PF269 FT-2102, AN IDH1 M INHIBITOR, COMBINED WITH AZACITIDINE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) OR MYELODYSPLASTIC SYNDROME (MDS): RESULTS FROM A PHASE 1 STUDY

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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. Azacitidine (AZA) has shown synergistic effects with IDHm inhibitors by releasing the differentiation block in IDHm leukemia models in vitro. Aims: To report safety and clinical activity data from the first-in-human phase 1 study of FT-2102 in combination with AZA in IDH1m AML/MDS pts. Methods: The Phase 1 study assessed the safety, pharmacokinetics, pharmacodynamics, and clinical activity of FT-2102 combined with AZA 75 mg/m2 x 7 days each cycle in pts with IDH1m AML or MDS (NCT02719574). Eligible pts had treatment naïve (TN) for whom AZA is considered standard treatment or relapsed/refractory (R/R) IDH1m AML/MDS and had adequate liver and renal function. Prior IDH1m inhibitors and hypomethylating agents were allowed, and there were no restrictions for concomitant non-anticancer medications. Results: As of 31 Oct 2018, 41 pts had been treated with FT-2102+AZA, with a median of 4 months on treatment (range: <1 to 18). The 41 treated pts included 35 with AML (26 R/R; 9 TN) and 6 with MDS (2 R/R; 4 TN). Six pts had received prior AZA. Doses of FT-2102 were 150 mg QD (n = 7) and 150 mg BID (n = 34). MTD was not reached and 150 mg BID was selected as the RP2D. Twenty-six pts (63%) discontinued treatment; the most common reasons were HSCT (n = 6), progressive disease (n = 5), death (n = 4), and AEs (n = 3). Severe (Grade 3/4) AEs in >10% of pts included febrile neutropenia, thrombocytopenia (29% each), neutropenia, anemia, fatigue (17% each), leukocytosis (15%), leukopenia, and hypertension (12% each). Four pts (10%) had differentiation syndrome, which resolved with temporary interruption of FT-2102 and treatment with dexamethasone, hydroxyurea, and supportive care. None led to treatment discontinuation. Two pts experienced transient QTcF prolongation associated with concomitant medications. Seven pts died on treatment or within 30 days of the last dose, none considered related to study drug. Clinical responses (Table 1) were first observed after a median of 1.9 mo (range 1 – 6) in AML pts. Clinical benefit (SD > 8 wks) in pts without an IWG-defined response and durable CR/CRh (> 6mo) were observed. Of 30 AML pts who were transfusion-dependent at baseline, 15 (50%) and 7 (23%) became transfusion-independent during 28 and 56 days on treatment, respectively in all response categories. Data on IDH1 mutation clearance and co-mutation analysis will be presented.Summary/Conclusion: The RP2D of 150 mg BID was selected for AML and MDS patients treated with FT-2102 in combination with AZA based on safety, PK and PD response. Treatment resulted in deep responses and durable disease control in a subset of pts. Although numbers were small, an ORR rate of 78% was observed among TN subjects. The Phase 2 study is ongoing.