According to interim data from a first-in-human phase I trial, treatment with FT-2102, a selective inhibitor of mutant IDH1, was tolerable and demonstrated anti-leukemic activity in patients with IDH1-mutated acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Justin M. Watts, MD, from the University of Miami Sylvester Comprehensive Cancer Center, presented the results at the 2018 ASCO Annual Meeting.
As of April 7, 2018 (data cutoff), the researchers enrolled 58 patients with AML or MDS. FT-2102 was evaluated as a single agent in patients with relapsed/refractory disease (at either 150 mg daily, 300 mg daily, or 150 mg twice-daily), and as twice-daily 150 mg in combination with azacitidine in patients with treatment-naïve disease.
“Consistent with the nature of these diseases, a predominantly older population was enrolled,” Dr. Watts reported. The median age in the single-agent cohort was 71 years (range = 35-87 years) and 66 years in the combination cohort (range = 31-88 years). Patients with AML were heavily pretreated, having received a median of two and three prior therapies (ranges = 0-9), respectively.
In the pharmacokinetic analysis, the researchers reported that FT- 2102 has a half-life of 60 hours and “an exposure which is consistent throughout the treatment duration.” Steady-state plasma concentrations were reached by day 15 of cycle one in the three dose levels, including in patients who received combination therapy. “And, importantly, the 150 mg twice-daily exposure remains constant throughout the treatment period, with some of these patients on treatment for six months or more,” Dr. Watts added.
The maximum tolerated dose was not reached in either the single-agent or combination cohorts. FT-2102 150 mg twice daily was selected as the optimal dose.
The median time on treatment for both groups was three months (ranges not reported), and nearly half of patients enrolled are still receiving study treatment (13 [42%] in the single-agent cohort and 13 [50%] in the combination cohort).
The most common reasons for discontinuing therapy were death, progressive disease, or proceeding to transplant. “More patients on the single-agent arm were taken off study for death or progression, compared to the combination arm (32% vs. 15%),” Dr. Watts noted, “and there was no discontinuation for drugrelated toxicities on either arm.” The most common non-hematologic, treatment-emergent adverse events (AEs) across each cohort included fatigue, nausea, dyspnea, constipation, and diarrhea – most of which were grade 1 or 2. “Fatigue, gastrointestinal toxicity, and electrolyte imbalance were all more common with the azacitidine combination, as might be expected,” Dr. Watts said.
Hematologic treatment-emergent AEs (occurring in ≥15%) were similar between each group, though neutropenia appeared to be more common in patients receiving azacitidine:
- thrombocytopenia: 8 (26%) for single-agent and 7 (27%) for combination
- anemia: 6 (19%) and 6 (23%)
- neutropenia: 2 (7%) and 6 (23%)
- febrile neutropenia: 7 (23%) and 7 (27%)
- leukocytosis: 6 (19%) and 5 (19%)
“Otherwise, most of these cytopenias were likely reflective of underlying disease,” he added.
Differentiation syndrome occurred in six patients (11%), including three each in the single-agent and combination cohorts. All resolved with treatment interruption, dexamethasone, and supportive care, after which patients were able to resume FT-2102. Thirteen participants died on treatment, and no deaths were considered related to FT-2102 treatment.
Preliminary data from the efficacy analysis of 28 patients in the single-agent cohort and 24 in the combination cohort showed that the overall response rate after a median follow-up of approximately three months was 32 percent and 42 percent, respectively. Four patients in the single-agent group and three in the combination group achieved a complete response.
“Several patients have prolonged stable disease, some for more than a year,” Dr. Watts said, adding that “almost two-thirds of single-agent patients had either a response or stable disease.”
The findings of this analysis are limited by the small patient population, and validating these data requires further follow-up. For instance, Dr. Watts commented, “the benefit of adding azacitidine to any IDH inhibitor, has not yet been established. This merits further study on ours and other protocols, which are ongoing.” Based on these interim data, a global phase II study of FT-2102 in patients with relapsed/refractory AML, including those with disease that failed to respond to an IDH1 inhibitor, is underway.
Corresponding authors report financial relationships with Forma Therapeutics, which also sponsored this trial.
Watts JM, Baer MR, Lee S, et al. A phase 1 dose escalation study of the IDH1m inhibitor, FT-2102, in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Abstract #7009. Presented at the 2018 ASCO Annual Meeting, June 4, 2018; Chicago, IL.