ASCO 2018 | A phase I dose-escalation study of FT-2102 in IDH1 mutated AML patients

Isocitrate dehydrogenase 1 (IDH1) mutations are reported in 7–14% of patients with acute myeloid leukemia (AML) and 3% of patients with myelodysplastic syndrome (MDS). Justin M. Watts from the University of Miami, Coral Gables, FL, USA, and colleagues conducted a phase I/II trial (NCT02719574), investigating the safety, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD)/recommended phase II dose, and efficacy of FT-2102, a highly potent, selective small molecule inhibitor of mutant IDH1, as a single agent or in combination with azacitidine (AZA) or cytarabine in IDH-1 mutated AML or MDS patients. Interim data from this study was presented at the 2018 ASCO Annual Meeting, Chicago, IL, USA, on 1–5 June 2018.

As of April 2018, a total of 58 patients with AML or MDS have been enrolled in this study. Patients were administered FT-2102 monotherapy (n = 31, median age = 71 years [range: 25–87]) or in combination with AZA (n = 27, median age = 66 years [range: 31–88]). Thirty-seven patients were included in the dose escalation phase of this study. FT-2102 was administered orally at a dose of 150 mg QD (n = 8), 300 mg QD (n = 4), and 150 mg BID (n = 7) or in combination with AZA (75 mg/m² IV or SC daily for 7 days of each 28-day cycle) at a dose of 150 mg QD (n = 7) and 150 mg BID (n = 8). The MTD was not reached, however, 150 mg BID of FT-2102 was selected as the RP2D based on safety, pharmacokinetics and pharmacodynamics.

Twenty-one patients were treated across three expansion cohorts in the dose expansion. Cohort 1 consisted of relapsed/refractory AML or MDS patients (n = 9) who were administered single agent FT-2102. Cohort 2 and 3 consisted of R/R AML or MDS patients (n = 8) and treatment-naïve AML patients (n = 4) who were administered 150 mg BID FT-2102 in combination with AZA.

Key findings:

• Pharmacokinetics (PK)

  • Steady state reached by Week 2 (T_1/2 ̴ 60 hours)
  • 150 mg BID steady state exposures > IC₉₀ and lower levels expected to increase the potential of QTcF (QT interval corrected by the Fridericia formula)
  • Stable plasma exposures were achieved during the course of treatment
  • 150 mg twice daily was recommended for dose expansion

• Pharmacodynamics (PD)

  • Plasma 2-hydroxyglutarate reduction to normal levels was detected in the majority of patients at all doses of FT-2102
  • Optimal PD response was observed with 150 mg BID of FT-2102
  • PD response was constant during treatment with 150 mg BID

• Safety

  • The most common Grade 1/2 treatment emergent adverse events (TEAEs)

    • FT-2102: nausea (36%), fatigue (36%) pyrexia (29%)
    • FT-2102 plus AZA: nausea (50%), constipation (42%), diarrhea (39%), hypokalemia (39%)

  • The most common Grade 3/4 TEAEs

    • FT-2102: thrombocytopenia (26%), febrile neutropenia (23%), anemia (19%), and pneumonia (13%)
    • FT-2102 plus AZA: febrile neutropenia (27%), thrombocytopenia (19%), anemia (19%), leukocytosis (19%)
  • IDH differentiation syndrome occurred in 11% (n = 6) of patients, which did not cause treatment discontinuation
  • One patient experienced Grade 3 QTcF
  • In total, 13 deaths occurred due to AEs (not FT-1202 related)

• Efficacy in evaluable patients

  • Overall response rate (ORR)

    • FT-2102: 32% (9/28)
    • FT-2102 plus AZA: 42% (10/24)

  • R/R AML

    • ORR in the FT-2102 cohort: 33% (7/21)
    • ORR in the FT-2102 plus AZA cohort: 32% (6/19)

  • Treatment-naïve AML

    • ORR in the FT-2102 cohort: 33% (1/3)
    • ORR in the FT-2102 plus AZA cohort: 75% (3/4)

  • MDS

    • ORR in the FT-2102 cohort: 25% (1/4)
    • ORR in the FT-2102 plus AZA cohort: 100% (1/1)

In summary, FT-2102 “is well tolerated as single agent and in combination with AZA” in patients with AML or MDS. The results of this phase I study show encouraging safety, pharmacodynamics, pharmacokinetics, and efficacy for FT-2102 in patients with IDH1 mutated AML/MDS. Complete response rates (CR/CRi) were superior with both single agent FT-2102 (CR/CRi = 32%) and combination therapy with AZA (CR/CRi = 42%). Professor Watts added that a phase II study is required to further investigate these findings. 

Reference

1. Watts J.M. et al. A phase I dose escalation study of the IDH1m inhibitor, FT-2102, in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Abstract 7009. 2018 ASCO Annual Meeting. 2018 June 1–5.