Allen, Katie L.

13013 Background: The glutathione metabolic pathway is directly involved in the inactivation of platinum compounds. Our earlier work indicated that genotypes corresponding to varied glutathione-related enzyme activities may predict survival in patients with advanced lung cancer. Herein, we evaluated the role of glutathione-related genotypes on clinical outcomes in stage IIIB/IV non-small cell lung cancer patients who were stable or responding from one prior platinum-based chemotherapy. Methods: DNA samples from patients who had tumor regression or stable disease after treatment with one platinum based chemotherapy regimen were analyzed using 6 polymorphic DNA markers that encode 5 important enzymes in the glutathione metabolic pathway. The contrasting genotypes used in the analysis were GCLC (homozygous repeat 77 vs. heterozygous 7*), GPX1 (CC vs. other), GSTP1-I105V (AA vs. other), GSTP1-A114V (CC vs. other), GSTM1 (null vs. present), and GSTT1 (null vs. present). Multivariable Cox proportional hazards models adjusted for age, gender, treatment arm, ECOG performance status, stage, and prior tumor response, were used to evaluate the prognostic significance of the genotypes at each locus. Results: Data from 112 patients with a median follow-up of 10.6 (range: 0.4–56.3) months was used. No significant difference in time to disease progression was observed for any of the genotypes. Among the 6 genomic DNA markers, the GCLC genotype was an important prognostic factor for overall survival after adjusting for other factors. In particular, patients carrying a 77 repeat genotype (homozygous) had a significantly worse survival (Hazard ratio = 1.67, 95% CI: 1.05–2.63). Conclusions: Genotypes of glutathione-related enzymes, especially GCLC, may be used as host factors in predicting patients’ prognosis after platinum-based chemotherapy. Further investigation to define and measure the effects of these genes in chemotherapeutic regimens is needed. (This work was partly supported by NIH research grants CA77118, CA80127, and CA84354.) No significant financial relationships to disclose.

19503 Background: This study was performed to assess the value of combined modality therapy in elderly patients by comparing the differences in outcome of those who received radiotherapy (RT) alone or RT plus chemotherapy for stage III NSCLC. Methods: North Central Cancer Treatment Group (NCCTG) performed 2 recent phase III trials for stage III NSCLC. The first trial, 90–24–51, included 3 arms: once-daily radiotherapy (QDRT) alone, twice daily RT (BIDRT) alone, and concurrent chemotherapy plus BIDRT. The second trial, 94–24- 52 included 2 arms and compared concurrent chemotherapy with either QDRT or BIDRT. The chemotherapy arms of both trials included etoposide and cisplatin administered concurrently with RT. Only the patients ≥65 years of age (elderly) who participated in these trials were included in this analysis. Results: Of the 166 elderly patients included in this analysis, 37 received RT alone and 129 received concurrent chemotherapy plus RT. The median and 5-year survival rates were 10.5 months and 5.4% for the RT alone group compared to 13.7 months and 14.7% for the RT plus chemotherapy group (log-rank p=0.05). Patients who received RT plus chemotherapy experienced significantly greater severe (grade ≥3) toxicity than those who received RT alone (89.9% versus 32.4%, p < 0.01). Conclusions: Elderly patients who participated in these trials appear to gain a survival advantage from RT and chemotherapy compared to RT alone. As is the case with younger patients, this benefit comes at the cost of additional toxicity. No significant financial relationships to disclose.

Abstract Purpose: SR13668, an orally active AKT pathway inhibitor, has demonstrated cancer chemopreventive potential in preclinical studies. To accelerate the clinical development of this promising agent, we designed and conducted the first-ever phase 0 chemoprevention trial to evaluate and compare the effects of food and formulation on SR13668 bioavailability. Patients and Methods: Healthy adult volunteers were randomly assigned to receive a single 38-mg oral dose of SR13668 in one of five different formulations, with or without food. Based on existing animal data, SR13668 in a PEG400/Labrasol@ oral solution (formulation 1) was defined as the reference formulation. Four self-emulsifying solid dispersion test formulations in capsules were also investigated: Solutol@ HS 15 (formulation 2), Solutol@ HS 15/Vitamin E TGPS (50/50 w/w %) (formulation 3), Vitamin E TGPS (formulation 4), and Myrj 53 (formulation 5). SR163668 bioavailability was compared using a two-stage study design. In stage I, participants were randomized to receive the formulation 1 with or without a high-fat meal after an overnight fast. In Stage II, participants were randomly assigned to receive the test formulations, using the preferred dietary condition identified in stage I. Blood samples were obtained pre- and post-agent administration for pharmacokinetic analyses. Area under the plasma concentration-time curve (AUC) was defined as the primary endpoint. Data were analyzed and compared using established statistical methods for phase 0 trials with a limited sample size. Results: Participants (N=20) were rapidly accrued over a 5-month period. Complete pharmacokinetic data were available for 18 randomized participants. The time to peak plasma concentration and half-life values for SR13668 were 3 hours (range, 2 — 6 hours) and 11.2 ± 3.1 hours, respectively, and were not dependent on the formulation. In stage I, the oral bioavailability of SR13668 in formulation 1 was greater under the fed versus fasting dietary state (p = 0.05, Wilcoxon rank-sum test). Therefore, the fed state was selected as the preferred dietary condition for stage II. In stage II, the bioavailability of SR13668 for each of the test formulations were compared with the bioavailability of formulation 1 in the fed state. While not significantly different from formulation 1, formulation 2 AUC0-24h was significantly different (p = 0.004, ANOVA) from formulation 3, 4, and 5 (AUC0-24h, formulation 1- 222 ± 53 ng/ml·hr; AUC0-24h, formulation 2 — 302 ± 78 ng/ml·hr; AUC-177±39ng/ml·hr; AUC-144±29 0-24h, formulation30-24h, formulation 4 ng/ml·hr; AUC0-24h, formulation 5- 98 ± 21 ng/ml·hr). Formulation 1 AUC0-24h was almost 40% lower than the value achieved with formulation 2, and not significantly different from formulation 3, 4, and 5. Thus, formulation 2 provided the highest bioavailability of SR13668. Conclusions: Using a novel, highly efficient study design, we rapidly identified a lead formulation (Solutol@ HS 15) of SR13668 for further clinical testing. Our findings support application of the phase 0 trial paradigm to accelerate chemoprevention agent development. Supported by NIH grants N01-CN-35000, CA15083-34C3 and UL1 RR024150. Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN02-03.