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FDA Halts Mid-Stage Study of Recombinant Hyaluronidase in Pancreatic Cancer

Thromboembolic events raise concerns

The FDA has informed Halozyme Therapeutics, Inc. that a clinical hold has been placed on patient enrollment and dosing of PEGPH20, an investigational recombinant human hyaluronidase, in an ongoing phase II trial evaluating PEGPH20 in patients with pancreatic cancer. According to the FDA, this action was taken in view of the company’s recent decision to temporarily halt enrollment and dosing of PEGPH20 in the study.

Halozyme is gathering information relevant to assessing the possible difference in the thromboembolic event rates between patients treated with PEGPH20 versus patients treated without PEGPH20 in the trial. The company will provide this information to the study’s data monitoring committee and to the FDA in parallel so that they can complete their respective assessments.

Certain cancers, including pancreatic, breast, colon, and prostate, have been shown to accumulate high levels of hyaluronan (HA). Aberrant accumulation of this component of the tumor’s infrastructure supports a protective network or “halo” that surrounds certain tumors. This pathologic accumulation of HA along with other matrix components also increases tumor interstitial fluid pressure, thereby constricting tumor vasculature and creating a unique microenvironment for the growth of tumor cells compared with that of normal cells. These mechanisms generate barriers to drug delivery that inhibit the potential effectiveness of many anticancer agents. According to Halozyme, dismantling the HA component of the tumor architecture disrupts this tumor microenvironment and opens the previously constricted vessels, which may increase blood flow to the tumor. This may allow cancer therapies to be more efficiently delivered to their target and thus may be more effective.

Halozyme’s FDA-approved Hylenex recombinant human hyaluronidase (rHuPH20) is administered subcutaneously, and temporarily and reversibly degrades HA to facilitate the absorption and dispersion of other injected drugs or fluids and for subcutaneous fluid administration. However, rHuPH20 acts only locally at the injection site, is rapidly inactivated in the body, and does not survive in the blood. Halozyme has developed an investigational PEGylated form of rHuPH20, PEGPH20, which increases the half-life of the compound in the blood and allows intravenous (IV) administration.

Halozyme is currently conducting clinical trials with PEGPH20 in the treatment of solid tumors. In these studies, a dose of oral dexamethasone, a steroid, is administered to all patients before and after IV administration of PEGPH20 to minimize the side effects of PEGPH20.

Preliminary efficacy and safety results from a single-arm phase I trial were presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting. In this study, the overall response rate (ORR; complete response + partial response) by RECIST 1.1 criteria was 42% (95% confidence interval, 22% to 62%) for those treated at therapeutic dose levels of PEGPH20 (1.6 and 3.0 mcg/kg), as assessed by an independent radiology review (n = 24).

In addition, in subjects with high levels of HA, the ORR was 64% (seven of 11 subjects with available biopsy). Moreover, 43% (six of 14 subjects) experienced a reduction of at least 70% in serum carbohydrate antigen 19-9 (CA 19-9), a biomarker that often correlates with tumor cell burden.

As a result, Halozyme initiated the new phase II, randomized clinical trial evaluating PEGPH20 as first-line therapy in approximately 124 patients with stage IV metastatic pancreatic cancer. The patients received gemcitabine and nab-paclitaxel with or without PEGPH20. The primary outcome was progression-free survival between patients who were given PEGPH20 and those who were not.

Sources: Halozyme Therapeutics; April 9, 2014; and PEGPH20; 2012.

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