Introduction: The PIM serine/threonine kinases (PIM1, PIM2 and PIM3) integrate multiple signaling networks and phosphorylate downstream substrates important for cell survival and proliferation (Abstract 5397, AACR 2015). Whereas the PIM kinase isozymes are differentially expressed across cancers, PIM overexpression is associated with a poor prognosis in various hematologic malignancies. An ongoing 4-part, phase 1/2 study is evaluating INCB053914, a small-molecule pan-PIM inhibitor, in patients with advanced hematologic malignancies (NCT02587598). Results from part 1 (monotherapy dose escalation), including preliminary safety, pharmacokinetics (PK), and pharmacodynamics (PD) are reported. Methods: Eligible patients (age ≥18 y) carried a diagnosis of an advanced hematologic malignancy, had an Eastern Cooperative Group performance status of ≤1 and adequate organ function. The study was conducted in 2 disease-specific treatment groups (TG): TGA - acute myeloid leukemia, high-risk myelodysplastic syndrome (MDS), and MDS/myeloproliferative overlap neoplasm (MDS/MPN); and TGB - multiple myeloma, lymphoma, and other lymphoproliferative neoplasms. Patients received continuous oral INCB053914 in 21-d cycles on either daily (QD) or twice daily (BID) dosing schedules. Dose escalation in each TG followed a standard 3+3 design to evaluate safety, PK and PD, and to determine the maximum tolerated dose (MTD) of INCB053914 monotherapy and recommended phase 2 dose (RP2D). Results: At data cutoff (April 14, 2017), 39 patients (TGA, n=30; TGB, n=9) had been enrolled in dose escalation. Pts in TGA received INCB053914 monotherapy at a dose of 100 mg QD or at doses ranging from 50-115 mg BID; patients in TGB received INCB053914 monotherapy at 50 or 100 mg BID. In TGA, the MTD and RP2D were 100 mg BID and 80 mg BID, respectively. In TGB, 100 mg BID was not tolerated, and enrollment at 80 mg BID is ongoing. Six patients had dose-limiting toxicities (DLTs; Table 1). Of 39 patients treated, 4 (10%) are ongoing at 100 mg BID, and 35 (90%) discontinued therapy due to progressive disease (56%), adverse events (AEs; 10%), physician decision (10%), patient withdrawal (8%) or death (5%). Median (range) duration of exposure in TGA and TGB were 60 (6-194) and 23 (10-63) d, respectively. Thirty-two patients (82%) had treatment-related treatment-emergent AEs (TEAEs; Table 2). Eight patients (21%) had treatment-related serious TEAEs, most commonly elevated AST (n=4, 100%), elevated ALT (n=4, 100%), and maculopapular rash (n=3, 8%). ALT/AST elevations and rashes were most often reversible upon dose interruption or dose reduction. Two (5%) deaths occurred on study, each due to an AE of febrile neutropenia as the main cause; neither was considered related to the investigational drug. Preliminary PK results demonstrate exposures appear to increase proportionally with dose, a geometric mean half-life of ~11 h (%CV, 53%), and a median time to maximal concentrations of 1 h (range 0.5-4) across doses and TGs. Steady-state trough levels of INCB053914 at RP2D (80 mg BID) inhibited Bcl-2-associated death promoter protein phosphorylation by 77% (range 63%-100%) compared with baseline, and exceeded levels previously shown to be required for maximal efficacy in preclinical combination studies. Conclusions: INCB053914 monotherapy demonstrated preliminary safety in Part 1; elevated ALT/AST were the most common treatment-related TEAEs and DLTs, and were most often reversible with drug interruption or dose reduction. A RP2D dose has been identified that is safe and effectively inhibits PIM signaling and will be studied in combination with other targeted therapies or standard-of-care agents. Updated data in all cohorts, including preliminary efficacy, will be presented. Disclosures Byrne: Karyopharm: Research Funding; Concert Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Membership on an entity9s Board of Directors or advisory committees. Patel: Medivation: Speakers Bureau; Genentech: Speakers Bureau; BMS: Speakers Bureau; Gilead: Speakers Bureau; Exelixis: Speakers Bureau. Zeidan: Otsuka: Consultancy; Takeda: Speakers Bureau; AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria. Cherry: Pfizer: Membership on an entity9s Board of Directors or advisory committees; Ariad: Membership on an entity9s Board of Directors or advisory committees; Incyte: Membership on an entity9s Board of Directors or advisory committees; Astellas: Research Funding. Fathi: Medimmune: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Honoraria; Agios: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Juno: Membership on an entity9s Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Takeda: Research Funding. Kaplan: Millennium: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding. Zhou: Incyte: Employment, Equity Ownership. Zheng: Incyte: Employment, Equity Ownership. Barbour: Incyte: Employment, Equity Ownership. Savona: Karyopharm: Consultancy, Equity Ownership; Takeda: Research Funding; TG Therapeutics: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Astex: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; Gilead: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Incyte Corporation: Consultancy, Research Funding; Amgen: Membership on an entity9s Board of Directors or advisory committees.