PS1051 FT‐2102, AN IDH1 M INHIBITOR, INDUCES MUTATION CLEARANCE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) OR MYELODYSPLASTIC SYNDROME (MDS) TREATED IN PHASE 1 DOSE ESCALATION AND EXPANSION STUDY

Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7–14% of AML patients (pts) and 3% of MDS pts. FT‐2102 is a highly potent, selective small molecule inhibitor of IDH1m with the therapeutic potential to restore normal cellular differentiation Aims: to evaluate updated safety and ongoing clinical activity and mutation clearance of IDH1m in pts with AML/MDS treated with single‐agent (SA) FT‐2102. This is the first report on mutation clearance with FT‐2102 Methods: The Phase 1 study assessed the safety, pharmacokinetics, pharmacodynamics, and clinical activity of FT‐2102 in patients with IDH1m AML or MDS (NCT02719574). Eligibility criteria included: IDH1m AML/MDS [relapsed/refractory (R/R) or treatment naïve (TN) pts for whom standard therapy was contraindicated], adequate liver and renal function, no prior IDH1 inhibitors. There were no restrictions for concomitant non‐anticancer medications. IDH1m variant allele frequency (VAF) was measured at baseline and on‐treatment by central droplet digital PCR (ddPCR) assay (peripheral blood) Results: As of 31 Oct 2018, 31 pts had been treated with SA FT‐2102, with a median of 4 mo on treatment (range: <1 to 27). The 31 treated pts included 25 with AML (22 R/R; 3 TN) and 6 with MDS (4 R/R; 2 TN). FT‐2102 doses were: 150 mg QD (n = 8), 300 mg QD (n = 4), 150 mg BID (n = 16). A separate cohort explored 100 mg QD with food (n = 3; not part of dose escalation). No DLTs were observed during dose escalation and 150 mg BID was selected for expansion. Twenty‐eight pts discontinued treatment, most commonly due to progressive disease (n = 10), death (n = 6), HSCT (n = 4), or lack of response (n = 3). Severe (Grade 3/4) AEs in >10% of pts included thrombocytopenia (29%), febrile neutropenia (23%), anemia (23%), pneumonia (16%), and leukocytosis (13%). Four pts (13%) had differentiation syndrome, which resolved with temporary interruption of FT‐2102, treatment with dexamethasone, hydroxyurea, and supportive care. None led to treatment discontinuation. No AEs of QTcF prolongation were reported. Nine pts died on treatment or within 30 days of the last dose, none considered treatment‐related. Clinical responses (Table 1) were first observed after a median of 1.9 mo (range 1 – 3) in AML pts. Clinical benefit (SD > 8 wks) in subjects without an IWG‐defined response and durable CRs (> 18 mo) were observed. Of 22 AML pts who were transfusion‐dependent at baseline, 11 (50%) and 8 (36%) became transfusion‐independent during 28 and 56 days on treatment, respectively. Transfusion independence was observed in AML patients in all response categories. Thirty‐two patients (treated with SA FT‐2102 or in combination with azacitidine) had pre‐ and on‐treatment peripheral blood samples available. The IDH1 mutations were undetectable by ddPCR in 5/32 (16%) patients who had either CR/CRi or SD. Reduced mutant IDH1 VAF (≤ 1%) was observed in an additional 7/32 (22%) patients. Updated IDH1 mutation clearance data and results of co‐mutation analysis will be presentedSummary/Conclusion: FT‐2102 has shown favorable safety and clinical activity in IDH1m AML with a single‐agent ORR rate of 41% (95% CI: 21, 64) in R/R AML, and durable disease control. FT‐2102 induces deep responses with IDH1 mutation clearance in a subset of treated patients. The Phase 2 study is ongoing at 150 mg BID