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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 singleagent 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 .

TABLE 4 . Responses Per Investigator Assessment

FT-2102 ( n = 28 )

FT-2102 + Azacitidine ( n = 24 )

ORR = overall response rate ; CR = complete response ; CRi = CR with incomplete hematologic recovery ; MLFS = morphologic leukemia-free state ; AML = acute myeloid leukemia

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 ( TABLE 4 ).

“ 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 .

REFERENCE

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 .

Attendees browsing the posters at the 2018 ASCO Annual Meeting .

28 ASH Clinical News July 2018 Bonus Mid-Year Edition