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

Phase 1

Completed

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

Interventions: Drug: erlotinib hydrochloride
Other: pharmacological study
Other: laboratory biomarker analysis

Registration Number: NCT00045110

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 136

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 2 recurrent malignant gliomas and nonprogressive GBM	erlotinib hydrochloride	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.
Phase 1 Dose Escalation	pharmacological study	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.
Phase 2 recurrent malignant gliomas and nonprogressive GBM	pharmacological study	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.
Phase 2 recurrent malignant gliomas and nonprogressive GBM	laboratory biomarker analysis	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.
Phase 1 Dose Escalation	erlotinib hydrochloride	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.

Primary Outcome Measures

Name	Time	Method
Define Maximum Tolerated Dose (MTD) of Erlotinib by Phase 1 Cohorts	cycle 1 - 28 days	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.
6 Months Progression-free Survival in Recurrent Malignant Gliomas (Phase II)	6 months	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).
Number of Dose Limiting Toxicity (DLT) Each Dose Level Phase I	28 days	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.

Secondary Outcome Measures

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

Trial Locations

Locations (7): University of California Los Angeles
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Los Angeles, California, United States
University of California San Francisco
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San Francisco, California, United States
Memorial Sloan Kettering Cancer Center
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New York, New York, United States
University of Texas Southwestern Medical Center
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Dallas, Texas, United States
University of Pittsburgh
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Pittsburgh, Pennsylvania, United States
National Cancer Institute Neuro-Oncology Branch
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Bethesda, Maryland, United States
University of Wisconsin
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Madison, Wisconsin, United States