Michelson, Glenn

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.

17502 Background: CHIR-258 is an orally active small molecule receptor tyrosine kinase (RTK) inhibitor which has potent activity against multiple RTKs involved in tumor growth and angiogenesis (IC50 ≤13 nM for FGFR, VEGFR, PDGFR, C-KIT, and FLT3). Approximately 15% of newly diagnosed MM patients harbor a t(4;14) translocation, which results in ectopic expression of FGFR3 and MMSET and is associated with poor treatment outcome [0]and reduced survival. CHIR-258 inhibits proliferation and induces apoptosis in FGFR3-expressing MM tumor xenografts as well as FGFR3-expressing primary MM cells (Trudel et al, Blood 2005). CHIR-258 was synergistic with dexamethasone (dex) in vitro. Methods: CHIR-258 was administered once daily in a dose-escalating phase 1 study to patients with relapsed/refractory MM. Drug tolerability and safety, pharmacokinetics (PK) and pharmacodynamics (PD) were assessed. Results: as of December 2005, 9 total pts have been treated (50, 100, and 200mg qd cohorts) [6M, 3F; median age: 58 (range: 44–68), median of 3 prior therapies(range:1–7)]. Prior tx: 9/9 pts-thalidomide; 8/9 -Velcade; 8/9-transplant; 8/9- had progressed through dex. 4 of 9 pts treated were FGFR3+ and 4 pts remain on study (3 are FGFR3+). No CR or PR have been observed; stable disease has been noted. CHIR-258 has been generally well tolerated, and most drug related AEs were CTC grade 1 or 2, including: headache, dysgeusia, fatigue and anorexia. No neuropathy. One DLT has been observed to date: neutropenia (200mg cohort). Five pts had dex added to CHIR-258 of which 3 are ongoing (all FGFR3+). FGFR3+ pts receiving dex and CHIR-258 have a greater decline in urine and serum paraproteins (pp) vs CHIR-258 alone. Plasma exposure and Cmax increased proportionally across the doses. Conclusions: CHIR-258 is a novel inhibitor of RTKs involved in MM growth and proliferation. FGFR3+ pts have a more marked reduction in pp than FGFR3- pts. CHIR-258 has generally been well tolerated and further accrual continues. [Table: see text]