A phase 1b/2, dose-escalation, randomized, multicenter study of maintenance (maint) ivaltinostat (ival) plus capecitabine (cap) or capecitabine monotherapy in patients (pts) with metastatic pancreatic adenocarcinoma (PDAC) whose disease has not progressed on first-line FOLFIRINOX chemotherapy (CT)

TPS4181 Background: The mainstay of treatment (TX) for pts with advanced or mPDAC consists of CT, with FOLFIRINOX and gemcitabine (gem)/nab-paclitaxel currently representing the front-line standards of care. TX is generally continued until either dis progression (progr) or cumulative toxicity, with pts often reaching a plateau in response after 4-6 mos. For those who have achieved dis control (stable dis or better) on front-line CT, a maint TX strategy that can effectively delay dis progr while preserving quality of life with minimal cumulative toxicity is highly desirable. However, aside from PARP inhibition in the subset of PDAC pts with gBRCA mutated dis, there is no current standard of care in this maint setting. Ival is a pan-HDAC (histone deacetylation) inhibitor that increases histone acetylation (HA), suppresses PDAC cell proliferation, and promotes apoptosis in PDAC cell lines in a dose-dependent manner. It has demonstrated synergy with 5-FU in cholangiocarcinoma cell lines and shows promising antitumor activity when combined with cap in syngeneic PDAC mouse models. On these bases, we are conducting a ph1b/randomized ph2 trial of ival plus cap vs cap alone in the maint setting for pts with mPDAC who have not progressed on front-line FOLFIRINOX. Methods: Key eligibility criteria include pts with mPDAC; no evidence of dis progr following at least 16 wks of front-line FOLFIRINOX at full or modified doses; ECOG PS 0-1; and no known gBRCA1/2 mutation. The study includes an initial dose-esc ph1b evaluating 3 dose levels of ival, (60, 125, and 250mg/m2 iv weekly on days 1 and 8) in combination (comb) with cap (1000mg/m2 po BID on days 1-14) of a 21-day cycle, using a standard 3 + 3 dose-esc design. Of note, ival 250 mg/m2 represents the RP2D identified in prior clinical studies of this agent both as monotherapy in solid tumors and in comb with gem/erlotinib in advanced PDAC pts. In the ph2 portion, pts will be randomized 1:1 to receive either ival plus cap or cap alone, in 21-day cycles, until dis progr, with tumor assessments occurring at 6-wk intervals. Blood will be collected at pre-specified serial timepoints for pharmacodynamic assessments, including HA of PBMCs. Primary endpoint for ph2 is investigator-adjudicated PFS. The primary analysis will compare PFS distributions in the ival/cap and cap alone arms using a one-sided log rank test with an alpha = 0.10. The assumed true 6-mo PFS rates are 35% (cap), based on historic data, and 60% (ival/cap), which corresponds to an HR of 0.487. Assuming an accrual duration of 18 mos and a dropout/lost to follow-up rate of 10%, the estimated total number of pts in the randomized ph2 portion is 52 (26 per arm). Enrollment is expected to being in spring 2022 across 25 U.S. sites.