Erlotinib and Radiation Therapy in Treating Young Patients With Newly Diagnosed Glioma

MTD was defined as the highest dosage level in which no more than one of six assessable participants experienced dose-limiting toxicities (DLT). The dosage of erlotinib was increased by approximately 30% in each dosage level starting at 80% of the MTD in adults with solid tumors. A traditional 3+3 dose escalation scheme was used to estimate the MTD.

Time frame: During the first 8 weeks of therapy.

Population: 22 participants were analyzed for MTD over 4 dose levels. One of 23 enrolled participants was not evaluable due to early disease progression.

DLT was defined as any of the following toxicities attributable to erlotinib therapy: thrombocytopenia grade 3 and 4; neutropenia grade 4; or any grade 3 and 4 non-hematologic toxicity except for grade 3 diarrhea and grade 3 nausea and vomiting lasting ≤48 hours in participants not receiving optimal supportive therapy, grade 3 skin rash, which did not affect normal daily activities, grade 3 fever or nonneutropenic infection, grade 3 seizures, grade 3 weight gain or loss, and grade 3 transaminase elevation that returned to grade 1 or baseline within 7 days. After enrollment of the first 4 participants, grade 3 and 4 electrolyte abnormalities that resolved to ≤grade 2 within 7 days were excluded as DLT. Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 3.0.

Time frame: During the first 8 weeks of therapy

Population: 23 participants were enrolled on Phase I component; 22 were analyzed for DLT over 4 dose levels. 1 treated at dose level 120mg/m\^2 was not assessable for DLT due to early tumor progression. 4 were treated before and 19 after the study was amended to exclude grade 3 and 4 electrolyte abnormalities that resolved to ≤ grade 2 within 7 days.

Progression-free survival (PFS) distributions for the Phase II participants with anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were calculated using Kaplan-Meier estimates (n=41). PFS was defined as the interval between treatment start and initial failure, including clinical or radiologic progression or death from any cause. PFS was not calculated for the other disease types.

Time frame: 1 and 2 years after end of therapy

Population: Per protocol, 41 participants with either anaplastic astrocytoma or glioblastoma multiforme were analyzed for this outcome.

The objective was to test the ability of erlotinib to inhibit the EGFR signaling in patients with high-grade glioma who required a second surgery. This outcome was not assessed due to insufficient availability of tumor and control samples for analysis.

Time frame: 5 Years

Population: This outcome was not assessed due to insufficient availability of tumor and control samples for analysis.

Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient. The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose.

Time frame: After first dose of therapy, and Day 8 of therapy

Population: Pharmacokinetic variables were obtained in 17 patients enrolled on the Phase I portion of the study.

Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient. The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose.

Time frame: After first dose of therapy, and Day 8 of therapy

Population: Pharmacokinetic variables were obtained in 17 patients enrolled on the Phase I portion of the study.

This objective was to prospectively investigate the correlation between standard magnetic resonance imaging (MRI) and investigational radiologic techniques (MR spectroscopy, perfusion/diffusion, PET scan, DEMRI/BLAST) in assessing tumor response to this treatment.

Time frame: at diagnosis and regular intervals during therapy (up to 2 years after start of therapy)

Population: This objective became obsolete over the course of the protocol, and data was not collected.

Although the calculated dose of erlotinib was rounded to the nearest 25 mg, the actual dosage administered to patients was within 12% of the prescribed dosage in all but 1 patient. The latter patient received erlotinib at the lowest dosage level and the actual dosage was 19% higher than the calculated dose.

Time frame: After first dose of therapy

Population: Pharmacokinetic variables were obtained in 17 patients enrolled on the Phase I portion of the study.

Adverse events were collected systematically for each of the 44 Phase II participants from the time of enrollment to the completion of therapy (approximately 2 years from start of therapy).

Time frame: From start of therapy through 2 years.

Population: All 44 Phase II participants were evaluated. Eight of 16 participants with lymphopenia received dexamethasone within 4 weeks of the recorded toxicity. In both participants with headache, there was a documented progressive disease within 3 days of the recorded headache.

Statistical analyses of genomic changes, expression profiles and validation studies should be considered in an exploratory and hypothesis-generating context. Fresh frozen tumor tissue was obtained at the time of tumor resection and diagnosis. DNA was extracted from formalin-fixed, paraffin-embedded tissue. The entire PTEN coding sequence (exons 1-9), exons 1, 9 and 20 of PIK3CA, and exons 17-24 of EGFR were evaluated using exon-specific PCR amplification, and immunohistochemistry was done. Tumor lesions were considered positive if \>25% cells were immunoreactive.

Time frame: Once at tumor resection and diagnosis

Population: Unstained slides were available for immunohistochemistry analysis in 21 of the 23 Phase I participants.

This objective was to determine the plasma and CSF levels of the VEGF, bFGF, and SDF1 at diagnosis, and the plasma levels of these factors at regular intervals during therapy, and to analyze the association of these results with tumor response.

Time frame: at diagnosis and regular intervals during therapy (up to 2 years after start of therapy)

Population: This objective became obsolete over the course of the protocol, and data was not collected.

Time frame: 5 Years

Population: This objective became obsolete over the course of the protocol, and data was not collected.