Abstract 4830: Preclinical anti-tumor activity of nanoliposomal irinotecan (Nal-IRI, MM-398) + 5-FU + oxaliplatin in pancreatic cancer
2016
Nanoliposomal irinotecan (Nal-IRI, MM-398) recently gained approval in combination with 5-fluorouracil/leucovorin (5-FU/LV) in post-gemcitabine metastatic pancreatic cancer based on results of the Phase 3 NAPOLI-1 trial. Nal-IRI, in combination with 5-FU/LV, improved overall survival in gemcitabine-refractory metastatic PDAC relative to 5-FU/LV alone with a well-defined and manageable toxicity profile in pretreated patients. FOLFIRINOX (5-FU/LV, irinotecan and oxaliplatin) is a chemotherapy regimen active in first-line metastatic PDAC. Herein, we evaluate the preclinical anti-tumor activity of a nal-IRI + 5-FU + oxaliplatin regimen relative to the FOLFIRINOX regimen. Using pancreatic cancer cell lines, we demonstrate enhanced cell death when nal-IRI treatment is simulated using prolonged exposure of SN-38 (the active metabolite of irinotecan) in combination with 5-FU and oxaliplatin. In cell line-derived and patient-derived xenograft models of pancreatic cancer we demonstrate improved anti-tumor activity of nal-IRI relative to exposure-matched doses of unencapsulated irinotecan. Further, nal-IRI consistently improved tumor growth inhibition and survival relative to unencapsulated irinotecan in preclinical models, both as a monotherapy and in combination with 5-FU and oxaliplatin. The addition of nal-IRI to 5-FU and/or oxaliplatin did not exacerbate the baseline toxicities of these agents, including weight loss and neutropenia, and tolerability could be further improved by delaying the administration of oxaliplatin to 1 day post-MM-398. These findings illustrate the therapeutic potential of nal-IRI in combination with 5-FU/LV and oxaliplatin and support an ongoing Phase 2 trial (NCT02551991) of this triplet regimen in first-line PDAC. Citation Format: Daniel F. Gaddy, Helen Lee, Nancy Paz, Shannon C. Leonard, Ashish Kalra, Ninfa L. Straubinger, Robert M. Straubinger, Bryan M. Gillard, Michael T. Moser, Daryl C. Drummond, Stephan G. Klinz, Bart S. Hendriks, Jonathan B. Fitzgerald. Preclinical anti-tumor activity of nanoliposomal irinotecan (Nal-IRI, MM-398) + 5-FU + oxaliplatin in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4830.
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