Abstract 2075: Differential tissue clearance results in improved therapeutic index for irinotecan liposome injection (ONIVYDE) when combined with the PARP inhibitor veliparib in preclinical cervical tumors
Authors: Koshkaryev Alexander , Fitzgerald Jonathan , Kim Jaeyeon , Kalra Ashish , Kamoun Walid , Blanchette Sarah , Luus Lia , Klinz Stephan , Alkan Ozan , Kornaga Tad , Bates Susan , Pommier Yves , Drummond Daryl C. 
Published: July 2016

Abstract
PARPs (poly ADP ribose polymerases) are a family of enzymes involved in DNA repair via two mechanisms: catalytic inhibition and trapping of PARP-DNA complexes. Inhibition of this repair pathway can result in cell death following DNA damage. Irinotecan liposome injection has shown promising preclinical and clinical activity in a range of cancer types, and was recently approved in the United States in combination with 5-FU/LV for patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Irinotecan liposome injection is a highly stabilized liposomal formulation of irinotecan. It is hypothesized that combining PARP inhibitors with Top I inhibitors will result in increased efficacy compared to either agent alone. However, the preclinical promising activity has also given rise to unacceptable toxicity in the clinic for the combinations.
In preclinical study, compared with free irinotecan, irinotecan liposome injection has an extended PK profile with prolonged local tumor exposure of irinotecan and SN-38. Since SN-38 is cleared more quickly from normal tissues than from tumor, it is hypothesized that delayed dosing of the PARP inhibitor, veliparib, relative to irinotecan liposome injection will allow for the expected window of maximum irinotecan-induced toxicity to pass in the absence of concurrent veliparib toxicity. However, the tumor levels of SN-38 are predicted to be sustained by the time veliparib is given, therefore maintaining the ability of both drugs to act on tumor tissue simultaneously to maintain synergy.
To test the hypothesis that delayed dosing of veliparib relative to irinotecan liposome can alleviate systemic toxicity, a pre-clinical dose tolerability study was performed. Mice were dosed chronically with irinotecan liposome once weekly at various doses on Day 1, while veliparib was dosed once daily at a fixed dose for 3 consecutive days each week (either on Days 2-4, Days 3-5, or Days 4-6) and body weight was followed as a gross measure of toxicity. Toxicity of the combination was seen at the highest doses of irinotecan liposome when given in close proximity to the veliparib doses. However, this toxicity could be alleviated either by dose reducing irinotecan liposome or delaying the start of veliparib dosing. This dosing schedule was followed in studies in two cervical cancer tumor xenograft models, one in which veliparib alone was not efficacious, and a second in which neither irinotecan liposome or veliparib were efficacious as single agents, however the combination demonstrated tumor growth inhibition.
This promising preclinical regimen will be examined further in a clinical novel phase I study design led by the NCI/CTEP where both the dose and schedule will be optimized in parallel. The study is currently planned to be initiated in 2016.
Citation Format: Alexander Koshkaryev, Jonathan Fitzgerald, Jaeyeon Kim, Ashish Kalra, Walid Kamoun, Sarah Blanchette, Lia Luus, Stephan Klinz, Ozan Alkan, Tad Kornaga, Susan Bates, Yves Pommier, Daryl C. Drummond. Differential tissue clearance results in improved therapeutic index for irinotecan liposome injection (ONIVYDE) when combined with the PARP inhibitor veliparib in preclinical cervical tumors. [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 2075.