Reference Detail

Ref Type

PMID

Authors

Mark J. Levis, Catherine Choy Smith, Alexander E. Perl, Gary J. Schiller, Amir Tahmasb Fathi, Gail J. Roboz, Eunice S. Wang, Jessica K. Altman, Makoto Ando, Takeaki Suzuki, Ruth Ann Subach, Gary Maier, Timothy Madden, Mary Johansen, Kin Cheung, Michael R. Kurman

Title

Phase 1 first-in-human study of irreversible FLT3 inhibitor FF-10101-01 in relapsed or refractory acute myeloid leukemia.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of Clinical Oncology	39	no. 15_suppl

URL

https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.7008

Abstract Text

Background: FF-10101-01 is a selective and irreversible FMS-like tyrosine kinase 3 (FLT3) inhibitor with potent in vitro activity against FLT3-mutated AML. FF-10101-01 is highly active against FLT3 internal tandem duplication (ITD) mutations associated with high relapse and low survival/remission rates, as well as resistance-conferring D835 and F691 tyrosine kinase domain (TKD) and non-canonical FLT3 activating mutations. Here we report on a Phase 1 dose escalation trial examining the safety, efficacy, pharmacokinetics, and pharmacodynamics of FF-10101-01 in patients (pts) with relapsed/refractory primary or secondary AML. Methods: To determine the recommended Phase 2 dose, pts with or without a FLT3 mutation received FF-10101-01 orally once (QD) or twice (BID) daily until unacceptable toxicity was observed or pts had no further clinical benefit (1 cycle = 28 days). Composite complete remission (CRc) and partial remission (PR) rates were assessed. Inhibition of FLT3 phosphorylation was evaluated using a plasma inhibitory activity assay and was correlated with associated FF-10101-01 exposure. Results: Fifty-two pts [median age 61 (range, 21-84); 52% female; FLT3: ITD [22 (42%)], TKD [5 (10%)], ITD+TKD [1 (2%)], Wt [24 (46%)] received continuous dosing of FF-10101-01 at 10 - 225 mg QD or 50 - 100 mg BID. Median number of prior therapies was 3 (range, 0-6) and the majority [23/28 (82%)] of pts with known FLT3 mutations had received prior FLT3 inhibitors. The median duration on study was 5.7 (range, 0.1-36) weeks. FF-10101-01 was generally well-tolerated up to total daily doses of 150 mg. The most common treatment related adverse events included nausea [n = 18 (35%)] diarrhea [14 (27%), 2 Grade (Gr) 3/4], elevations in creatine kinase [CK; 14 (27%), 4 Gr 3/4], vomiting [10 (19%)] and increased AST [10 (19%), 2 Gr 3]. Grade 3/4 differentiation syndrome (n = 4, 8%) was observed at 75 - 150 mg/day. Dose-limiting cardiac toxicity (heart failure with reduced ejection fraction; Gr 3 increased troponin/CK) was observed at total daily doses ≥200 mg. The CRc rate was 13% (4/30 pts evaluable for response): 1 CR at 75 mg BID (FLT3-ITD); 1 CRp at 100 mg BID (Wt-FLT3); and 2 CRi’s at 50 mg BID, one that previously progressed on gilteritinib. The median time to overall response was ̃13.3 weeks. Four pts achieved a PR (≥50% decrease in BM blasts to 5 - 25% abnormal cells) at total daily doses of 50 - 150 mg; 2 had ITD mutations, and all had received prior FLT3 kinase inhibitors. At ≥75 mg BID, trough plasma concentrations were > 90 ng/ml and associated with > 90% p-FLT3 inhibition maintained over the dosing interval. Conclusions: The FF-10101-01 FLT3 inhibitor has shown activity in pts with refractory/relapsed AML, including those with activating FLT3-ITD mutations resistant to gilteritinib and other FLT3 kinase inhibitors. Doses of 50-75 mg BID were well tolerated and resulted in sustained FLT3 inhibition. Clinical trial information: NCT03194685.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	FF-10101	Phase I	Actionable	In a Phase I trial, FF-10101 treatment was well tolerated, and resulted in a composite complete remission (CRc) in 13% (4/30) and a partial remission (PR) in 13% (4/30) of patients with relapsed or refractory acute myeloid leukemia, 1 of the patients achieved CRc and 2 of the patients achieved PR harbored FLT3 ITD mutations (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7008-7008; NCT03194685).	detail...