Abstract 1240: Evaluating clinically relevant pharmacological agents in a rat ambulation model to ameliorate PEGylated recombinant hyaluronidase PH20 (PEGPH20)-mediated musculoskeletal adverse events (2017)

Abstract Some cancers accumulate high levels of the glycosaminoglycan hyaluronan (HA) within the tumor microenvironment (TME), and this HA accumulation is associated with rapid tumor progression and poor clinical outcomes. As preclinical data have demonstrated that enzymatic degradation of HA, via intravenous (IV) administration of PEGylated recombinant human hyaluronidase PH20 (PEGPH20), increases therapeutic efficacy in HA-accumulating tumors, several clinical trials evaluating PEGPH20 in combination with anti-cancer therapies are ongoing. The most advanced clinical trial (Phase 3) is evaluating PEGPH20 plus Abraxane® (nab-paclitaxel)/gemcitabine (AG) in patients with stage IV untreated pancreatic ductal adenocarcinoma (PDA)(NCT02715804). The safety profile of PEGPH20/Abraxane/gemcitabine (PAG) was generally similar to AG alone in an interim analysis of the Phase 2 data, with the exception of a potential imbalance of thromboembolic events (TEs), and an increased incidence of musculoskeletal events (MSEs) in the PAG arm, with the predominant MSE being muscle spasms (55.4% PAG vs. 1.6% AG, all grades)(Bullock, ASCO 2016). In an effort to find pharmacological agent(s) that might decrease MSEs in PAG-treated patients, a rat locomotor activity assay was developed. In brief, locomotor activity of male Sprague Dawley rats was measured with an automated infrared photobeam monitoring apparatus (Hamilton/Kinder®, San Diego) during the 12h dark cycle when rats are normally active. Any PEGPH20-mediated decrease in rat locomotor activity was interpreted as MSE-like effects. In response to PEGPH20 (1 mg/kg) the locomotor activity of male rats was reduced by ~75% for the first 2 dark cycles post-treatment (48h), and then gradually returned to vehicle baseline levels by days 4-5. FDA approved drugs used clinically to alleviate pain were subsequently tested for their ability to ameliorate the effects of PEGPH20 on locomotor activity. Agents included anti-inflammatories, anti-spasmodics, neuropathic pain medications, neuroleptics, diuretics, anti-hypertensives, anti-fibromyalgics and opioids. The steroid dexamethasone, currently being used in the Phase 2 and Phase 3 PDA clinical trials to manage MSEs, was the positive control. As a class, nonsteroidal anti-inflammatory drugs (NSAIDs), including ketorolac, ketoprofen, diclofenac, and piroxicam, increased rat ambulation by ~40% on the first night following PEGPH20 treatment compared to PEGPH20 alone. Mobility in rats treated with NSAIDs/PEGPH20 increased ~60% on the second night compared to PEGPH20 alone. No other drug classes increased rodent ambulation. These data suggest that NSAIDs may be useful in partially alleviating the MSEs experienced by patients receiving PEGPH20. Citation Format: Li Ma, Marc R. Azar, Michael Shepard, Ya Huang, Piet A. Vervaet, Daniel C. Maneval, Curtis B. Thompson, Rudy Paladini. Evaluating clinically relevant pharmacological agents in a rat ambulation model to ameliorate PEGylated recombinant hyaluronidase PH20 (PEGPH20)-mediated musculoskeletal adverse events [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1240. doi:10.1158/1538-7445.AM2017-1240