A randomized, multicenter, double-blind, placebo-controlled study of the Bruton tyrosine kinase inhibitor, ibrutinib, versus placebo in combination with nab-paclitaxel and gemcitabine in the first-line treatment of patients with metastatic pancreatic adenocarcinoma (RESOLVE).

Abstract

TPS483 Background: Advanced pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis and short survival. Nab-paclitaxel/gemcitabine (Nab-P/GCB) is a preferred regimen for front-line treatment. The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (ibr) shows antitumor activity in preclinical PDAC models, in part, due to modulation of the tumor microenvironment. Ibr treatment inhibits mast-cell degranulation and decreases tumor-associated inflammation and desmoplasia with simultaneous enhanced presence and activity of cytotoxic T cells in tumors (Affara et al, Cancer Cell, 2014; Masso-Valles et al, Cancer Res, 2015). This randomized trial will evaluate the efficacy of ibr in combination with Nab-P/GCB. Methods: The randomized, multicenter, double-blind RESOLVE trial (NCT02436668; PCYC-1137-CA) will compare ibr vs. placebo in combination with Nab-P/GCB in approximately 320 patients with untreated metastatic PDAC. Key eligibility criteria include histologically confirmed metastatic PDAC; stage IV diagnosis within 6 weeks of randomization; adequate hematologic, hepatic, and renal function; and Karnofsky performance score ≥ 70. Key exclusion criteria include prior therapies (chemotherapy for primary PDAC, BTK inhibitor, or radiotherapy), neuroendocrine or acinar pancreatic carcinoma, known brain or leptomeningeal disease, and history of stroke or intracranial hemorrhage < 6 months prior to enrollment. Patients will be randomized to oral ibr (560 mg) or matched placebo given daily in combination with Nab-P (125 mg/m2) and GCB (1,000 mg/m2) on days 1, 8, and 15 of a 28-day cycle until disease progression or treatment is no longer tolerated. A safety run-in phase will evaluate the ibr combination prior to the randomization portion of the study. The primary endpoint is progression-free survival; secondary endpoints include overall survival and safety. Enrollment in the trial has been initiated. Clinical trial information: NCT02436668.