Sorafenib is an inhibitor of multiple kinases that has demonstrated antiproliferative and antiangiogenic activity in a number of in vitro and in vivo model systems. A phase I study was conducted to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Sorafenib was given orally, twice a day (BID), continuously in 28-day cycles. The dose was escalated in 2 groups of patients stratified by use of enzyme-inducing antiseizure drugs (± EIASDs). Dose-limiting toxicity (DLT) was defined as any grades 3-4 nonhematological toxicity, grade 4 hematological toxicity, and febrile neutropenia. The number of evaluable patients enrolled in the +EIASD and -EIASD arms were 23 and 24, respectively. DLTs were predominantly dermatological and gastrointestinal effects, as observed in previous clinical trials of sorafenib. The MTD was 600 mg BID for patients receiving EIASDs and 800 mg BID for those who were not. The plasma pharmacokinetics of sorafenib were not significantly affected by the concurrent administration of EIASDs. The MTD of sorafenib given orally BID on a continuous basis was established as 600 mg BID in patients with malignant glioma who were concurrently receiving EIASDs and 800 mg BID in those who were not. Further evaluation is warranted of sorafenib at the recommended MTD against recurrent or progressive malignant glioma in combination with other molecularly targeted drugs or in the newly diagnosed setting concurrent with chemoradiation.

PURPOSE:This multi-institutional phase I trial was designed to determine the maximum-tolerated dose (MTD) of cilengitide (EMD 121974) and to evaluate the use of perfusion magnetic resonance imaging (MRI) in patients with recurrent malignant glioma.PATIENTS AND METHODS:Patients received cilengitide twice weekly on a continuous basis. A treatment cycle was defined as 4 weeks. Treatment-related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity of any duration.RESULTS:A total of 51 patients were enrolled in cohorts of six patients to doses of 120, 240, 360, 480, 600, 1,200, 1,800, and 2,400 mg/m2 administered as a twice weekly intravenous infusion. Three patients progressed early and were inevaluable for toxicity assessment. The DLTs observed were one thrombosis (120 mg/m2), one grade 4 joint and bone pain (480 mg/m2), one thrombocytopenia (600 mg/m2) and one anorexia, hypoglycemia, and hyponatremia (800 mg/m2). The MTD was not reached. Two patients demonstrated complete response, three patients had partial response, and four patients had stable disease. Perfusion MRI revealed a significant relationship between the change in tumor relative cerebral blood flow (rCBF) from baseline and area under the plasma concentration versus time curve after 16 weeks of therapy.CONCLUSION:Cilengitide is well tolerated to doses of 2,400 mg/m2, durable complete and partial responses were seen in this phase I study, and clinical response appears related to rCBF changes.

1518 Purpose The aim of this study was to evaluate response and survival following the administration of R115777 prior to and following radiation therapy in newly diagnosed patients with GBM who had residual contrast enhancing tumor. Methods: Following surgery, patients with residual contrast enhancing tumor were eligible for this study. Patients were stratified based on their usage or non-usage of EIACs. After informed consent was obtained, patients were started on oral R115777. Patients on EIACs received 600mg b.i.d and those not on EIACs received 300mg b.i.d. R115777 was given continuously for 3 weeks followed by a one week rest. MRIs were performed monthly to establish response. Patients with evidence of progression went to immediate radiation therapy. Progression was defined as a 25% increase in the volume of tumor on MRI or progressive neurologic symptoms not explained by medication or systemic disease. For patients completing 3 cycles of R115777, the drug was stopped and radiation started, 60 Gy in 6 weeks. After radiation non-progressing patients were to have R11577 restarted until progression. The primary endpoint of the study was overall survival. The secondary endpoints were response rate, progression free survival, and toxicity. Results: From August 28, 2003 until April 13, 2004, 28 patients were accrued into the study. The mean age was 59.6 years and the mean KPS 84.6 All patients had histologically confirmed glioblastoma. A total of 15 patients were on EIACs. Fifteeen patients remain alive with a maximum follow-up of 350 days. Progressive disease occurred quickly on this therapy: 12 pts (48%) in the first month, 9 pts (36%) in the 2nd month, and 3 pts (12%) in the 3rd month. Only 2 patients completed all 3 cycles of induction therapy and radiation. No patient achieved a CR or PR. One patient was off study due to toxicity. To date 14 of 28 patients have died with a median overall survival of 7.5 months. Conclusions: R115777 administered prior to radiation therapy in patients with newly diagnosed GBM with residual contrast enhancing disease did not result in any measurable responses. No significant toxicities were noted in this group of patients. These patients continue to be followed for survival. No significant financial relationships to disclose.

The American Cancer Society has estimated that in 2002 ovarian cancer will strike 23,300 women, and 13,900 women will die from the disease.[1] Five-year survival is about 80% for women with stage I disease, 50% for women with stage II disease, 25% for women with stage III disease, and 15% for women with stage IV disease. Among women with advanced-stage disease, optimal debulking surgery, as well as platinum/taxane-based adjuvant therapy prolongs disease-free and median survival.[2,3] Population-based data suggests that guidelines for therapy are not uniformly followed in community practice.[4] In addition, older patients appear to receive less aggressive treatment than younger patients.

The American Cancer Society has estimated that 23,300 women will develop ovarian cancer in 2002, and 13,900 women will die from the disease.[1] The 5-year survival rate is about 80% for women with stage I disease, 50% for women with stage II disease, 25% for women with stage III disease, and 15% for women with stage IV disease. Among women with advanced-stage disease, optimal debulking surgery, as well as platinum/taxane-based adjuvant therapy prolongs disease-free and median survival.[2,3] Population-based data suggest that guidelines for therapy are not uniformly followed in community practice.[4] In addition, older patients appear to receive less aggressive treatment than younger patients.