Erlotinib in Treating Patients With Recurrent Malignant Glioma or Recurrent or Progressive Meningioma

Study Overview
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Brief Summary
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Phase I/II trial to study the effectiveness of erlotinib in treating patients who have recurrent malignant glioma or recurrent or progressive meningioma. Erlotinib may stop the growth of tumor cells by blocking the enzymes necessary for tumor cell growth.

Detailed Description
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OBJECTIVES: Phase 1 I. Determine the maximum tolerated dose of erlotinib in patients with recurrent malignant glioma or recurrent or progressive meningioma. II. Determine the safety profile of this drug in these patients. III. Determine the pharmacokinetics of this drug in these patients. Phase 2 I. Determine the 6-month progression-free survival (recurrent malignant glioma) II.12-month survival of patients treated with this drug (stable glioblastoma post radiation therapy) Phase 2 - Secondary Recurrent Malignant Glioma I. Objective Tumor Response rate associated with erlotinib therapy in recurrent or progressive malignant glioma. III. 12-month survival of patients treated with this drug Determine the safety profile of this drug in these patients. IV.. Determine the pharmacokinetics of this drug in these patients OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to study phase (I vs II), concurrent enzyme-inducing antiepileptic drugs (EIAEDs) (yes vs no), histology (recurrent GBM vs recurrent anaplastic glioma vs recurrent meningioma vs stable GBM), preoperative candidacy (yes vs no), and concurrent steroids (yes vs no). Phase I: Patients concurrently receiving EIAEDs receive oral erlotinib once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined. The MTD is the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Once the MTD is determined, additional patients concurrently receiving EIAEDs are treated with erlotinib as above at the phase II dose. Patients not concurrently receiving EIAEDs are treated with erlotinib as above at a predetermined dose. Patients are followed for survival.

Official Title
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A Phase I/II Trial of OSI-774 in Patients With Recurrent Malignant Gliomas and Malignant Gliomas Post Radiation Therapy

Conditions
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Adult Anaplastic Astrocytoma, Adult Anaplastic Oligodendroglioma, Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Adult Grade I Meningioma, Adult Grade II Meningioma, Adult Grade III Meningioma, Recurrent Adult Brain Tumor

Intervention / Treatment
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* Drug: erlotinib hydrochloride
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: One of the following diagnoses: Histologically confirmed intracranial malignant glioma Glioblastoma multiforme (GBM), anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed oligoastrocytoma, or malignant astrocytoma not otherwise specified Original histology of low-grade glioma allowed provided a subsequent histology of malignant glioma is confirmed Histologically or radiographically confirmed recurrent or progressive benign or malignant meningioma Progressive disease or tumor recurrence on MRI or CT scan Phase I: No more than 3 prior relapses and no more than 2 prior chemotherapy* or biologic therapy regimens Phase II: No more than 2 prior relapses and no more than 2 prior chemotherapy* or biologic therapy regimens Patients with progressive disease must have failed prior radiotherapy* that was completed at least 4 weeks ago Patients with progressive disease between 4 and 12 weeks after completion of external beam radiotherapy must have clear evidence of progression on MRI Patients with GBM who have completed external beam radiotherapy and do not show progression are eligible Patients with progressive disease after interstitial brachytherapy or stereotactic radiosurgery must have confirmed true progression rather than radiation necrosis based upon positron-emission tomography, thallium scanning, MRI, or surgical documentation Measurable or evaluable disease Performance status - Karnofsky 60-100% More than 8 weeks WBC at least 3,000/mm^3 Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hemoglobin at least 10 mg/dL (transfusion allowed) Bilirubin less than 1.5 times upper limit of normal (ULN) SGOT less than 1.5 times ULN Creatinine less than 1.5 mg/dL None of the following ophthalmic abnormalities: Abnormalities of the cornea (e.g., dry eye syndrome or Sjögren's syndrome) Congenital abnormality (e.g., Fuch's dystrophy) Abnormal slit-lamp examination using a vital dye (e.g., fluorescein or Bengal-Rose) Abnormal corneal sensitivity test (Schirmer test or similar tear production test) Patients found to have dry eyes on examination but have an otherwise normal examination allowed No active infection No other serious concurrent medical illness No other malignancy within the past 3 years except nonmelanoma skin cancer or carcinoma in situ of the cervix No other disease that would obscure toxicity or dangerously alter drug metabolism No 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 12 weeks after study participation See Disease Characteristics At least 1 week since prior thalidomide At least 1 week since prior interferon At least 4 weeks since prior SU5416 or other experimental biologic agents See Disease Characteristics No prior chemotherapy (including polifeprosan 20 with carmustine implant [Gliadel wafers]) for patients with stable GBM At least 2 weeks since prior vincristine At least 3 weeks since prior procarbazine At least 6 weeks since prior nitrosoureas At least 1 week since prior tamoxifen See Disease Characteristics Recovered from prior radiotherapy No more than 6 weeks since prior external beam radiotherapy for patients with GBM without evidence of progression Recovered from prior surgery Recovered from prior therapy At least 1 week since prior noncytotoxic agents (e.g., isotretinoin) except radiosensitizers At least 4 weeks since prior cytotoxic therapy At least 4 weeks since prior tipifarnib or imatinib mesylate No prior erlotinib or other epidermal growth factor receptor inhibitors No concurrent combination antiretroviral therapy for HIV-positive patients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Escalation<br>Phase I: Patients concurrently receiving EIAEDs receive oral erlotinib once daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined. The MTD is the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. erlotinib hydrochloride given orally Other: pharmacological study. | Drug: erlotinib hydrochloride<br>* given orally<br>* Other names: OSI-774;Other: pharmacological study<br>* correlative studies<br>|
| Experimental: Phase 2 recurrent malignant gliomas and nonprogressive GBM<br>Phase II: Patients not concurrently receiving EIAEDs are treated with erlotinib as above at a predetermined dose (150mg/day. patients requiring surgery treated 7 days prior to tumor removal (150mg/day) PK analysis and effects of erlotinib on epidermal growth factor receptor (EGFR) erlotinib hydrochloride given orally Other: pharmacological study, laboratory biomarker analysis. | Drug: erlotinib hydrochloride<br>* given orally<br>* Other names: OSI-774;Other: laboratory biomarker analysis<br>* correlative studies<br>Other: pharmacological study<br>* correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Dose Limiting Toxicity (DLT) Each Dose Level Phase I | DLT Definition: any grade 3 thrombocytopenia and grade 4 anemia and neutropenia; any non-hematologic grade 3 toxicity; failure to recover from toxicities to be eligible for re-treatment with erlotinib within 2 weeks of the last dose of erlotinib. | 28 days | 
| Define Maximum Tolerated Dose (MTD) of Erlotinib by Phase 1 Cohorts | standard 3+3 dose escalation design 3 patients in each dose level, observed for 28 days before enrollment to next level. if none of the patients experienced DLT dose escalated, if 1 of 3 experienced DLT 3 more enrolled at that level, if none of the 3 additional pts had DLT escalate to next level, if one or more of the additional pts experienced DLT, the MTD was exceeded and 3 more patients were treated at the next lower dose (if only 3 pts treated at the lower dose). The MTD is the dose at which 0/3 or 1/6 patients have experienced a DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT. | cycle 1 - 28 days | 
| 6 Months Progression-free Survival in Recurrent Malignant Gliomas (Phase II) | Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over 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). | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With a Grade 3 or 4 Adverse Events Phase 1 | CTCAE | 1 year | 
| 1 Year Survival - Phase II Newly Diagnosed GBM Post RT | 12 month survival for newly diagnosed stable GBM post RT treated with erlotinib post RT | At 1 year | 
| Overall Survival Newly Diagnosed GBM Post RT | Overall Survival defined as Time from Start of treatment to time of death due to any cause | 2 years | 
| Response Rate (Complete or Partial Response) Graded Using Modified RECIST Criteria Phase II | 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 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). | At 1 year | 
| Percent of Patients With One or More Grade 3-5 Toxicity Described Based on the CTC Severity Grading Phase II | Summarized by descriptive statistics. | Up to 1 year | 
| Time of Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | plasma concentrations relative to erlotiniab administration and sample time and dose level | baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. | 
| Peak Plasma Concentration Per Dose Level Phase I (on Anticonvulsants) - | plasma concentrations relative to erlotiniab administration and sample time and dose level | baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5 | 
| Estimation of the Area Under the Curve Per Dose Level Phase I (on Anticonvulsants) - | plasma concentrations relative to erlotiniab administration and sample time and dose level | baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5 | 
| Trough Level Per Dose Level Phase I (on Anticonvulsants) - | plasma concentrations relative to erlotiniab administration and sample time and dose level | cycle 1 day eight | 
| Peak Plasma Concentration Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg - | plasma concentrations relative to erlotiniab administration and sample time and dose level | baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5 | 
| Time to Peak Plasma Concentration for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg - | plasma concentrations relative to erlotiniab administration and sample time and dose level | baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5 | 
| Estimation of Area Under the Curve for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg- | plasma concentrations relative to erlotiniab administration and sample time and dose level | baseline, 1,2,4,6,8,12,24h post administration day 1 cycle 1. One sample on day 8 cycle 1 and day 1 of cycle 2,3 and 5 | 
| Trough Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs - Phase 2 - Dose 150mg - | plasma concentrations relative to erlotiniab administration and sample time and dose level | One sample on day 8 cycle 1 | 
| Pharmacokinetics (Plasma) Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs | Drug administered 6 days prior to surgery | Pre-surgery and time of resection | 
| Pharmacokinetics (Tissue) Level for Recurrent Patients Not on Enzyme-inducing Antiepileptic Drugs | Drug administered 6 days prior to surgery | Pre-surgery and time of resection |