Clinical Trial Protocol
HALO-109–301: a Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer
Published Online:23 Oct 2017https://doi.org/10.2217/fon-2017-0338
Abstract
The outlook for patients with advanced pancreatic cancer remains poor, despite significant advances in our understanding of pancreatic tumor biology. One emerging theme highlights the distinct composition of the pancreatic tumor microenvironment. Hyaluronic acid is a hydrophilic glycosaminoglycan whose production within the tumor leads to increased interstitial tumor pressure, thereby limiting the access of potentially effective circulating anticancer drugs via reduced tumor perfusion. PEGylated rHuPH20 is a multiply PEGylated recombinant human hyaluronidase that has shown promising efficacy in preclinical models and early phase clinical trials in pancreatic cancer patients. Here, we discuss these findings, and the rationale for the ongoing randomized Phase III trial (HALO-109–301), which seeks to definitively define the efficacy of PEGylated rHuPH20 alongside gemcitabine and nab-paclitaxel in previously untreated, hyaluronic acid-high, stage IV pancreatic cancer.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369(18), 1691–1703 (2013).
- 2 FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364(19), 1817–1825 (2011).
- 3 . Current management and future directions in metastatic pancreatic adenocarcinoma. Cancer 122(24), 3765–3775 (2016).
- 4 MAESTRO: A randomized, double-blind Phase III study of evofosfamide (Evo) in combination with gemcitabine (Gem) in previously untreated patients (pts) with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC). J. Clin. Oncol. 34(15 Suppl.), 4007 (2016).
- 5 A randomized, placebo-controlled Phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer. Ann. Oncol. 26(6), 1194–1200 (2015).
- 6 . Molecular targeted therapy for pancreatic adenocarcinoma: a review of completed and ongoing late phase clinical trials. Cancer Genet. 209(12), 567–581 (2016).
- 7 . Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy. Ann. Oncol. 27(8), 1482–1492 (2016).
- 8 . Pancreatic cancer: stroma and its current and emerging targeted therapies. Cancer Lett. 391, 38–49 (2017).
- 9 Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin. Cancer Res. 21(15), 3561–3568 (2015).
- 10 Effective targeting of the tumor microenvironment for cancer therapy. Anticancer Res. 32(4), 1203–1212 (2012).
- 11 . Hyaluronan: a constitutive regulator of chemoresistance and malignancy in cancer cells. Semin. Cancer Biol. 18(4), 244–250 (2008).
- 12 . Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21(3), 418–429 (2012). •• Used preclinical models to convincingly demonstrate the role of hyaluronan as a major barrier to perfusion and diffusion within tumors, and how this can be reversed by hyaluronidase to allow chemotherapeutic delivery.
- 13 . The where, when, how, and why of hyaluronan binding by immune cells. Front. Immunol. 6, 150 (2015).
- 14 . RHAMM is differentially expressed in the cell cycle and downregulated by the tumor suppressor p53. Cell Cycle 7(21), 3448–3460 (2008).
- 15 Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression. Cell 134(1), 62–73 (2008).
- 16 Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival. Am. J. Pathol. 156(2), 529–536 (2000).
- 17 Hyaluronan expression in gastric cancer cells is associated with local and nodal spread and reduced survival rate. Br. J. Cancer 79(7–8), 1133–1138 (1999).
- 18 Tumor cell-associated hyaluronan as an unfavorable prognostic factor in colorectal cancer. Cancer Res. 58(2), 342–347 (1998).
- 19 Strong stromal hyaluronan expression is associated with PSA recurrence in local prostate cancer. Urol. Int. 69(4), 266–272 (2002).
- 20 . High stromal hyaluronan level is associated with poor differentiation and metastasis in prostate cancer. Eur. J. Cancer 37(7), 849–856 (2001).
- 21 . High levels of stromal hyaluronan predict poor disease outcome in epithelial ovarian cancer. Cancer Res. 60(1), 150–155 (2000).
- 22 Prognostic value of hyaluronan expression in non-small-cell lung cancer: increased stromal expression indicates unfavorable outcome in patients with adenocarcinoma. Int. J. Cancer 95(1), 12–17 (2001).
- 23 . Recombinant human hyaluronidase (rHuPH20): an enabling platform for subcutaneous drug and fluid administration. Expert Opin. Drug Deliv. 4(4), 427–440 (2007).
- 24 Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models. Mol. Cancer Ther. 9(11), 3052–3064 (2010).
- 25 Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clin. Cancer Res. 22(12), 2848–2854 (2016). •• Helped define the recommended Phase II dose of PEGPH20 (PEGylated rHuPH20) in combination with gemcitabine, and convincingly demonstrated increased tumor perfusion after PEGPH20 administration.
- 26 FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364(19), 1817–1825 (2011).
- 27 Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369(18), 1691–1703 (2013).
- 28 Randomized Phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) vs AG in patients (Pts) with untreated, metastatic pancreatic ductal adenocarcinoma (mPDA). J. Clin. Oncol. 35(15 Suppl.), 4008 (2017). •• Established preliminary evidence of efficacy for the addition of PEGPH20 to gemcitabine and nab-paclitaxel.
