H. Ian Robins

CONTEXT: Activation of the epidermal growth factor receptor (EGFR) pathway has been implicated with mediating treatment resistance in glioblastoma multiformes (GBMs). OBJECTIVES: To identify a subset of GBM patients who may benefit from the addition of gefitinib to radiation therapy (RT) through molecular profiling. Using preclinical models, to identify strategies to overcome putative resistance to both RT alone and RT + gefitinib identified from the correlative clinical study. DESIGN: RTOG 0211 was a phase I/II study with 31 patients enrolled for phase I and 147 patients for phase II. Tissue microarrays (70 cases from RTOG 0211, 112 from historical controls) were used for clinical molecular correlative analysis. RESULTS: There was no median overall survival benefit for patients treated with gefitinib + RT versus RT alone. Younger age was significantly associated with better outcome (HR ≥ 50 vs. P = 0.0037) in RTOG 0211-treated patients. After adjusting for age, higher levels of SRC and IGFR1 were associated with adverse overall survival in RTOG 0211-treated patients. A cautionary note, GBM patients with elevated levels of SRC and PTEN appeared to have significantly improved overall survival if treated by RT alone versus RT + gefitinib. Patients with lower levels of PTEN appeared to trend towards improved clinical outcome when treated with RT + gefitinib versus RT alone. Addition of SRC inhibitors in the context of high SRC expression or overexpression of PTEN in the context of low PTEN expression could restore the therapeutic benefit of gefitinib in preclinical models. CONCLUSIONS: The addition of gefitinib to RT does not appear to benefit the general, unselected population of GBM patients. Of cautionary significance, our findings reveal biomarker profiles that predict worse outcomes in the setting of combined gefitinib + RT versus RT alone.

Laboratory and clinical studies support the concept that heparins, particularly the low molecular component, may serve as an inhibitor of angiogenesis, providing anti-neoplastic effects. Further, treatment with low molecular weight heparin (LMWH) may provide prophylaxis for thromboembolic events (TEE), in glioblastoma (GBM) patients. Dalteparin (5,000 U sub-Q daily) was given with and after conventional radiotherapy to newly diagnosed GBM patients. Forty-five patients were accrued between 5/02 and 9/04; 3 were ineligible. At time of progression, patients could continue dalteparin in addition to standard regimens. Pretreatment characteristics included: median age 61 (range 26–78); ECOG Performance status: 0 = 38%, 1 = 57%, 2 = 5%; gross total resection 45%. There were no grade 3/4 bleeding or thrombocytopenic events, and no TEE occurred while on dalteparin. Median time on dalteparin was 6.3 months, median time to progression was 3.9 months; median survival was 11.9 months. There was no significant improvement in survival when compared to the RTOG GBM database (with various radiation/drug doublets including BCNU) using recursive partitioning analysis. Historically the incidence of TEE in GBM patients is ∼30%. As this study suggests dalteparin reduces the incidence of TEE, and does not have significant overlapping toxicities with most other drugs; its testing in a combined modality approach with other medications may be warranted in future trials.

1571 Background: The Radiation Therapy Oncology Group (RTOG) initiated a Phase I/II clinical study of the EGFR tyrosine kinase inhibitor, Gefitinib, in combination with radiation for newly diagnosed GBM patients. This report is an update of Phase I toxicity data. Methods: Patients entered on RTOG 0211 were stratified into two groups based on whether they were on enzyme-inducing anticonvulsant drugs (EIACDs:Group I) or not (non-EIACDs: Group II). The planned Gefitinib dose escalation during radiation was from 250 to 750mg in Group I and 250 to 500mg in Group II in 250 mg increments. A standard 3+3 design was used to evaluate dose-limiting toxicities (DLTs), which were defined as designated acute (90 days) Grade 3 elevation of SGOT. In Group II, one subject experienced a Grade 3 elevation of SGOT at the 250 mg dose level within 90 days. At the 500 mg dose level in Group II, one patient had late Grade 3 elevation of SGOT and one patient had acute Grade 4 elevation of SGOT. Other observed side-effects (e.g. fatigue, skin rash, headaches, seizures) did not fit the definition of DLTs or were deemed to be unrelated to Iressa. Conclusions: Gefitinib in combination with radiation appears to be well-tolerated in GBM patients at the dose levels examined. Further dose escalation is being planned for Group I, given the favorable side-effect profile in EIACD patients in this, as well as previously reported studies in the setting of recurrent disease. For non-EIACD patients, the Phase II component of the study has been initiated at the 500 mg dose level. No significant financial relationships to disclose.

1529 Background: Preclinical studies support the concept that inhibition of protein kinase C (PKC) by TAM should provide both anti-neoplastic effects and radiosensitization. Methods: High dose TAM (80 mg/m²PO daily in divided doses) was given with and after conventional XRT to inhibit PKC mediated signaling, which is known to be enhanced in GBM. Patients (n=77) were accrued between 12/00–12/01; 75 patients were analyzable. Pretreatment characteristics included: 52%<60 years of age; 39% had a Zubrod score of 0, 70% had minor or no neurological symptoms; 65% were RTOG -recursive partition analysis (RPA) class III & IV. Results: A sample of 46 patients was reviewed for TAM delivery; 78% achieved acceptable dosing. Notable toxicity included: Late radiation Grade (G) G3 =2; Thrombo-embolic disease G2=2, G3=8, G4=3, G5=1 for an incidence of 18.7%, (which is lower than expected, based on the literature for DVT in GBM patients not receiving TAM). Median survival time (MST) was 9.7 months (M). This result was compared (using 3 different statistical methodologies) to the historical GBM control database of 1443 drug / XRT treated patients RPA class III, IV, & V. After controlling for RPA class IV, the MST was 11.3M, which compares to the historical RPA control of 11.2 M (p=0.38).Conclusions: 1) The results obtained do not exhibit a substantial advance over previous studies with various XRT/drug doublets including BCNU. As TAM does not have significant overlapping toxicities with most other drugs, its testing in a combined modality approach with other medications may be justified in future clinical trails. 2) Historically the incidence of thrombo-embolic events in GBM patients is ∼30%. The lower than expected incidence seen here has also been observed in other high dose TAM GBM studies. We speculate that TAM inhibited the PKC mediated phosphorylation of coagulation factors. No significant financial relationships to disclose.

PURPOSE: To evaluate the biologic interactions and toxicities of carboplatin combined with a 24-hour infusion of thymidine 75 mg/m² in a phase I trial. PATIENTS AND METHODS: Thirty-two patients with cancer refractory to conventional therapy were treated. The first set of patients (n = 7) received thymidine alone 4 weeks before subsequent planned courses of thymidine combined with carboplatin followed (4 weeks) by carboplatin alone. Carboplatin was administered over 20 minutes at hour 20 of the 24-hour thymidine infusion. The carboplatin dose was escalated in patient groups: 200 mg/m² (n = 3); 300 mg/m² (n = 7); 350 mg/m² (n = 4); 400 mg/m² (n = 3); 480 mg/m² (n = 10); and 576 mg/m² (n = 5). At the maximum-tolerated dose (480 mg/m²), five patients received combined therapy first and carboplatin alone second, and five patients received carboplatin first and combined therapy second. Maintenance therapy for stable or responding patients was combined therapy. RESULTS: Evaluation demonstrated a trend toward thymidine protection of carboplatin-induced treatment-limiting thrombocytopenia. Neutropenia with carboplatin alone or in combination was negligible. Thymidine alone had no myelosuppressive effects and produced reversible grade 1 or 2 nausea and vomiting (57%), headache (25%), and grade 1 neurotoxicity (22%). Thymidine did not enhance expected carboplatin toxicities. There was no therapy-related infection or bleeding. Analysis of platinum in plasma ultrafiltrate and urine showed no effect by thymidine. Similarly, thymidine pharmacokinetics was not affected by carboplatin. As predicted, nicotinamide adenine dinucleotide levels in peripheral lymphocytes were increased during exposure to carboplatin and/or thymidine but were decreased by carboplatin alone. In three patients with high-grade glioma, responses included one complete remission (21 months) and one partial remission (14 months) at the 480-mg/m²-dose level, and disease stabilization (7 months) at the 400-mg/m^2-dose level. A minor response was observed in a patient with metastatic colon cancer (5 months) at the 480-mg/m²-dose level. CONCLUSION: The combination of carboplatin and thymidine as described is well tolerated. The data presented have resulted in a phase II study by the North American Brain Tumor Consortium.