BMF-219 for Blood Cancers

Recruiting at 41 trial locations

Overseen By Mona Vimal

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Biomea Fusion

Disqualifiers: APL, CML, CNS involvement, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

55 Participants Needed

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.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

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. ^{1 2 3 4 5}

What data supports the effectiveness of the drug BMF-219 for blood cancers?

Research on similar drugs, like menin inhibitors, shows promising results in treating certain types of leukemia. For example, a phase II study of a menin inhibitor called revumenib showed a 63% response rate in patients with specific genetic changes in their leukemia, suggesting that targeting the menin-MLL interaction can be effective. ^{1 2 3 4 5}

What 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. ^{6 7 8 9 10}

Is the drug BMF-219 a promising treatment for blood cancers?

Yes, BMF-219 is a promising drug for blood cancers because it targets a specific protein interaction involved in leukemia, showing strong potential to stop cancer cell growth and even shrink tumors in studies. ^{1 2 3 4 11}

What makes the drug BMF-219 unique for treating blood cancers?

BMF-219 is unique because it is a covalent menin inhibitor, which means it forms a strong, lasting bond with the menin protein to block its interaction with MLL, a protein involved in certain blood cancers. This approach is novel compared to traditional treatments, as it specifically targets the menin-MLL interaction, offering a new strategy for treating these cancers. ^{1 2 3 4 11}

Research Team

Steve Morris, MD

Principal Investigator

Biomea Fusion Inc.

Eligibility 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.

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.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of BMF-219 to identify the Optimal Biologic Dose (OBD) and Recommended Phase 2 Dose (RP2D)

4 weeks

Daily oral administration

Dose Expansion

Participants receive BMF-219 at the OBD/RP2D to further assess safety and efficacy

4 weeks

Daily oral administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• BMF-219

Trial Overview 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.

Participant Groups

Group I: Dose Expansion Experimental Treatment 1 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 Phase Experimental Treatment 1 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.

Who Is Running the Clinical Trial?

Biomea Fusion

Lead Sponsor

Trials

1

Recruited

60+

Biomea Fusion Inc.

Lead Sponsor

Trials

5

Recruited

780+

Findings from Research

M-1121 is a new oral inhibitor that targets the menin-MLL protein interaction, showing complete and lasting tumor regression in acute leukemia with MLL rearrangements, while having no effect on leukemia with wild-type MLL.

The drug works by covalently binding to a specific site on the menin protein, leading to reduced expression of key genes associated with leukemia, and demonstrates strong antitumor activity in animal models at safe doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of M-1121 as an Orally Active Covalent Inhibitor of Menin-MLL Interaction Capable of Achieving Complete and Long-Lasting Tumor Regression. Zhang, M., Aguilar, A., Xu, S., et al.[2022]

M-808 is a newly developed covalent menin inhibitor that shows strong effectiveness in inhibiting leukemia cell growth at low nanomolar concentrations, indicating its potential as a powerful treatment for MLL leukemia.

In mouse models, M-808 not only inhibited tumor growth but also achieved partial tumor regression, demonstrating its efficacy and safety at a well-tolerated dosing schedule.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin-MLL Interaction with Strong In Vivo Antitumor Activity. Xu, S., Aguilar, A., Huang, L., et al.[2023]

M-525 is a first-in-class small-molecule inhibitor that irreversibly targets the menin-MLL interaction, showing high potency at sub-nanomolar concentrations and effectively inhibiting cell growth in MLL leukemia cells.

This compound demonstrates over 30 times greater potency compared to reversible inhibitors and selectively suppresses MLL-regulated gene expression, indicating its potential as a promising therapeutic strategy for treating MLL leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction. Xu, S., Aguilar, A., Xu, T., et al.[2022]

A new class of small-molecule inhibitors targeting the menin-MLL protein interaction has been developed, with the compound M-89 showing a very strong binding affinity (Kd value of 1.4 nM) and effective engagement of menin at low concentrations.

M-89 demonstrated significant anti-leukemic activity, inhibiting cell growth in MLL fusion leukemia cell lines with IC50 values of 25 nM and 55 nM, while being over 100 times more selective for these cells compared to a leukemia cell line without MLL fusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein-Protein Interaction. Aguilar, A., Zheng, K., Xu, T., et al.[2020]

Revumenib, a menin inhibitor, showed a 63% response rate in a phase II study for patients with relapsed or refractory acute leukemias with KMT2A rearrangements.

In a phase I trial, combining revumenib with three chemotherapies resulted in complete remissions in patients with acute myeloid leukemia, highlighting its potential effectiveness in treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Menin Inhibitors Trigger Leukemia Remissions. [2023]

The combination of encorafenib and binimetinib was found to be safe and showed promising activity in patients with BRAF V600E-mutant solid tumors, with a recommended phase 2 dose established for further studies.

In phase II, the treatment resulted in confirmed responses in 67% of BRAFi-naïve melanoma patients, indicating significant efficacy, while the most common serious side effect was increased alanine aminotransferase levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of the BRAF Inhibitor Encorafenib Plus the MEK Inhibitor Binimetinib in Patients with BRAFV600E/K -mutant Solid Tumors. Sullivan, RJ., Weber, J., Patel, S., et al.[2021]

In a phase II study involving 98 patients with BRAFV600E-mutant metastatic non-small-cell lung cancer (NSCLC), the combination of encorafenib and binimetinib achieved a confirmed objective response rate of 75% in treatment-naïve patients and 46% in previously treated patients, indicating significant efficacy.

The treatment was generally well-tolerated, with common side effects including nausea (50%) and diarrhea (43%), but it also led to dose reductions in 24% of patients and one serious adverse event of intracranial hemorrhage, highlighting the importance of monitoring safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non-Small-Cell Lung Cancer. Riely, GJ., Smit, EF., Ahn, MJ., et al.[2023]

The combination of encorafenib and binimetinib is now the standard treatment for patients with advanced melanoma harboring BRAF V600 mutations, based on the phase III COLUMBUS study.

While this combination therapy is effective, it is associated with specific adverse events such as serious retinopathy and cardiovascular toxicities, highlighting the importance of proactive management to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment experience with encorafenib plus binimetinib for BRAF V600-mutant metastatic melanoma: management insights for clinical practice. Augustyn, K., Joseph, J., Patel, AB., et al.[2023]

The combination of the allosteric MEK inhibitor refametinib and sorafenib was found to be well tolerated in a phase I study involving 32 patients, with the maximum tolerated dose established at refametinib 50 mg and sorafenib 400 mg, showing common side effects like diarrhea and fatigue.

This treatment effectively reduced ERK phosphorylation in tumors, particularly in patients with KRAS or BRAF mutations, and stabilized disease in about half of the participants, with one patient experiencing a partial response lasting around one year.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer. Adjei, AA., Richards, DA., El-Khoueiry, A., et al.[2022]

In a phase Ib study involving 89 patients with advanced solid tumors, the combination of binimetinib (a MEK inhibitor) and buparlisib (a PI3K inhibitor) showed some efficacy, particularly in RAS/BRAF-mutant ovarian cancer, where 12% of patients achieved a partial response.

However, the treatment was associated with significant toxicities, leading to a lower than expected dose intensity, suggesting that alternative dosing strategies, like pulsatile dosing, may be necessary to improve safety and tolerability in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Bardia, A., Gounder, M., Rodon, J., et al.[2023]

The study identifies menin as a crucial factor in MLL1-mediated leukemia, suggesting that inhibiting the menin-MLL1 interaction could be an effective strategy to combat this type of cancer.

A newly designed macrocyclic peptidomimetic inhibitor, MCP-1, shows exceptional potency with a binding affinity of 4.7 nM, making it over 600 times more effective than the original peptide, indicating its potential as a lead compound for further development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structure-based design of high-affinity macrocyclic peptidomimetics to block the menin-mixed lineage leukemia 1 (MLL1) protein-protein interaction. Zhou, H., Liu, L., Huang, J., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Discovery of M-1121 as an Orally Active Covalent Inhibitor of Menin-MLL Interaction Capable of Achieving Complete and Long-Lasting Tumor Regression. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin-MLL Interaction with Strong In Vivo Antitumor Activity. [2023]

3. Germany pubmed.ncbi.nlm.nih.gov

Design of the First-in-Class, Highly Potent Irreversible Inhibitor Targeting the Menin-MLL Protein-Protein Interaction. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein-Protein Interaction. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Menin Inhibitors Trigger Leukemia Remissions. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of the BRAF Inhibitor Encorafenib Plus the MEK Inhibitor Binimetinib in Patients with BRAFV600E/K -mutant Solid Tumors. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients With BRAFV600-Mutant Metastatic Non-Small-Cell Lung Cancer. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Treatment experience with encorafenib plus binimetinib for BRAF V600-mutant metastatic melanoma: management insights for clinical practice. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

A Phase I Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Combination Therapy with Refametinib plus Sorafenib in Patients with Advanced Cancer. [2022]

10. England pubmed.ncbi.nlm.nih.gov

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]

11. United States pubmed.ncbi.nlm.nih.gov

Structure-based design of high-affinity macrocyclic peptidomimetics to block the menin-mixed lineage leukemia 1 (MLL1) protein-protein interaction. [2019]