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PV QA 2 - Poster Viewing Q&A 2

MO_6_2621 - Initial clinical and advanced imaging outcomes from a multi-institutional phase I dose-escalation trial of RRx-001 plus whole brain radiation for patients with brain metastases

Monday, October 22
10:45 AM - 12:15 PM
Location: Innovation Hub, Exhibit Hall 3

Initial clinical and advanced imaging outcomes from a multi-institutional phase I dose-escalation trial of RRx-001 plus whole brain radiation for patients with brain metastases
M. M. Kim1, H. Parmar2, M. P. Aryal1, M. Schipper3, T. P. Devasia2, S. Kesari4, A. Morikawa2, D. E. Spratt1, L. Junck2, J. A. Hayman5, T. S. Lawrence1, C. Tsien6, R. Aiken7, S. Goyal8, S. J. Knox9, S. Caroen10, C. Carter10, B. Oronsky10, Y. Cao1, and C. Lao2; 1Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 2University of Michigan, Ann Arbor, MI, 3Department of Biostatistics, University of Michigan, Ann Arbor, MI, 4John Wayne Cancer Institute, Santa Monica, CA, 5Michigan Medicine, Ann Arbor, MI, 6Washington University School of Medicine, Department of Radiation Oncology, St. Louis, MO, 7Rutgers Cancer Institute, New Brunswick, NJ, 8George Washington University, Department of Radiation Oncology, Washington, DC, 9Stanford Cancer Institute, Stanford, CA, 10EpicentRx, Inc, San Diego, CA

Purpose/Objective(s): RRx-001, a novel redox modulator, was evaluated as a potential radiosensitizer in combination with whole brain radiation (WBRT) for adults with brain metastases. The primary endpoint was to determine maximum tolerated dose. Secondary endpoints included intracranial response rate (IRR), survival and correlation of DCE-MRI parameters with outcome. Materials/Methods: Five centers participated in this phase I trial evaluating the safety and tolerability of escalating dose levels of intravenous RRx-001, given once pre-WBRT (30 Gy/10 fractions) then twice weekly during WBRT for 5 total infusions. Four dose levels were planned (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, 27.5 mg/m2). Patients were followed for 28 days from the end of WBRT for monitoring of dose-limiting toxicity (DLT). Dose-escalation was managed by the Time to Event Continual Reassessment Model (TITE-CRM) design to establish the MTD at a 20% estimated rate of DLT. Target accrual was 30 patients. Correlative DCE-MRI was performed in a subset of patients at baseline (prior to WBRT or RRx), 24 hours after RRx but prior to WBRT, 1 month and 4 months post-WBRT. Linear mixed models (with patient-level random intercepts) were used to correlate baseline and change in 24-hour T1, Ktrans (capillary permeability) and Vp (plasma volume) with change in tumor volume at 1 and 4 months. Results: Between February 2015-February 2017, 31 patients were enrolled on study. Two patients dropped out at baseline, and 7 patients were treated on an amendment with RRx and concurrent temozolomide and will be reported in a separate analysis, for a total of 22 evaluable patients. Median age of evaluable patients was 60 years (range, 35-85) and 13 were male. The most common primary tumor histologies were melanoma (55%) and non-small cell lung cancer (23%). No DLTs were observed in any evaluable patient and 5 patients were treated at the highest dose level (16.5 mg/m2 due to a study amendment prior to reaching highest dose level). IRR was 50% in 22 evaluable patients. Five patients survived longer than 12 months, and 3 were alive at last follow-up. Twelve patients underwent correlative DCE-MRI, and 10 were evaluable with a total of 64 lesions at baseline. at baseline. Among evaluated covariates, lower baseline Vp and a reduction in Vp at 24 hours were both associated with a reduction in tumor volume at 1 month (p≤0.002) for both) and 4 months (p≤0.003 for both). Conclusion: RRx-001 in combination with WBRT appears well-tolerated in adult patients with brain metastases, with several long-term survivors observed and an IRR of 50%. Following a single dose administration of RRx, a reduction in Vp by DCE-MRI is associated with tumor volume response at 1 month and 4 months, suggesting activity at the level of the tumor vasculature and potential value as a biomarker of longer-term response.
Author Disclosure: M.M. Kim: Research Grant; EpicentRx. H. Parmar: Research Grant; EpicentRx. M.P. Aryal: None. M. Schipper: None. T.P. Devasia: None. S. Kesari: None. A. Morikawa: Employee; University of Michigan. L. Junck: Data safety monitoring board member; Orbus Therapeutics. J.A. Hayman: Research Grant; Blue Cross Blue Shield of Michigan. T.S. Lawrence: royalties; Lippincott, Williams and Wilkins. Honoraria; Massachusetts General Hospital, Pfizer Oncology Innovation Summit, Sidney Kimmel Foundation for Cancer Research. Consultant; Pfizer Oncology Innovation Summit. Advisory Board; ASTRO Radiation Oncology Institute, Dana Farber Cancer Institute, Massachusetts General Hospital, Sidney Kimmel Compreh Cancer Ctr at Johns Hopkins, Sidney Kimmel Foundation for Cancer Research, St. Jude Children's Research Hospital, University of Wisconsin Comprehensive Cancer Ctr. Travel Expenses; AACR, ASTRO Radiation Oncology Institute, Dana Farber Cancer Institute, Lippincott, Williams and Wilkins, Massachusetts General Hospital, Pfizer Oncology Innovation Summit, RSNA, Sidney Kimmel Compreh Cancer Ctr at Johns Hopkins, Sidney Kimmel Foundation for Cancer Research, St. Jude Children's Research Hospital, University of Wisconsin Comprehensive Cancer Ctr. Patent/License Fees/Copyright; Pi Squared Therapeutics. Editor, Cancer Discovery; AACR. Member, Editorial Advisory Board, Cancer Today; AACR. Senior Editor, Cancer Research; AACR. Member, External Advisory Board for Lung SPORE; Dana Farber Cancer Institute. Co-Editor of Principles and Practices of Oncology; Lippincott, Williams and Wilkins. Member, NCI Board of Scientific Advisors; NCI - BSA. President; ROI. Member, External Advisory Board for the Cancer Ctr; Sidney Kimmel CCC at Johns Hopkins University. Member of the Medical Advisory Board; Sidney Kimmel Foundation for Cancer Research. Vice-Chair, St. Jude Scientific Advisory Board; St. Jude Children's Research Hospital. Member, V Foundation Scientific Advisory Board; V Foundation for Cancer Research. C. Tsien: Speaker's Bureau; Merck, Varian. R. Aiken: None. S. Goyal: Employee; Princeton Medical Group. Independent Contractor; Isoray Medical, Hines Associates. Research Grant; American Lung Association. Consultant; Hines Associates. Travel Expenses; American Lung Association. Senior Editor; Advances in Radiation Oncology. Division Chief; George Washington University. S.J. Knox: Research Grant; NIH, BARDA, Ludwig. Stock; EpicentRx. Partnership; EpicentRx. Patent/License Fees/Copyright; EpicentRx. Chair; DSMC. S. Caroen: None. B. Oronsky: Partner; EpicentRx. Chief medical officer; EpicentRx. Y. Cao: Research Grant; NIH, Siemens. Honoraria; Siemens. C. Lao: Research Grant; BMS.

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