Adult Grade III Meningioma, Adult Grade II Meningioma, Adult Grade I Meningioma, Adult Meningeal Hemangiopericytoma, Adult Meningioma, Recurrent Adult Brain Tumor
Conditions
Brief summary
Phase II trial to study the effectiveness of imatinib mesylate in treating patients who have recurrent meningioma. Imatinib mesylate may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth
Detailed description
PRIMARY OBJECTIVE: I. Determine the efficacy of imatinib mesylate, in terms of 6-month progression-free survival, of patients with recurrent meningioma. SECONDARY OBJECTIVES I. Determine the response rate and overall survival of patients treated with this drug. II. Evaluate the safety profile of this drug in these patients. III. Determine the pharmacokinetics of this drug in these patients. IV. Develop exploratory data concerning surrogate markers of of angiogenic activity in vivo using functional neuro-imaging studies and in vitro assays of serum angiogenic peptides of this drug in these patients. V. Develop exploratory data concerning evidence of platelet-derived growth factor (PDGF) inhibition in tumor specimens taken from patients undergoing surgery VI. Develop exploratory data correlating molecular abnormalities in the tumor with response in patients treated with this drug. OUTLINE: This is a multicenter study. Patients are stratified according to concurrent use of enzyme-inducing antiepileptic drugs (yes vs no), histology (benign vs atypical or malignant), neurofibromatosis positivity (yes vs no), and preoperative candidacy (yes vs no). Patients receive oral imatinib mesylate once or twice daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months. PROJECTED ACCRUAL: A total of 60 patients (30 per stratum) will be accrued for this study within 8-12 months.
Interventions
DRUGimatinib mesylate
Given orally
OTHERlaboratory biomarker analysis
Correlative studies
OTHERpharmacological study
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed meningioma * Benign, malignant, or atypical disease * Neurofibromatosis (NF) type 1 or 2 allowed * Hemangiopericytoma allowed * Unequivocal evidence of tumor recurrence or progression by MRI or CT scan (on steroid dosage that is stable for at least 5 days) * Evaluable residual disease by MRI or CT scan if previously treated with surgical resection for recurrent or progressive disease * Newly diagnosed recurrent disease that requires surgical debulking allowed * Prior standard external-beam radiotherapy, interstitial brachytherapy, or gamma-knife radiosurgery allowed provided disease has progressed since completion of therapy * Patients who have had prior brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis based upon positron-emission tomography or thallium scanning, magnetic resonance spectroscopy, or surgical documentation * Patients with a history of NF may have other stable Central Nervous System (CNS) tumors (e.g., schwannoma, acoustic neuroma, or ependymoma) provided those lesions have been stable in size for the past 6 months * Performance status - Karnofsky 60-100% * More than 8 weeks * Absolute neutrophil count at least 2,000/mm\^3 * Platelet count at least 120,000/mm\^3 * Hemoglobin at least 10 g/dL (transfusions allowed) * No bleeding disorders * Bilirubin less than 2 times upper limit of normal (ULN) * Serum glutamic oxaloacetic transaminase (SGOT) less than 2 times ULN * Prothrombin Time (PT), Partial thromboplastin time (PTT), and International normalized Ratio (INR) no greater than 1.5 times ULN * Creatinine less than 1.5 mg/dL * Creatinine clearance at least 60 mL/min * No deep venous or arterial thrombosis within the past 6 weeks * No pulmonary embolism within the past 6 weeks * No serious active infection * No prior intracranial hemorrhage * No concurrent disease that would obscure toxicity or dangerously alter drug metabolism * No other malignancy except nonmelanoma skin cancer or carcinoma in situ of the cervix unless the patient is in complete remission and off all therapy for that disease for at least 3 years * No other significant medical illness that would preclude study participation * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective barrier contraception during and for 3 months after study participation * At least 1 week since prior interferon or thalidomide * No concurrent immunotherapy * Concurrent epoetin alfa allowed * At least 4 weeks since prior cytotoxic chemotherapy * At least 2 weeks since prior vincristine * At least 6 weeks since prior nitrosoureas * At least 3 weeks since prior hydroxyurea or procarbazine * No concurrent chemotherapy * At least 1 week since prior tamoxifen * No concurrent hormonal therapy * At least 4 weeks since prior radiotherapy * No concurrent radiotherapy * Recovered from prior surgery * Recovered from all prior therapy * At least 1 week since prior noncytotoxic therapy (e.g., isotretinoin) except radiosensitizers * At least 2 weeks since prior drugs that affect hepatic metabolism * At least 4 weeks since prior investigational agents * No concurrent warfarin (heparin or low-molecular weight heparin allowed) * No other concurrent investigational agents * No concurrent acetaminophen of more than 500 mg/day * No other concurrent anticancer therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6 Months - Progression-free Survival According to Response Evaluation Using Macdonald Criteria | At 6 months | The Macdonald criteria, roughly similarly to other systems, divides response into 4 types of response based on imaging (magnetic resonance imaging \[MRI\]) and clinical features 1: complete response; 2: partial response; 3:stable disease; 4:progression Complete response imaging features: disappearance of all enhancing disease (measurable and non-measurable) sustained for at least 4 weeks; no new lesions clinical features; no corticosteroids; clinically stable or improved Partial response imaging features: 50% or more decrease of all measurable enhancing lesions sustained for at least 4 weeks: no new lesions clinical features: stable or reduced corticosteroids; clinically stable or improved Stable disease imaging features: does not qualify for complete response, partial response or progression clinical features: clinically stable Progression imaging features: 25% of more increase in enhancing lesions; any new lesions clinical features: clinical deterioration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity as Assessed by the Cancer Therapy Evaluation Program Common Toxicity Criteria (CTC) Version 2.0 | Up to 5 years after completion of study treatment | percentage of patients who had grade 3 or grade 4 adverse events |
| Tumor Response as Assessed by MRI Using Macdonald Criteria | Up to 5 years | The Macdonald criteria, roughly similarly to other systems, divides response into 4 types of response based on imaging (MRI) and clinical features 1: complete response; 2: partial response; 3:stable disease; 4:progression Complete response imaging features: disappearance of all enhancing disease (measurable and non-measurable) sustained for at least 4 weeks; no new lesions clinical features; no corticosteroids; clinically stable or improved Partial response imaging features: 50% or more decrease of all measurable enhancing lesions sustained for at least 4 weeks: no new lesions clinical features: stable or reduced corticosteroids; clinically stable or improved Stable disease imaging features: does not qualify for complete response, partial response or progression clinical features: clinically stable Progression imaging features: 25% of more increase in enhancing lesions; any new lesions clinical features: clinical deterioration |
| Concentration (Steady State) of Imatinib During Cycle One (Pharmacokinetics) | pre dosing on day 8 and 24 hour dosing day 8 of Pre-dosing Day 9 | Blood collected before and at 1,2,4 ad 24 hours after ingestion of imatinib on day 8 of cycle 1 result is the measurement of the before dosing on day 8 (trough level) and the 24 hour dosing day 8 |
| Determine Survival for Patients Treated With Imatinib Mesylate | 3 years | survival determined from start of treatment to date of death |
| Progression-free Survival According to Response Evaluation Using Macdonald Criteria | 3 years | The Macdonald criteria, roughly similarly to other systems, divides response into 4 types of response based on imaging (MRI) and clinical features 1: complete response; 2: partial response; 3:stable disease; 4:progression Complete response imaging features: disappearance of all enhancing disease (measurable and non-measurable) sustained for at least 4 weeks; no new lesions clinical features; no corticosteroids; clinically stable or improved Partial response imaging features: 50% or more decrease of all measurable enhancing lesions sustained for at least 4 weeks: no new lesions clinical features: stable or reduced corticosteroids; clinically stable or improved Stable disease imaging features: does not qualify for complete response, partial response or progression clinical features: clinically stable Progression imaging features: 25% of more increase in enhancing lesions; any new lesions clinical features: clinical deterioration |
Other
| Measure | Time frame | Description |
|---|---|---|
| Determine Correlating Molecular Abnormalities in the Tumor With Response to Treatment | 3 years | Measurable: Bidimensionally measurable lesions w/ clearly defined margins by MRI Evaluable: Unidimensionally measurable lesions, masses w/margins not clearly defined. Complete Response (CR): Complete disappearance of all measurable/evaluable disease. No new lesions. No evidence of non-evaluable disease. Patients on minimal/no steroids. Partial Response (PR): \>/= to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. Responders must be on same/decreasing doses of dexamethasone. Stable/No Response: Does not qualify for CR, PR, or progression. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over Baseline (BL) if no decrease), OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). |
| Evidence of Platelet-derived Growth Factor (PDGF) Inhibition in Tumor Specimens | - 3 years | insufficient samples to allow Platelet-derived growth factor receptor (PDGFR-alpha and -beta expression to be correlated Of 22 patients only 7 samples available and only 5 yielded adequate tissue |
| Determine Surrogate Markers of Angiogenic Peptides Using Functional Neuro-imaging and in Vitro Bioassays | 5 years | Study terminated early, only 22 patients entered on study. Hence, this secondary outcome was never analyzed due number of patients. |
Countries
United States
Participant flow
Recruitment details
patients enrolled between June 2003 ad August 2005 in an outpatient clinic setting.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Imatinib Mesylate) Patients receive oral imatinib mesylate once or twice daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Other: pharmacological study/ laboratory biomarker analysis
imatinib mesylate: Given orally
laboratory biomarker analysis: Correlative studies
pharmacological study: Correlative studies | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Treatment (Imatinib Mesylate) |
|---|---|
| Age, Continuous | 58 years |
| Histology Anaplastic (WHO grade III) | 5 participants |
| Histology Atypical (WHO grade II) | 5 participants |
| Histology Benign (WHO grade I) | 13 participants |
| Karnofsky Performance Status Scale (KPS) | 80 units on a scale |
| Prior Chemotherapy Regimens | 0 Chemotherapy Regimens |
| Prior Radiation Therapies | 1 Radiation Therapies |
| Prior Surgeries | 3 surgeries |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 10 / 22 |
| serious Total, serious adverse events | 0 / 22 |
Outcome results
Primary
6 Months - Progression-free Survival According to Response Evaluation Using Macdonald Criteria
The Macdonald criteria, roughly similarly to other systems, divides response into 4 types of response based on imaging (magnetic resonance imaging \[MRI\]) and clinical features 1: complete response; 2: partial response; 3:stable disease; 4:progression Complete response imaging features: disappearance of all enhancing disease (measurable and non-measurable) sustained for at least 4 weeks; no new lesions clinical features; no corticosteroids; clinically stable or improved Partial response imaging features: 50% or more decrease of all measurable enhancing lesions sustained for at least 4 weeks: no new lesions clinical features: stable or reduced corticosteroids; clinically stable or improved Stable disease imaging features: does not qualify for complete response, partial response or progression clinical features: clinically stable Progression imaging features: 25% of more increase in enhancing lesions; any new lesions clinical features: clinical deterioration
Time frame: At 6 months
Population: Only 19 of the 23 patients were evaluable for response
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Imatinib Mesylate) | 6 Months - Progression-free Survival According to Response Evaluation Using Macdonald Criteria | 29.4 percentage of participants |
Secondary
Concentration (Steady State) of Imatinib During Cycle One (Pharmacokinetics)
Blood collected before and at 1,2,4 ad 24 hours after ingestion of imatinib on day 8 of cycle 1 result is the measurement of the before dosing on day 8 (trough level) and the 24 hour dosing day 8
Time frame: pre dosing on day 8 and 24 hour dosing day 8 of Pre-dosing Day 9
Population: Only 14 samples available / evaluable for analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment (Imatinib Mesylate) | Concentration (Steady State) of Imatinib During Cycle One (Pharmacokinetics) | Day 8 Pre Dosing | 2129 ng/ml | Standard Deviation 1600 |
| Treatment (Imatinib Mesylate) | Concentration (Steady State) of Imatinib During Cycle One (Pharmacokinetics) | Day 8 24 hour dosing | 2248 ng/ml | Standard Deviation 1408 |
Secondary
Determine Survival for Patients Treated With Imatinib Mesylate
survival determined from start of treatment to date of death
Time frame: 3 years
Population: death date of 7 patients were unknown at time of analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Imatinib Mesylate) | Determine Survival for Patients Treated With Imatinib Mesylate | 16.8 months |
Secondary
Progression-free Survival According to Response Evaluation Using Macdonald Criteria
The Macdonald criteria, roughly similarly to other systems, divides response into 4 types of response based on imaging (MRI) and clinical features 1: complete response; 2: partial response; 3:stable disease; 4:progression Complete response imaging features: disappearance of all enhancing disease (measurable and non-measurable) sustained for at least 4 weeks; no new lesions clinical features; no corticosteroids; clinically stable or improved Partial response imaging features: 50% or more decrease of all measurable enhancing lesions sustained for at least 4 weeks: no new lesions clinical features: stable or reduced corticosteroids; clinically stable or improved Stable disease imaging features: does not qualify for complete response, partial response or progression clinical features: clinically stable Progression imaging features: 25% of more increase in enhancing lesions; any new lesions clinical features: clinical deterioration
Time frame: 3 years
Population: Of the 22 eligible patients only 19 were evaluable for response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Imatinib Mesylate) | Progression-free Survival According to Response Evaluation Using Macdonald Criteria | 2 months |
Secondary
Toxicity as Assessed by the Cancer Therapy Evaluation Program Common Toxicity Criteria (CTC) Version 2.0
percentage of patients who had grade 3 or grade 4 adverse events
Time frame: Up to 5 years after completion of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Imatinib Mesylate) | Toxicity as Assessed by the Cancer Therapy Evaluation Program Common Toxicity Criteria (CTC) Version 2.0 | 2.3 percentage of patients |
Secondary
Tumor Response as Assessed by MRI Using Macdonald Criteria
The Macdonald criteria, roughly similarly to other systems, divides response into 4 types of response based on imaging (MRI) and clinical features 1: complete response; 2: partial response; 3:stable disease; 4:progression Complete response imaging features: disappearance of all enhancing disease (measurable and non-measurable) sustained for at least 4 weeks; no new lesions clinical features; no corticosteroids; clinically stable or improved Partial response imaging features: 50% or more decrease of all measurable enhancing lesions sustained for at least 4 weeks: no new lesions clinical features: stable or reduced corticosteroids; clinically stable or improved Stable disease imaging features: does not qualify for complete response, partial response or progression clinical features: clinically stable Progression imaging features: 25% of more increase in enhancing lesions; any new lesions clinical features: clinical deterioration
Time frame: Up to 5 years
Population: response at first scan
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Imatinib Mesylate) | Tumor Response as Assessed by MRI Using Macdonald Criteria | Progression | 10 participants |
| Treatment (Imatinib Mesylate) | Tumor Response as Assessed by MRI Using Macdonald Criteria | Stable | 9 participants |
Other Pre-specified
Determine Correlating Molecular Abnormalities in the Tumor With Response to Treatment
Measurable: Bidimensionally measurable lesions w/ clearly defined margins by MRI Evaluable: Unidimensionally measurable lesions, masses w/margins not clearly defined. Complete Response (CR): Complete disappearance of all measurable/evaluable disease. No new lesions. No evidence of non-evaluable disease. Patients on minimal/no steroids. Partial Response (PR): \>/= to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. Responders must be on same/decreasing doses of dexamethasone. Stable/No Response: Does not qualify for CR, PR, or progression. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over Baseline (BL) if no decrease), OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time frame: 3 years
Population: Study terminated early, only 22 patients entered on study. Hence, this secondary outcome was never analyzed due to number of patients.
Other Pre-specified
Determine Surrogate Markers of Angiogenic Peptides Using Functional Neuro-imaging and in Vitro Bioassays
Study terminated early, only 22 patients entered on study. Hence, this secondary outcome was never analyzed due number of patients.
Time frame: 5 years
Population: Study terminated early, only 22 patients entered on study. Hence, this secondary outcome was never analyzed due to number of patients.
Other Pre-specified
Evidence of Platelet-derived Growth Factor (PDGF) Inhibition in Tumor Specimens
insufficient samples to allow Platelet-derived growth factor receptor (PDGFR-alpha and -beta expression to be correlated Of 22 patients only 7 samples available and only 5 yielded adequate tissue
Time frame: - 3 years
Population: insufficient samples to allow PDGFR-alpha and -beta expression to be correlated Of 22 patients only 7 samples available and only 5 yielded adequate tissue