BMF-500 for Leukemia

Recruiting in Palo Alto (17 mi)

+26 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Biomea Fusion Inc.

Must be taking: Azole antifungals

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Cardiovascular disease, High WBC, Pregnancy, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing BMF-500, a pill that blocks a protein called FLT3, in adults with aggressive types of leukemia. The goal is to stop cancer cells from growing by blocking this protein.

Will I have to stop taking my current medications?

The trial requires that participants in Arm A stop taking moderate or strong CYP3A4 inhibitors at least 7 days before joining and avoid them for at least 4 weeks. Participants in Arm B must continue taking a necessary azole antifungal that is a moderate or strong CYP3A4 inhibitor for at least 4 weeks.

What data supports the effectiveness of the drug BMF-500 for leukemia?

The research does not provide direct evidence about BMF-500, but it discusses the use of granulocyte colony-stimulating factors (G-CSF) in leukemia treatment, which are known to reduce the duration of neutropenia (low white blood cell count) and modestly decrease infection rates during chemotherapy. However, these factors have not shown significant improvements in overall survival or complete remission rates. ^{1 2 3 4 5}

How does the drug BMF-500 differ from other leukemia treatments?

BMF-500 is unique because it involves the use of bone marrow fibroblasts-conditioned medium, which can regulate the growth of leukemic cells by releasing specific factors. This approach is different from standard treatments as it targets the microenvironment of the bone marrow to influence leukemia cell proliferation. ^{6 7 8 9 10}

Research Team

Eligibility Criteria

Adults over 18 with acute leukemia (AML, ALL, or MPAL) that has come back or didn't respond to treatment. They must have a FLT3 mutation and be able to follow rules about using certain other drugs. People can't join if they have very high white blood cell counts, serious heart problems, recent strokes, or are pregnant.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

I am 18 years old or older.

My liver and kidneys are working well.

Exclusion Criteria

My white blood cell count is over 50,000 and cannot be controlled with treatment.

I haven't had major heart problems or strokes in the last 6 months.

I am not pregnant, breastfeeding, nor planning to become pregnant.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-escalation

Participants receive BMF-500 in a dose-escalation format to determine the recommended Phase 2 Dose (RP2D)

28 days per cycle, up to 32 cycles

Visits at the end of each 28-day cycle

Dose-expansion

Participants receive BMF-500 in a dose-expansion format to further evaluate safety and efficacy

28 days per cycle, up to 32 cycles

Visits at the end of each 28-day cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• BMF-500 (Tyrosine Kinase Inhibitor)

Trial Overview The trial is testing BMF-500, an oral drug for acute leukemia targeting the FLT3 gene mutation. It's a first-in-human study where doses will gradually increase to find safe levels before expanding to more patients.

Participant Groups

Group I: Arm C: Escalation Phase Experimental Treatment 1 Intervention

BMF-500 taken twice daily by participants who are receiving necessary azole antifungals that are moderate CYP3A4 inhibitors.

Group II: Arm B: Escalation Phase Experimental Treatment 1 Intervention

BMF-500 taken twice daily by participants who are receiving necessary azole antifungals that are Strong CYP3A4 inhibitors.

Group III: Arm A: Escalation Phase Experimental Treatment 1 Intervention

BMF-500 taken twice daily by participants who are not receiving drugs that inhibit CYP3A4 activity.

Who Is Running the Clinical Trial?

Biomea Fusion Inc.

Lead Sponsor

Trials

5

Recruited

780+

Findings from Research

The addition of granulocyte colony-stimulating factor (G-CSF) to chemotherapy significantly improves overall survival (OS) and disease-free survival (DFS) in patients with acute myeloid leukemia (AML), particularly in those who have not received prior treatment.

For patients with relapsed or refractory AML, G-CSF did not show a significant benefit in survival or remission rates compared to those not receiving G-CSF, indicating its effectiveness may be limited to earlier stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact on acute myeloid leukemia relapse in granulocyte colony-stimulating factor application: a meta-analysis. Feng, X., Lan, H., Ruan, Y., et al.[2018]

Myeloid growth factors, such as granulocyte-colony stimulating factors, are safe and well-tolerated in patients with acute leukemias, effectively reducing the duration of neutropenia during chemotherapy.

While these growth factors help shorten neutropenia and improve disease-free survival in some patients, they do not significantly impact overall survival or complete remission rates in acute myeloid and lymphoblastic leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of myeloid growth factors in acute leukemia. Wadleigh, M., Stone, RM.[2019]

In a phase II trial involving 26 patients with relapsed/refractory AML treated with sargramostim (GM-CSF) and bexarotene, 31% showed hematologic improvement in neutrophils, although no complete or partial remissions were achieved.

Another trial with 10 patients using GM-CSF and entinostat resulted in 10% achieving partial remission and 20% showing hematologic improvement, indicating that while the treatments were well tolerated, their clinical efficacy was modest.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differentiation therapy in poor risk myeloid malignancies: Results of companion phase II studies. Norsworthy, KJ., Cho, E., Arora, J., et al.[2022]

In a study involving 271 children with acute myeloid leukemia (AML), 80% achieved complete remission, but there were significant early deaths (7%) due to hemorrhage and leukostasis, highlighting the need for improved initial treatment strategies.

Both studies (BFM-78 and BFM-83) showed similar long-term outcomes, with event-free survival rates around 37-40%, but initial hyperleukocytosis was identified as a high-risk factor for complications and relapses, indicating that targeted interventions for these patients are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current results of cooperative AML therapy studies in children: BFM-78 and 83]. Creutzig, U., Ritter, J., Budde, M., et al.[2013]

Bone marrow fibroblasts (BMF) from leukemia patients can inhibit the proliferation of leukemic cells, showing both direct effects and those mediated by autocrine signaling.

The effectiveness of BMF in inhibiting leukemic cell growth varies based on the specific type of leukemia and the cell line tested, indicating that the disease context and cellular interactions play significant roles in this process.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of media conditioned with bone marrow fibroblasts on proliferation of leukemic blast cell lines]. Maliulaĭtene, ER., Blagosklonnyĭ, MV.[2020]

Normal human bone marrow fibroblast-conditioned medium (BMF-CM) can suppress the growth of certain leukemic cells, specifically K562 cells and undifferentiated acute myelocytic leukemia cells, indicating a potential therapeutic role in these types of leukemia.

Conversely, BMF-CM appears to stimulate the proliferation of differentiated leukemic cells and those from patients with chronic myelogenous leukemia, suggesting that its effects vary based on the differentiation stage of the leukemia cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bone marrow fibroblasts-conditioned medium regulates the proliferation of leukemic cells. Kubota, T., Nagao, T., Arimori, S.[2007]

B-lineage acute lymphoblastic leukemia (ALL) cells, both Philadelphia chromosome-positive and negative, universally express the BAFF-R receptor, which is crucial for their survival and growth, indicating a potential target for therapy.

Stimulation of BAFF-R not only activates survival pathways in ALL cells but also protects them from apoptosis induced by nilotinib, suggesting that blocking BAFF-R could enhance treatment effectiveness in ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A functional receptor for B-cell-activating factor is expressed on human acute lymphoblastic leukemias. Parameswaran, R., Müschen, M., Kim, YM., et al.[2021]

Bone marrow fibroblasts (BMF) from normal adults and patients in complete remission (CR) enhanced the growth of colony-forming units in culture (CFU-C), while BMF from patients with acute leukemia (AL) at diagnosis did not support this growth, indicating a potential impairment in the bone marrow microenvironment during active disease.

BMF from patients with AL at diagnosis exhibited a significantly higher inhibitory effect on CFU-C growth compared to BMF from normal subjects, suggesting that the disease state alters the supportive role of bone marrow fibroblasts in hematopoiesis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abnormal regulation of granulopoiesis by bone marrow fibroblasts in leukemia. Shimizu, M., Nagao, T., Arimori, S.[2004]

This study found that both high-molecular-weight (HMW) and low-molecular-weight (LMW) B cell growth factors (BCGF) bind to B cell precursor cells in acute lymphoblastic leukemia (ALL), with LMW-BCGF showing a stronger stimulatory effect in 75% of cases compared to 33% for HMW-BCGF.

The research indicates that patients with specific chromosomal abnormalities, such as those involving 12p11-13 or the Philadelphia chromosome, have a greater response to HMW-BCGF, suggesting that these genetic factors may influence the effectiveness of BCGF in promoting B cell proliferation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B-cell growth factor receptor expression and B-cell growth factor response of leukemic B cell precursors and B lineage lymphoid progenitor cells. Uckun, FM., Fauci, AS., Heerema, NA., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Impact on acute myeloid leukemia relapse in granulocyte colony-stimulating factor application: a meta-analysis. [2018]

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

Less toxicity by optimizing chemotherapy, but not by addition of granulocyte colony-stimulating factor in children and adolescents with acute myeloid leukemia: results of AML-BFM 98. [2019]

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

The role of myeloid growth factors in acute leukemia. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Differentiation therapy in poor risk myeloid malignancies: Results of companion phase II studies. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

[Current results of cooperative AML therapy studies in children: BFM-78 and 83]. [2013]

6. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Effect of media conditioned with bone marrow fibroblasts on proliferation of leukemic blast cell lines]. [2020]

7. Japan pubmed.ncbi.nlm.nih.gov

Bone marrow fibroblasts-conditioned medium regulates the proliferation of leukemic cells. [2007]

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

A functional receptor for B-cell-activating factor is expressed on human acute lymphoblastic leukemias. [2021]

9. Japan pubmed.ncbi.nlm.nih.gov

Abnormal regulation of granulopoiesis by bone marrow fibroblasts in leukemia. [2004]

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

B-cell growth factor receptor expression and B-cell growth factor response of leukemic B cell precursors and B lineage lymphoid progenitor cells. [2021]