FF-10101

Among 40 response-evaluable participants, the composite complete response rate was 10%, and the overall response rate (including partial responses) was 12.5%, including patients who had progressed on gilteritinib. The recommended phase 2 dose (RP2D) was 75 mg BID. FF-10101 potentially represents a next-generation advance in the management of FLT3-mutated AML.

We sought to determine whether combination of azacitidine with a FLT3 inhibitor (gilteritinib, quizartinib, LT-850-166, FN-1501 or FF-10101) displayed synergy or antagonism. The results show that combinations that involved non-covalent FLT3 inhibitors, including the two clinically approved drugs gilteritinib and quizartinib were antagonistic. On the other hand combinations with the covalent inhibitor FF-10101 had some range of concentrations where synergy was observed.

While there are numerous examples of KIT TKIs that do not inhibit FLT3 (imatinib, avapritinib, dasatinib), to date, all clinically active FLT3 TKIs (quizartinib, gilteritinib, midostaurin, sorafenib) fail to spare KIT inhibition...Compared to FF-10101 and gilteritinib, BGS-2456 exhibited the least amount of hematologic toxicity, facilitating in vitro proliferation and differentiation of normal hematopoietic progenitor cells even at 100x EC50 concentration against Molm14 cells... This is the first description of a potent and exquisitely specific FLT3 inhibitor that spares KIT inhibition and displays no myelosuppression in vitro at >100x EC50 concentration. The potent inhibitory effects of BGS-2456 on both D835Y and F691L mutants support its promise as a best-in-class TKI for the treatment of FLT3-mutant AML. Efforts to molecularly dissect the basis of the high degree of selectivity of BGS-2456 are ongoing.

Thus, these observations demonstrated combination of RSK inhibitor LJH-685 and FLT3 inhibitor FF-10101 showed synergism anti-leukemia effects in AML cell lines with FLT3-ITD mutations via inhibiting MAPK-RSKs-YB-1 pathway and provided new targets for therapeutic intervention especially for AML with FLT3-ITD mutations and Daunorubicin-resistant AML.

To overcome this problem, novel agents such as FF-10101 have shown promising potential. Multitarget strategies directed at FLT3 and anomalous signaling factors simultaneously are in active clinical development and show promising results.

We also demonstrate that FF-10101 can potentially address resistance mechanisms associated with growth factors present in the bone marrow microenvironment but is vulnerable to mutation at C695, the amino acid required for covalent FLT3 binding. These data suggest that FF-10101 possesses a favorable resistance profile that may contribute to improved single-agent efficacy when used in patients with FLT3-mutant AML.

P1/2, N=97, Completed, Fujifilm Pharmaceuticals U.S.A., Inc. | Active, not recruiting --> Completed | Trial completion date: Jan 2023 --> Jul 2021 | Trial primary completion date: Jul 2022 --> Jul 2021

To test if FLT3 signaling was important for resistance, we exposed parental cells to higher concentrations of gilteritinib, which have been shown to partly overcome F691L, as well as the FLT3i FF-10101, which binds FLT3 at a different site and is not affected by the F691L mutation. We have developed a robust cell line model of early and late resistance to FLT3i that mimics the timing and expansion of resistance mutations in the clinic. Our model of early and late resistance to GILT combinations can prospectively predict mechanisms of resistance. Although uncommon as a mechanism of resistance to GILT monotherapy, our model and early patient data predicts that F691L mutations are more important for GILT + VEN resistance.

P1/2, N=97, Active, not recruiting, Fujifilm Pharmaceuticals U.S.A., Inc. | Recruiting --> Active, not recruiting

Conclusion 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.

FLT3 inhibitors such as midostaurin, gilteritinib and quizartinib show excellent response rates in patients with FLT3-mutated AML, but its duration of response may not be sufficient yet. To overcome these mechanisms, the development of novel agents such as covalently-coupling FLT3 inhibitor FF-10101 and the investigation of combination therapy with different class agents are now ongoing. Along with novel agents, gene sequencing may improve clinical approaches by detecting additional targetable mutations and determining individual patterns of clonal evolution.

The mainstay of treatment of acute myelogenous leukemias include daunorubicin or idarubicin and cytarabine. Older patients who are not candidates for such traditional therapy are usually given 5-azacitidine, decitabine, or clofarabine...Midostaurin is US FDA-approved in combination with standard cytarabine and daunorubicin for first-line induction chemotherapy and in combination with cytarabine for second-line consolidation chemotherapy in the treatment of acute myelogenous leukemias with FLT3-postive mutations...Gilteritinib and quizartinib bind to Flt3 with the inactive DFG-D structure and are classified as type II inhibitors. Furthermore, ponatinib is a multikinase inhibitor that is approved for the treatments of Philadelphia chromosome-positive acute lymphoblastic and chronic myelogenous leukemias; it is used off label for the treatment of patients with acute myelogenous leukemias. Other drugs that are in clinical trials for the treatment of this disorder include sorafenib, sunitinib, crenolanib, FF10101, and lestaurtinib. Unlike chronic myelogenous leukemias which result solely from the formation of the BCR-Abl chimeric protein kinase, acute myelogenous leukemias result from multi-factorial causes and are prone to be resistant to both cytotoxic and targeted therapies. Consequently, there is a pressing need for better understanding the etiologies of acute myelogenous leukemias and for the development of more effective therapies.