BMF-219 for Blood Cancers
Recruiting in Palo Alto (17 mi)
+41 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Waitlist Available
Sponsor: Biomea Fusion
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial is testing a new oral drug called BMF-219 that blocks a protein involved in cancer growth. It is aimed at adults with specific types of blood cancers that have certain genetic changes. The goal is to see if this drug can stop the cancer cells from growing.
Do I have to stop taking my current medications for the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, you must have progressed on or after your most recent anti-cancer therapy to be eligible.
What data supports the idea that BMF-219 for Blood Cancers is an effective treatment?
The available research shows that menin inhibitors, like BMF-219, have been effective in treating certain types of blood cancers. For example, a study on a similar menin inhibitor called revumenib showed a 63% response rate in patients with relapsed or hard-to-treat acute leukemia. Another study combining a menin inhibitor with chemotherapy resulted in complete remissions for some patients with acute myeloid leukemia. These findings suggest that BMF-219 could be a promising option for treating blood cancers.
12345What safety data is available for BMF-219 (Icovamenib, Covalent menin inhibitor) in blood cancers?
The provided research does not contain any safety data for BMF-219, Icovamenib, or Covalent menin inhibitor. The studies focus on different drugs, primarily BRAF and MEK inhibitors, and their safety profiles in various solid tumors, not blood cancers.
678910Eligibility Criteria
Adults with certain blood cancers like AML, ALL with specific mutations, DLBCL, MM, and CLL/SLL can join this trial. They must have relapsed or refractory cancer despite previous treatments, be over 18 years old with good organ function and willing to use birth control. People are excluded if they have active CNS involvement by their cancer or a history of certain other conditions.Inclusion Criteria
My lymphoma has worsened or remained despite treatment.
I can care for myself and doctors expect me to live more than 3 months.
My organs are working well.
+7 more
Exclusion Criteria
I have plasma cell leukemia, myeloma with amyloidosis, or systemic light chain amyloidosis.
My condition is primary mediastinal B-cell lymphoma or DLBCL not from indolent NHL.
I have APL or CML in blast crisis.
+10 more
Participant Groups
The study is testing BMF-219, an oral drug designed to block menin's action in the body. It's for adults who've seen their blood cancer return or not respond to treatment. The trial will gradually increase doses to find the safest and most effective level.
2Treatment groups
Experimental Treatment
Group I: Dose ExpansionExperimental Treatment1 Intervention
Experimental: ARM B:
Study participants who are receiving a moderate or strong CYP3A4 inhibitor.
Dose Escalation Phase:
• Cohort 1: Participants with acute leukemia will receive escalating dose BMF-219 orally to identify the OBD/ RP2D (Optimal Biologic Dose/Recommended Ph2 Dose).
Dose Expansion Phase:
Cohort 1 will receive BMF-219 at the OBD/ RP2D to further assess the safety and efficacy of the investigational drug.
Group II: Dose Escalation PhaseExperimental Treatment1 Intervention
Experimental: ARM A:
Study participants who are not receiving a moderate or strong CYP3A4 inhibitor.
Dose Escalation Phase:
* Cohort 1: Participants with acute leukemia
* Cohort 2: Participants with diffuse large B-cell lymphoma
* Cohort 3: Participants with multiple myeloma
* Cohort 4: Participants with chronic lymphocytic leukemia/ small lymphocytic lymphoma
Participants will receive escalating dose BMF-219 orally once per day to identify the OBD/RP2D (Optimal Biologic Dose/Recommended Ph2 Dose).
Dose Expansion Phase:
Cohorts 1, 2, 3, and 4 will receive BMF-219 at the OBD/ RP2D to further assess the safety/ efficacy of the investigational drug.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Virginia Cancer SpecialistsGainesville, VA
MD Anderson Cancer CenterHouston, TX
Moffitt Cancer CenterTampa, FL
Cleveland Clinic FoundationCleveland, OH
More Trial Locations
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Who Is Running the Clinical Trial?
Biomea FusionLead Sponsor
Biomea Fusion Inc.Lead Sponsor
References
Discovery of M-1121 as an Orally Active Covalent Inhibitor of Menin-MLL Interaction Capable of Achieving Complete and Long-Lasting Tumor Regression. [2022]Targeting the menin-MLL protein-protein interaction is being pursued as a new therapeutic strategy for the treatment of acute leukemia carrying MLL-rearrangements (MLLr leukemia). Herein, we report M-1121, a covalent and orally active inhibitor of the menin-MLL interaction capable of achieving complete and persistent tumor regression. M-1121 establishes covalent interactions with Cysteine 329 located in the MLL binding pocket of menin and potently inhibits growth of acute leukemia cell lines carrying MLL translocations with no activity in cell lines with wild-type MLL. Consistent with the mechanism of action, M-1121 drives dose-dependent down-regulation of HOXA9 and MEIS1 gene expression in the MLL-rearranged MV4;11 leukemia cell line. M-1121 is orally bioavailable and shows potent antitumor activity in vivo with tumor regressions observed at tolerated doses in the MV4;11 subcutaneous and disseminated models of MLL-rearranged leukemia. Together, our findings support development of an orally active covalent menin inhibitor as a new therapy for MLLr leukemia.
Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin-MLL Interaction with Strong In Vivo Antitumor Activity. [2023]Targeting the menin-MLL protein-protein interaction is a new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein the structure-based optimization of a class of covalent menin inhibitors, which led to the discovery of M-808 (16) as a highly potent and efficacious covalent menin inhibitor. M-808 effectively inhibits leukemia cell growth at low nanomolar concentrations and is capable of achieving partial tumor regression in an MV4;11 xenograft tumor model in mice at a well-tolerated dose schedule. Determination of the co-crystal structure of M-808 in complex with menin provides a structural basis for their high-affinity, covalent interactions. M-808 represents a promising, covalent menin inhibitor for further optimization and evaluation toward developing a new therapy for the treatment of MLL leukemia.
Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction. [2022]The structure-based design of M-525 as the first-in-class, highly potent, irreversible small-molecule inhibitor of the menin-MLL interaction is presented. M-525 targets cellular menin protein at sub-nanomolar concentrations and achieves low nanomolar potencies in cell growth inhibition and in the suppression of MLL-regulated gene expression in MLL leukemia cells. M-525 demonstrates high cellular specificity over non-MLL leukemia cells and is more than 30 times more potent than its corresponding reversible inhibitors. Mass spectrometric analysis and co-crystal structure of M-525 in complex with menin firmly establish its mode of action. A single administration of M-525 effectively suppresses MLL-regulated gene expression in tumor tissue. An efficient procedure was developed to synthesize M-525. This study demonstrates that irreversible inhibition of menin may be a promising therapeutic strategy for MLL leukemia.
Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein-Protein Interaction. [2020]Inhibition of the menin-mixed lineage leukemia (MLL) protein-protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors). Our efforts have resulted in the discovery of highly potent menin inhibitors, as exemplified by compound 42 (M-89). M-89 binds to menin with a Kd value of 1.4 nM and effectively engages cellular menin protein at low nanomolar concentrations. M-89 inhibits cell growth in the MV4;11 and MOLM-13 leukemia cell lines carrying MLL fusion with IC50 values of 25 and 55 nM, respectively, and demonstrates >100-fold selectivity over the HL-60 leukemia cell line lacking MLL fusion. The determination of a co-crystal structure of M-89 in a complex with menin provides the structural basis for their high-affinity interaction. Further optimization of M-89 may lead to a new class of therapy for the treatment of MLL leukemia.
Menin Inhibitors Trigger Leukemia Remissions. [2023]Menin inhibitors have proven effective in patients with acute leukemias. A phase II study of revumenib yielded a response rate of 63% in patients with relapsed or refractory disease and KMT2A rearrangements; a phase I trial combining the drug with three chemotherapies also yielded complete remissions in patients with acute myeloid leukemia. A phase I study of a different menin inhibitor detected responses in 63% of patients with acute leukemia and certain gene alterations.
A Phase Ib/II Study of the BRAF Inhibitor Encorafenib Plus the MEK Inhibitor Binimetinib in Patients with BRAFV600E/K -mutant Solid Tumors. [2021]Label="PURPOSE">This open-label, dose-finding phase Ib/II study reports the safety and activity of the first combination use with BRAF inhibitor (BRAFi) encorafenib plus MEK inhibitor (MEKi) binimetinib in patients with BRAF V600E-mutant solid tumors.
Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non-Small-Cell Lung Cancer. [2023]Label="PURPOSE">The combination of encorafenib (BRAF inhibitor) plus binimetinib (MEK inhibitor) has demonstrated clinical efficacy with an acceptable safety profile in patients with BRAFV600E/K-mutant metastatic melanoma. We evaluated the efficacy and safety of encorafenib plus binimetinib in patients with BRAFV600E-mutant metastatic non-small-cell lung cancer (NSCLC).
Treatment experience with encorafenib plus binimetinib for BRAF V600-mutant metastatic melanoma: management insights for clinical practice. [2023]For patients with locally advanced or metastatic melanoma who have BRAF V600 activating mutations, combination therapy with BRAF and MEK inhibitors is now the standard of care. The combination of encorafenib, a highly selective adenosine triphosphate-competitive BRAF inhibitor, plus binimetinib, a potent, selective, allosteric, non-adenosine triphosphate-competitive MEK1/2 inhibitor, was approved by the US Food and Drug Administration for unresectable or metastatic melanoma with BRAF V600E or V600K mutations based on data from the phase III COLUMBUS study (NCT01909453). Clinical data evaluating BRAF and MEK inhibitor combinations in advanced melanoma indicate a specific profile of adverse events that includes serious retinopathy, skin disorders, and cardiovascular toxicities. Here we provide an overview of the rationale for combining BRAF and MEK inhibitors for the treatment of melanoma, long-term safety results from COLUMBUS, and guidance on managing the most common adverse events associated with this combination based on clinical experience. Proactive and appropriate management of adverse events can allow for longer treatment durations and may result in better treatment outcomes.
A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer. [2022]To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies.
Phase Ib Study of Combination Therapy with MEK Inhibitor Binimetinib and Phosphatidylinositol 3-Kinase Inhibitor Buparlisib in Patients with Advanced Solid Tumors with RAS/RAF Alterations. [2023]This multicenter, open-label, phase Ib study investigated the safety and efficacy of binimetinib (MEK inhibitor) in combination with buparlisib (phosphatidylinositol 3-kinase [PI3K] inhibitor) in patients with advanced solid tumors with RAS/RAF alterations.
Structure-based design of high-affinity macrocyclic peptidomimetics to block the menin-mixed lineage leukemia 1 (MLL1) protein-protein interaction. [2019]Menin is an essential oncogenic cofactor for mixed lineage leukemia 1 (MLL1)-mediated leukemogenesis through its direct interaction with MLL1. Targeting the menin-MLL1 protein-protein interaction represents a promising strategy to block MLL1-mediated leukemogenesis. Employing a structure-based approach and starting from a linear MLL1 octapeptide, we have designed a class of potent macrocyclic peptidomimetic inhibitors of the menin-MLL1 interaction. The most potent macrocyclic peptidomimetic (MCP-1), 34, binds to menin with a K(i) value of 4.7 nM and is >600 times more potent than the corresponding acyclic peptide. Compound 34 is also less peptide-like and has a lower molecular weight than the initial MLL1 peptide. Therefore, compound 34 serves as a promising lead structure for the design of potent and cell-permeable inhibitors of the menin-MLL1 interaction.