningioma

• Recurrent or progressive disease after prior surgical resection

• Measurable disease by contrast-enhanced MRI

• Multifocal disease allowed

• No evidence of intratumor hemorrhage on pretreatment diagnostic imaging

• Stable postoperative grade 1 hemorrhage allowed

• No peripheral edema or central or systemic fluid collections ≥ grade 2 (e.g., pericardial effusion, pulmonary effusion, ascites)

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%

• Absolute neutrophil count > 1,500/mm³

• Hemoglobin > 9 g/dL

• Platelet count > 100,000/mm³

• Potassium normal*

• Calcium normal*

• Magnesium normal*

• Phosphorus normal*

• alanine aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times upper limit of normal (ULN)

• Bilirubin < 1.5 times ULN

• Creatinine < 1.5 times ULN OR creatinine clearance > 50 mL/min

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No excessive risk of bleeding, as defined by stroke within the past 6 months

• No active systemic bleeding (i.e., gastrointestinal bleeding or gross hematuria)

• No history of central nervous system (CNS) or intraocular bleeding or septic endocarditis

• No concurrent severe and/or uncontrolled medical disease, including any of the following:

• Uncontrolled diabetes

• Congestive cardiac failure

• Myocardial infarction within the past 6 months

• Poorly controlled hypertension

• History of labile hypertension

• History of poor compliance with antihypertensive regimen

• Chronic renal disease

• Active uncontrolled infection requiring intravenous antibiotics

• No acute or chronic liver disease (i.e., hepatitis, cirrhosis)

• No HIV positivity

• No impairment of gastrointestinal function or disease that may significantly alter the absorption of imatinib mesylate, including any of the following:

• Ulcerative disease

• Uncontrolled nausea

• Vomiting

• Diarrhea

• Malabsorption syndrome

• Bowel obstruction

• Inability to swallow tablets

• No other malignancy within the past 5 years except basal cell skin cancer or cervical carcinoma in situ NOTE: *Unless correctable with supplements

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Recovered from prior therapy

• More than 1 week since prior tumor biopsy

• More than 2 weeks since prior surgical resection

• Prior hydroxyurea allowed provided patient has not had progressive disease or toxicity

grade 3

• No prior imatinib mesylate or other platelet-derived growth factor-directed therapy

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas)*

• Chemotherapeutic agents such as etoposide that are normally given at shorter intervals allowed even if < 4 weeks from last prior dose of chemotherapy

• At least 4 weeks since prior radiotherapy*

• At least 1 week since prior biological, immunotherapeutic, or cytostatic drugs

• At least 2 weeks since prior investigational drugs

• No concurrent warfarin NOTE: *Unless there is unequivocal evidence of tumor progression

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke Cancer Institute	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Duke University
• National Cancer Institute (NCI)
• Novartis Pharmaceuticals

Investigators

• Principal Investigator: David A. Reardon, MD, Duke Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT00354913
• Other Study ID Numbers: Pro00006768; DUMC-7082-05-4R0; NOVARTIS-DUMC-7082-05-4R0; NCT00611234
• First Posted: Jul 20, 2006
• Last Update Posted: Jan 18, 2013
• Last Verified: Dec 1, 2012

• Keywords provided by Duke University: adult grade I meningioma; adult grade II meningioma; adult grade III meningioma; adult papillary meningioma; adult anaplastic meningioma; recurrent adult brain tumor; glioblastoma multiforme (GBM); Imatinib; Imatinib mesylate; Hydroxyurea; Droxia; Hydrea; Hydroxycarbamide; Gleevec; Meningioma
• Additional relevant MeSH terms: Glioblastoma; Meningioma; Gliosarcoma; Imatinib Mesylate; Hydroxyurea

Study Results

Participant Flow

Arm/Group Title	Imatinib Mesylate+Hydroxyurea
Arm/Group Description	All patients receive imatinib mesylate and hydroxyurea orally on a daily, continuous basis. Dosing of imatinib mesylate is adjusted for patients who are also receiving p450-inducing anti-epileptic drugs.
Period Title: Overall Study
STARTED	21
COMPLETED	21
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Imatinib Mesylate+Hydroxyurea
Arm/Group Description	All patients receive imatinib mesylate and hydroxyurea orally on a daily, continuous basis. Dosing of imatinib mesylate is adjusted for patients who are also receiving p450-inducing anti-epileptic drugs.
Overall Participants	21
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.0 (13.9)
Sex: Female, Male (Count of Participants)
Female	12 57.1%
Male	9 42.9%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival at 6 Months
Description	Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or death due to any cause.
Time Frame	From the date of study treatment initiation to the date of the first documented progression or death from any cause, whichever came first, assessed up to 69 months. For each participant, PFS was assessed at 6 months after treatment initiation.

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Imatinib Mesylate+Hydroxyurea
Arm/Group Description	All patients receive imatinib mesylate and hydroxyurea orally on a daily, continuous basis. Dosing of imatinib mesylate is adjusted for patients who are also receiving p450-inducing anti-epileptic drugs.
Measure Participants	21
Number (95% Confidence Interval) [percentage of participants]	61.9 294.8%

2. Secondary Outcome

Title	Median Progression-free Survival (PFS)
Description	Time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.
Time Frame	From the date of study treatment initiation to the date of the first documented progression or death from any cause, whichever came first, assessed up to 69 months.

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Imatinib Mesylate+Hydroxyurea
Arm/Group Description	All patients receive imatinib mesylate and hydroxyurea orally on a daily, continuous basis. Dosing of imatinib mesylate is adjusted for patients who are also receiving p450-inducing anti-epileptic drugs.
Measure Participants	21
Median (95% Confidence Interval) [months]	7

3. Secondary Outcome

Title	Median Overall Survival (OS)
Description	Time in months from the start of study treatment to date of death due to any cause. Patients alive at last follow-up are censored as of that follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Time Frame	From the date of study treatment initiation to the date of death from any cause, assessed up to 69 months.

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Imatinib Mesylate+Hydroxyurea
Arm/Group Description	All patients receive imatinib mesylate and hydroxyurea orally on a daily, continuous basis. Dosing of imatinib mesylate is adjusted for patients who are also receiving p450-inducing anti-epileptic drugs.
Measure Participants	21
Median (95% Confidence Interval) [months]	66

4. Secondary Outcome

Title	Objective Response Rate
Description	Percentage of participants with an objective response (complete response or partial response). Per modified Macdonald criteria and assessed by MRI, complete response (CR) was the disappearance of all target lesions and partial response (PR) was a ≥50% decrease in the sum of the longest diameter of target lesions. Objective response = CR+PR.
Time Frame	69 Months

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Imatinib Mesylate+Hydroxyurea
Arm/Group Description	All patients receive imatinib mesylate and hydroxyurea orally on a daily, continuous basis. Dosing of imatinib mesylate is adjusted for patients who are also receiving p450-inducing anti-epileptic drugs.
Measure Participants	21
Number [percentage of participants]	0 0%

Adverse Events

Adverse Event Reporting Description	Adverse Events were gathered in Common Terminology Criteria for Adverse Events (CTCAE) v. 3.0 and converted to CTCAE v. 4.0 for entry into ClinicalTrials.gov
Arm/Group Title	Imatinib Mesylate+Hydroxyurea
Arm/Group Description	All patients receive imatinib mesylate and hydroxyurea orally on a daily, continuous basis. Dosing of imatinib mesylate is adjusted for patients who are also receiving p450-inducing anti-epileptic drugs.
All Cause Mortality
	Imatinib Mesylate+Hydroxyurea
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Imatinib Mesylate+Hydroxyurea
	Affected / at Risk (%)	# Events
Total	1/21 (4.8%)
Infections and infestations
Sepsis	1/21 (4.8%)
Other (Not Including Serious) Adverse Events
	Imatinib Mesylate+Hydroxyurea
	Affected / at Risk (%)	# Events
Total	15/21 (71.4%)
Blood and lymphatic system disorders
Anemia	5/21 (23.8%)
Eye disorders
Blurred Vision	4/21 (19%)
Extraocular muscle paresis	1/21 (4.8%)
Eye disorders-Other, Inflammation: right eye	1/21 (4.8%)
Eye pain	1/21 (4.8%)
Vitreous hemorrhage	1/21 (4.8%)
Gastrointestinal disorders
Abdominal distension	1/21 (4.8%)
Constipation	3/21 (14.3%)
Diarrhea	2/21 (9.5%)
Gastrointestinal disorders-Other: increased Appetite	1/21 (4.8%)
Hemorrhoids	1/21 (4.8%)
Mucositis oral	1/21 (4.8%)
Nausea	5/21 (23.8%)
Rectal hemorrhage	1/21 (4.8%)
Vomiting	2/21 (9.5%)
General disorders
Edema limbs	2/21 (9.5%)
Fatigue	4/21 (19%)
Non-cardiac chest pain	1/21 (4.8%)
Infections and infestations
Infections and infestations-Other: ear drainage	1/21 (4.8%)
Sinusitis	1/21 (4.8%)
Upper respiratory infection	1/21 (4.8%)
Investigations
Investigations-Other: BUN, high	1/21 (4.8%)
Neutrophil count decreased	4/21 (19%)
Platelet count decreased	3/21 (14.3%)
Weight gain	1/21 (4.8%)
White blood count decreased	3/21 (14.3%)
Metabolism and nutrition disorders
Hyperglycemia	2/21 (9.5%)
Hypernatremia	1/21 (4.8%)
Hypoalbuminemia	1/21 (4.8%)
Hypocalcemia	1/21 (4.8%)
Hypokalemia	1/21 (4.8%)
Hyponatremia	1/21 (4.8%)
Hypophosphatemia	1/21 (4.8%)
Musculoskeletal and connective tissue disorders
Back pain	1/21 (4.8%)
Pain in extremity	2/21 (9.5%)
Nervous system disorders
Ataxia	2/21 (9.5%)
Cognitive disturbance	1/21 (4.8%)
Depressed level of consciousness	1/21 (4.8%)
Dizziness	3/21 (14.3%)
Dysphasia	2/21 (9.5%)
Headache	3/21 (14.3%)
Memory impairment	3/21 (14.3%)
Nervous systems disorders-Other: gait	1/21 (4.8%)
Nervous system disorders-Other: Mood Alteration NOS	1/21 (4.8%)
Peripheral motor neuropathy	2/21 (9.5%)
Peripheral sensory neuropathy	1/21 (4.8%)
Pyramidal tract syndrome	2/21 (9.5%)
Psychiatric disorders
Agitation	1/21 (4.8%)
Confusion	1/21 (4.8%)
Insomnia	3/21 (14.3%)
Psychosis	1/21 (4.8%)
Renal and urinary disorders
Renal and urinary disorders-Other: nocturia	1/21 (4.8%)
Reproductive system and breast disorders
Reproductive system and breast disorders-Other: NOS	1/21 (4.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/21 (4.8%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/21 (4.8%)

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.