FF-10101 / Fujifilm Holdings - LARVOL DELTA

BGS-2456 Is a Novel Potent Covalent Inhibitor of FLT3 That Highly Discriminates Against KIT and Is Not Toxic Toward Normal Hematopoiesis in Vitro (ASH 2023) - "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."

Preclinical • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Hematological Disorders • Oncology • Sarcoma • ABL1 • CSF1R • FLT3 • PDGFRA

Strengths and limitations of Ba/F3 cells in modelling FLT3-driven AML resistance. (PubMed, Bioorg Med Chem Lett) - "We used Ba/F3 cells that expressed mutated FLT3 (FLT3-ITD), a known drug target in acute myeloid leukaemia (AML), to study drug resistance against two potent and selective inhibitors (gilteritinib and FF-10101). The discovery of novel mutations is significant since few patients were tested upon relapse due to lack of therapeutic options. Finally, we discuss the pros and cons of the Ba/F3 cell lines in the context of AML where patients express FLT3-ITD mutations in comparison with other cell lines, when the aim is development of drugs that overcome resistance."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

Inhibition of FLT3-induced signalling in refractory acute myeloid leukaemia. (PubMed, Bioorg Chem) - "We had developed AML-specific cell lines resistant to two advanced FLT3 inhibitors: gilteritinib and FF-10101. The efficacy of most FLT3 inhibitors was only weakly (or not at all) affected by the NRAS/G12C activating mutation. Finally, no non-FLT3 inhibitor has shown sufficient efficacy in the cells, suggesting the central role of FLT3 in FLT3-mutated AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • NRAS

Resistance to FLT3 inhibitors involves different molecular mechanisms and reduces new DNA synthesis. (PubMed, Biochem Biophys Rep) - "To better understand the mechanisms leading to drug resistance, we generated four AML cell lines resistant to the inhibitors gilteritinib or FF-10101, and explored their resistance mechanisms. On the other hand, it is shown that DNA synthesis is reduced, which means that resistance has evolutionary consequences. Finally, the novel drug-resistant cell lines may serve as useful models for better understanding of the cellular events associated with inherent and acquired drug resistance."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CDK4 • FLT3 • MYCN • NRAS

Sustained inhibition of CSF1R signaling augments antitumor immunity through inhibiting tumor-associated macrophages. (PubMed, JCI Insight) - "Thus, FF-10101 acts as an immunomodulatory agent that can reduce immunosuppressive TAMs and augment tumor antigen-specific T cell responses, thereby generating an immunostimulatory TME. We propose that FF-10101 is a potential candidate for successful combination cancer immunotherapy with immune checkpoint inhibitors, such as PD-1/PD-L1 blockade."

IO biomarker • Journal • Oncology • CD8 • CSF1R

Study of FF-10101-01 in Patients With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=97 | Completed | Sponsor: Fujifilm Pharmaceuticals U.S.A., Inc. | Phase classification: P1/2 ➔ P1

Phase classification • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

CLINICAL OUTCOMES OF CONCURRENT FLT3 INHIBITOR AND IDH INHIBITOR THERAPY IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (EHA 2024) - "Approved therapies include the FLT3 inhibitors(FLT3i) gilteritinib (gilt), midostaurin (mido), sorafenib (sora), quizartinib (quiz); and IDH1/2 inhibitors (IDHi)ivosidenib (ivo), olutasidenib (olu), and enasidenib (ena)...8 (28%) pts had received prior IDHi (6 ivo, 2 ena), while 14 (50%) hadprior FLT3i (8 gilt, 6 mido, 2 quiz, 4 sora, 1 FF-10101)...3 pts received FLT3i+IDHi+hypomethylating therapy (decitabine or azacitidine), and 3FLT3i+IDHi+venetoclax... Our findings in this largely relapsed/refractory cohort suggest that concurrent IDHi/FLT3i is well-tolerated andclinically active."

Clinical • Clinical data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Mucositis • Nephrology • Oncology • DNMT3A • FLT3 • IDH1 • IDH2 • NPM1 • NRAS • RUNX1

Sustained inhibition of CSF1R signaling effectively augments antitumor immune responses through inhibiting tumor-associated macrophages (AACR 2024) - "Thus, FF-10101 acts as an immunomodulatory agent that can reduce immunosuppressive TAMs and augment tumor antigen-specific T cell responses, thereby generating an immunostimulatory TME. We propose that FF-10101 is a potential candidate for successful combination cancer immunotherapy with immune checkpoint inhibitors, such as PD-1/PD-L1 blockade."

IO biomarker • Oncology • CD8 • CSF1R

A phase 1 study of the irreversible FLT3 inhibitor FF-10101 in relapsed or refractory acute myeloid leukemia. (PubMed, Blood Adv) - P1/2 | "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."

Journal • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

Synergy and antagonism between azacitidine and FLT3 inhibitors. (PubMed, Comput Biol Med) - "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."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

Use of FLT3 Inhibitors in AML (SOHO 2019) - "First generation, multi-targeted FLT3 tyrosine kinase inhibitors (TKIs) such as midostaurin, sorafenib and lestaurtinib were limited by poor drug selectivity, potency and unfavorable protein binding characteristics...In this study, adult patients with previously untreated FLT3 mutant (ITD or TKD) AML were randomized to receive either midostaurin or placebo in conjunction with standard daunorubicin and cytarabine (“7+3”) induction chemotherapy and high dose cytarabine (HiDAC) consolidation therapy.9 There was a significant benefit in event free survival (EFS) (HR 0.78, p=0.002) and OS (HR 0.78, p=0.009) for those in the midostaurin group...Significantly, FLT3-ITD+ patients who relapsed after achieving CRc on quizartinib acquired secondary FLT3-ITD kinase domain (KD) mutations involving either the “gatekeeper” F691 or activation loop (AL) D835 residues.12 This observation determined that the activity of quizartinib was mediated through inhibition of FLT3-ITD and not..."

The irreversible FLT3 inhibitor FF-10101 is active against a diversity of FLT3 inhibitor resistance mechanisms (AACR 2022) - P1/2 | "Background: FLT3 tyrosine kinase inhibitors (TKIs) such as midostaurin and gilteritinib have improved clinical outcomes for patients with FLT3-mutant acute myeloid leukemia (AML), but resistance remains a problem. FF-10101 is active against nearly all mutations associated with FLT3 TKI resistance except for C695 mutations (site of FF-10101 binding) and the gilteritinib/crenolanib-resistant Y693C mutation (which has yet to be identified clinically). FF-10101 potentially overcomes resistance associated with the BME but likely remains vulnerable to RAS activating mutants. In report of phase 1 study of FF-10101 in relapsed/refractory AML (NCT03194685), 8/30 evaluable patients exhibited response (27%) with five responding patients previously receiving a FLT3 TKI, including one CRi after progression on gilteritinib."

Late-breaking abstract • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • NRAS

Developments and challenges of FLT3 inhibitors in acute myeloid leukemia. (PubMed, Front Oncol) - "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."

Journal • Review • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CXCL12 • FGF2 • FLT3

Combination of RSK inhibitor LJH-685 and FLT3 inhibitor FF-10101 promoted apoptosis and proliferation inhibition of AML cell lines. (PubMed, Cell Oncol (Dordr)) - "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."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • ANXA5 • FLT3

Study of FF-10101-01 in Patients With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2 | N=97 | Completed | Sponsor: 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

Trial completion • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

The Irreversible FLT3 Inhibitor FF-10101 Is Active Against a Diversity of FLT3 Inhibitor Resistance Mechanisms. (PubMed, Mol Cancer Ther) - "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."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

The FLT3 F691L Gatekeeper Mutation Promotes Clinical Resistance to Gilteritinib + Venetoclax (GILT + VEN) in AML (ASH 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."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FGF2 • FLT3 • NRAS

[VIRTUAL] PHASE 1 FIRST-IN-HUMAN STUDY OF IRREVERSIBLE FLT3 INHIBITOR FF-10101-01 IN RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA (EHA 2021) - "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."

P1 data • Acute Myelogenous Leukemia • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Malignancies • Leukemia • Oncology • FLT3

[VIRTUAL] Phase 1 first-in-human study of irreversible FLT3 inhibitor FF-10101-01 in relapsed or refractory acute myeloid leukemia. (ASCO 2021) - P1/2 | "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."

P1 data • Acute Myelogenous Leukemia • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Malignancies • Leukemia • Oncology • FLT3

First-in-Human Study Finds FF-10101-01 Has Clinical Activity in Relapsed/Refractory FLT3-Mutated AML (ASH Clinical News) - "'FF-10101-01 is highly active against FLT3-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,' the investigators, led by Mark J. Levis, MD, PhD...wrote."

P1 data

FF-10101-01: A novel FLT3 inhibitor for R/R AML (YouTube) - "Mark Levis, MD, PhD...gives an update on the Phase I trial (NCT03194685) investigating the use of an FMS-like tyrosine kinase 3 (FLT3) inhibitor, FF-10101-01, to treat patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). The aim of the trial was to establish a safe, tolerable dose and determine the efficacy of FF-10101-01 in gilteritinib-resistant patients. Dr Levis also discusses the difficulties of recruiting a large patient cohort who meet the trial requirements. This interview took place at the virtual European Hematology Association (EHA) Congress 2021."

Interview • Video

Mark Levis, MD, PhD, Discusses a Study on FLT3 Inhibition in R/R AML - "Dr Levis discusses a study examining the use of FF-10101-01, an irreversible FLT3 inhibitor, in patients with relapsed/refractory AML, the findings of which were presented at the 2021 ASCO Annual Meeting."

Video

[VIRTUAL] Concurrent FLT3 Inhibitor and IDH Inhibitor Therapy in Patients with Acute Myeloid Leukemia (AML) (ASH 2020) - "Characterization of pathogenic alterations in acute myeloid leukemia (AML) has led to development of promising targeted therapies, including FLT3 (FLT3i) and IDH1/2 inhibitors (IDHi), with several approved for use; midostaurin (MIDO), gilteritinib, enasidenib (ENA), and ivosidenib (IVO)...Six pts (50%) had received FLT3i monotherapy in a prior line of treatment; 4 sorafenib, 1 gilteritinib, 1 MIDO, and 1 with FF-10101 (one pt had 2 prior lines of FLT3i)...Three pts received hypomethylating therapy concurrent with combined FLT3i/IDHi therapy; 2 received azacitidine (AZA) with ENA/MIDO, and 1 received AZA with ENA/gilteritinib...These response rates are particularly intriguing, given the presence ofFLT3/ITDmutations, alterations thought to confer resistance to IDHi monotherapy. Larger, prospective studies are needed to fully assess the promise of concurrent FLT3i and IDHi therapy in co-mutated pts with AML."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • FLT3 • IDH1

Study of FF-10101-01 in Patients With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1/2; N=97; Active, not recruiting; Sponsor: Fujifilm Pharmaceuticals U.S.A., Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

The role of small molecule Flt3 receptor protein-tyrosine kinase inhibitors in the treatment of Flt3-positive acute myelogenous leukemias. (PubMed, Pharmacol Res) - "The mainstay for the care 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 as therapy for Philadelphia chromosome-positive acute lymphoblastic and chronic myelogenous leukemias; it is used off label for the treatment of patients with acute myelogenous leukemias. Moreover, sorafenib is FDA-approved for the treatment of hepatocellular, renal cell, and..."

Journal • Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Chronic Myeloid Leukemia • Endocrine Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Transplantation • FLT3