identified mibefradil dihydrochloride, a T-type calcium channel blocker. We and others ... dose-limiting toxicity (DLT) of mibefradil and radiation therapy (RT), in a.
Volume 96 Number 2S Supplement 2016 with P values of 0.036, 0.049, and 0.049, respectively. Complex genomic organization and lower IRS2 copy number retained prognostic significance for OS in multivariate analysis with P values of 0.026 and 0.011, respectively. Conclusion: Increased genomic complexity and lower IRS2 copy number were significantly correlated with longer OS. Both factors may serve as potential markers for increased sensitivity to therapy. Our findings are hypothesis generating and will require validation in a larger cohort. Author Disclosure: Z.S. Buchwald: None. M. Rossi: None. G. Smith: None. M. Abugideiri: None. J.E. Hauenstein: None. D.F. Saxe: None. S.G. Neill: None. A.N. Ali: None. D.J. Brat: None. J.J. Olson: None. I.R. Crocker: None. H. Shu: None.
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levels in the tumor correlate with that required for tumor cell radiosensitization in vitro. Conclusion: Our preliminary data suggest mibefradil can be safely coadministered with RT over a 17 day period at 200 mg/day. Promising local control signals apparent in a selection of patients, and we have demonstrated adequate levels of the drug directly in resected brain tumor tissue. Based on the positive results of this study, we are now designing a Phase I trial testing the efficacy of this drug in front-line GBM. Author Disclosure: N.H. Lester-Coll: Honoraria; Elekta AB. J. Kluytenaar: None. K.F. Pavlik: None. J.B. Yu: None. J.N. Contessa: None. J. Moliterno: None. J. Piepmeier: None. K.P. Becker: None. J. Baehring: None. A.J. Huttner: None. A.O. Vortmeyer: None. R. Ramani: None. R.J. Lampert: None. X. Yao: None. R.S. Bindra: None.
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Mibefradil Dihydrochloride With Hypofractionated Radiation for Recurrent Glioblastoma: Preliminary Results of a Phase 1 Dose Expansion Trial N.H. Lester-Coll,1 J. Kluytenaar,1 K.F. Pavlik,2 J.B. Yu,3 J.N. Contessa,1 J. Moliterno,4 J. Piepmeier,4 K.P. Becker,5 J. Baehring,5 A.J. Huttner,6 A.O. Vortmeyer,6 R. Ramani,7 R.J. Lampert,8 X. Yao,9 and R.S. Bindra1; 1 Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, 2Yale University School of Medicine, New Haven, CT, 3Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale School of Medicine, New Haven, CT, 4Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, 5 Department of Neurology, Yale University School of Medicine, New Haven, CT, 6Department of Pathology, Yale University School of Medicine, New Haven, CT, CT, 7Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, 8Department of Cardiology, Yale University School of Medicine, New Haven, CT, 9Yale Center for Analytical Sciences, Yale University School of Medicine, New Haven, CT
Comparison of Outcomes in Patients With Muscle-Invasive Bladder Cancer Treated With Radical Cystectomy Versus Bladder-Preserving Chemoradiation J. Zhong,1 J. Switchenko,2 N. Jegadeesh,3 T.W. Gillespie,4,5 V.A. Master,6 P. Nieh,7 M. Alemozaffar,6 O. Kucuk,8 B. Carthon,8 C.P. Filson,6,9 and A. Jani3; 1Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 2Department of Biostatistics and Bioinformatics, Winship Cancer Institute, Emory University, Atlanta, GA, 3 Department of Radiation Oncology, Winship Cancer Institute at Emory University, Atlanta, GA, 4Department of Surgery, Emory University, Atlanta, GA, 5Winship Cancer Institute, Emory University, Atlanta, GA, 6 Department of Urology, Winship Cancer Institute, Emory University, Atlanta, GA, 7Emory University, Atlanta, GA, 8Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 9 Department of Urology, Atlanta Veterans Administration Medical Center, Decatur, GA
Purpose/Objective(s): Recurrent Glioblastoma Multiforme (GBM) has limited treatment options and the prognosis is poor. Our group recently performed a high-throughput screen for novel DNA repair inhibitors which identified mibefradil dihydrochloride, a T-type calcium channel blocker. We and others subsequently revealed that mibefradil is active as a glioma radiosensitizer. More recent studies in our laboratory indicate that mibefradil blocks non-homologous end joining (NHEJ). Based on these findings, we sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of mibefradil and radiation therapy (RT), in a Phase I recurrent GBM study. Materials/Methods: The primary objective was to determine mibefradil MTD when administered with concurrent hypofractionated RT. Secondary objectives included safety, pharmacokinetics (PK), progression-free survival (PFS), and overall survival (OS). A tertiary objective included assessing intra-tumoral drug concentrations in patients enrolled in the translational sub-study within this trial. In this highly novel part of the study, patients were given mibefradil for 5 days prior to surgery, which was immediately followed by a re-resection. Resected tissues were then analyzed for the presence of drug in situ using LC/MS, in both T1-post contrast and FLAIR enhancing areas of disease; as identified by intraoperative MRI. Inclusion criteria included histologically proven GBM progressive or recurrent following RT and temozolomide. Patients received mibefradil, which was dose escalated from 150 mg/day until the maximum tolerated dose (MTD) is determined, or until a dose of 350 mg/day was reached using a standard 3 + 3 design. RT consisted of 5 fractions of 600 cGy each, delivered over two weeks for a total of 3,000 cGy using stereotactic, intensity-modulated RT. Results: To date, 12 patients have enrolled including two translational patients, and 11 have been successfully treated. There were three DLTs, and a final dose level of 200 mg/day was reached. One patient experienced a complete radiographic response on MRI. The median PFS was 5.25 months and the median OS was 12.75 months. Intriguingly, Mibefradil was detected at micromolar levels in GBM tumor tissue in two patients enrolled in the translational sub-study. Of note, we detected drug levels in biopsies specifically from T1-post contrast and FLAIR regions of disease. These
Purpose/Objective(s): Radical cystectomy remains the standard of care for muscle invasive bladder cancer (MIBC). However, removal of the bladder can be associated with considerable morbidity. There potentially exists a treatment strategy to preserve the bladder through concurrent chemoradiation following a maximal trans-urethral resection of the tumor. Multi-institutional clinical trials evaluating a bladder preservation approach have demonstrated overall survival (OS) comparable to radical cystectomy in highly selected patients. To date, there have been no large reports of bladder preservation outcomes outside of a clinical trial setting. Here, we compare outcomes of patients with MIBC treated with either radical surgery or bladder-preserving CRT (BPCRT) using a large national cancer database. Materials/Methods: Using the National Cancer Data Base (NCDB), patients with AJCC clinical T2-3, N0, M0 urothelial carcinoma diagnosed between 2004 and 2013 were identified for analysis. Only patients treated with definitive intent with either radical cystectomy (with or without chemotherapy) or concurrent chemotherapy and radiation were included. Only patients documented to undergo a trans-urethral tumor resection followed by a definitive course of radiation with chemotherapy were included in our BPCRT cohort. Kaplan-Meier, log-rank test, and multivariable Cox proportional hazards regression were performed with OS as the primary outcome. Propensity score matching was employed to reduce treatment selection bias. Results: Among 8,454 MIBC patients, 7,276 (86%) underwent radical cystectomy with or without chemotherapy, and 1,178 (14%) underwent BPCRT. Patients undergoing BPCRT were significantly older (median age 77 vs 68 years, P < 0.001) and had higher Charlson-Deyo comorbidity scores (P Z 0.002). The median follow up time was 4.5 years. The unadjusted 5-year OS were 45.0% and 31.8% for surgery and BPCRT cohorts, respectively (P < 0.001). Using matched propensity score analysis, there were 1,002 patients remaining in each cohort, and there was no significant difference in 5-year OS between the two groups (39.7% surgery vs 32.4% BPCRT, P Z 0.10). On multivariate analysis, age, Carlson-Deyo comorbidity score, T-stage, and tumor location significantly impacted survival.
