A Phase I Dose Escalation Study for Patients With Recurrent Malignant Gliomas

Description

Recurrent malignant gliomas are uniformly fatal, and there has been no standard treatment in this setting. Radiation therapy remains the main treatment. Although the efficacy of systemic chemotherapy has not been well defined, studies have shown that some new agents such as gefitinib and vandetanib have promising effects either as an antitumor agent or as a radiation sensitizer. To determine the maximum tolerated dose of hypofractionated stereotactic radiotherapy that can be delivered with gefitinib to patients with recurrent malignant gliomas who have failed prior combined therapy of surgery, chemotherapy and radiation therapy, we have been conducting a phase I dose escalation study (COMIRB 03-1249) of hypofractionated stereotactic radiotherapy. Patients with pathologically proven malignant gliomas (WHO grade 3 or 4) that recurred after initial surgery, chemotherapy and radiation therapy are eligible, provided that the recurrent tumor is 6 cm in the largest diameter on MRI T1-weighted imaging; patients have normal organ function and blood counts. Patients with a recurrent tumor in the brain stem, or with more than three lesions were excluded. Patients started gefitinib at 250 mg once a day 7 days before hypofractionated radiotherapy and continued during and after radiation for a total duration of one year, or until disease progression. Radiation therapy was delivered using Novalis BrainLab machine, in three fractions over three consecutive days. A removable BrainLab mask was used for immobilization. The target volume was the T1 post-contrast enhancing lesion on brain MRI with 2 mm margin. Radiation dose was prescribed to the 80-90% isodose line that encompassed the target volume. Dose limiting toxicity was defined as any grade 3 acute or delayed toxicity scored by NCI common toxicity criteria version 3. The study schema is depicted in the following table. Hypofractionated Stereotactic Radiotherapy Dose Escalation Dose level Dose - of patients Tumor ≤ 6 cm Radiation a Total dose/fraction size Gefitinib b 3 patients Level 1 18 Gy/6 Gy 250 mg p.o. daily 3 patients Level 2 24 Gy/8 Gy 250 mg p.o. daily 3 patients Level 3 30 Gy/10 Gy 250 mg p.o. daily 6 patients Level 4 36 Gy/12 Gy 250 mg p.o. daily a Radiation was given one fraction a day for three consecutive days. b Doses for gefitinib are stated as exact dose in mg. Gefitinib started 7 days before radiation and continued for 12 months, or until disease progression or dose-limiting toxicities 15 patients were enrolled on the study with three patients on the first three dose levels and 6 patients on the last dose level dose. There were 9 male and 6 female patients. The median age was 45.5 years with a range of 23 to 65 years. 6 patients had recurrent anaplastic astrocytoma and other 9 patients had recurrent glioblastoma multiforme. All patients received prior radiation therapy to a total dose of 6000 cGy except in one patient whose prior radiation dose was 5400 cGy. The median time interval from prior radiation therapy was 13 months with a range of 3 to 56 months. All patients received prescribed dose of hypofractionated stereotactic radiation. The median target volume treated was 36 cc with a range of 8.4 cc to 121 cc. With a median follow-up time of 8 months (range 3 to 16 months), there was no dose-limiting toxicity. One patient with recurrent anaplastic astrocytoma treated on dose level 1 (1800 cGy) developed seizures 6 moths after radiation and required surgery. Pathology showed radionecrosis with no viable tumor cells. Grade 1 gefitinib-related skin reaction was observed in two patients, and grade 1 diarrhea in one patient. Grade 2 skin reaction and diarrhea were observed in one patient. The preliminary results from our COMIRB 03-1249 study indicate that hypofractionated stereotactic radiotherapy to a total dose of 3600 cGy (36 Gy) in three fractions is well tolerated with gefitinib at daily dose of 250 mg. The results of this study were presented at 2006 American Society of Therapeutic Radiology and Oncology annual meeting in Philadelphia November 5-9, 2006. VANDETANIB is a potent inhibitor of the tyrosine kinase activity of kinase insert domain-containing receptor (KDR), VANDETANIB has demonstrated inhibition of both VEGFR and EGFR tyrosine kinases in vitro. VANDETANIB has shown excellent inhibition of tumor cell growth in a broad range of preclinical models, including lung cancer xenografts. Regression of established tumors in animals was observed following oral administration. VANDETANIB was considered to have an acceptable preclinical toxicology profile for the proposed therapeutic indication. VANDETANIB also inhibits EGF-stimulated cell proliferation, though at a concentration approximately 3-fold higher than that required for inhibition of VEGF-stimulated cell proliferation. Rationale for this study The EGFR signal transduction pathway may play an important role in tumor growth and therapy resistance of malignant gliomas. It is also well known that new vasculature formation is one of the characteristics of malignant gliomas indicating that angiogenesis plays a very important role in initial tumor growth, and tumor re-growth during or after definitive treatment. An EGFR and VEGFR dual inhibitor such as VANDETANIB holds tremendous promise in the treatment of malignant gliomas. Based on: 1) malignant glioma cells overexpress EGFR; 2) new vasculature formation is the rule of malignant gliomas; 3) our preliminary results from COMIRB 03-1249 study indicating that HSRT to 36 Gy in three fractions is well tolerated with gefitinib in patients with recurrent malignant gliomas who were previously treated with full dose radiation (60 Gy) and various regimens of chemotherapy, we propose a phase I dose escalation study of EGFR and VEGFR dual inhibitor VANDETANIB in combination with HSRT at a fixed dose of 36 Gy. Based on the phase I data once-daily dosing of VANDETANIB at 300 mg/day is well tolerated as a monotherapy in patients with advanced solid tumor and pharmacokinetic analysis confirmed that VANDETANIB was suitable for once-daily oral dosing. This dose escalation study will evaluate the toxicity and safety of VANDETANIB at daily dose of 100 mg/day, 200 mg/day and 300 mg/day in combination with hypofractionated stereotactic radiotherapy to a total dose of 36 Gy in patients with recurrent malignant gliomas.

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