Bexmarilimab + Standard Care for Acute Myeloid Leukemia

(BEXMAB Trial)

Recruiting at 10 trial locations

Overseen By Patient Enrollment Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Faron Pharmaceuticals Ltd

Must be taking: Azacitidine, Venetoclax

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: APL, Auto-immune disorders, others

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

Compensation: Varies

Number of Visits: Unknown

181 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a study to assess the safety of increasing dose levels of bexmarilimab when combined with standard of care (SoC) in patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) or acute myeloid leukemia (AML); Phase 1 aims to identify the recommended phase 2 dose (RP2D) of bexmarilimab based on safety, tolerability and pharmacological activity; Phase 2 will investigate the preliminary efficacy of the combination treatment in selected indications from Phase 1.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you require certain treatments like systemic corticosteroids or if you have had recent chemotherapy or immunotherapy.

What data supports the effectiveness of the drug combination Bexmarilimab, Azacitidine, and Venetoclax for treating acute myeloid leukemia?

Research shows that the combination of Venetoclax and Azacitidine significantly improves survival in patients with acute myeloid leukemia who cannot undergo intensive chemotherapy. Additionally, studies indicate that this combination is effective in older patients and those with other health issues, making it a promising treatment option. ^{1 2 3 4 5}

Is the combination of Bexmarilimab and standard care safe for treating acute myeloid leukemia?

The combination of venetoclax and azacitidine, which is part of the standard care for acute myeloid leukemia, has been shown to have acceptable safety in patients who are not fit for standard chemotherapy. It is generally well-tolerated and has been used successfully in various studies, including those involving older patients and those with relapsed or refractory leukemia. ^{1 3 5 6 7}

What makes the drug combination of Bexmarilimab, Azacitidine, and Venetoclax unique for treating acute myeloid leukemia?

This drug combination is unique because it combines Bexmarilimab, an anti-CLEVER-1 antibody that may enhance the immune system's ability to fight cancer, with Azacitidine and Venetoclax, which work together to stop cancer cell growth and survival. This approach targets both the immune system and cancer cells directly, offering a potentially more comprehensive treatment for acute myeloid leukemia. ^{8 9 10 11 12}

Research Team

Mika Kontro

Principal Investigator

Helsinki University Central Hospital

Eligibility Criteria

Adults with certain blood cancers like MDS, CMML-2, or AML who have specific risk levels or treatment histories can join. They need good kidney and liver function and a low enough white blood cell count. People with acute promyelocytic leukemia, poor physical status, recent transplants, active autoimmune diseases (with some exceptions), current heavy immunosuppression use, or recent other cancer treatments cannot participate.

Inclusion Criteria

My CMML or MDS did not improve with HMA treatment.

My kidneys are working well.

I have AML and cannot undergo standard treatment, but can take azacitidine-venetoclax.

Exclusion Criteria

I have APL or CMML with a high white blood cell count.

My physical condition limits my daily activities, except if I have newly diagnosed AML and am under 75.

Pregnant or lactating women.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive bexmarilimab at increasing dose levels combined with standard of care to identify the maximum tolerated dose

28-day cycle, repeated as necessary

Weekly visits for dose escalation, then bi-weekly

Phase 2 Treatment

Participants receive bexmarilimab at the recommended phase 2 dose combined with standard of care to evaluate safety and preliminary efficacy

28-day cycle, repeated as necessary

Bi-weekly visits

End of Treatment Follow-up

Participants are monitored for safety after the end of treatment

4 weeks

Disease Progression/Survival Follow-up

Participants are monitored for disease progression and survival

Long-term

Treatment Details

Interventions

• Azacitidine
• Bexmarilimab
• Venetoclax

Trial Overview The trial is testing Bexmarilimab combined with standard treatments Azacitidine and Venetoclax in patients with specific types of blood cancers. It's in two phases: the first to find the safest dose level of Bexmarilimab and the second to see how well it works at that dose for these conditions.

Participant Groups

Group I: Phase 2 - Intermediate/high risk MDS, CMML, MDS/CMML failure to HMA, r/r AML & newly diagnosed AML Experimental Treatment 3 Interventions

Standard of care venetoclax and/or azacitidine as per label plus bexmarilmab

Group II: Phase 1 - Newly diagnosed AML patients non-fit for induction therapy Experimental Treatment 3 Interventions

Standard of care azacitidine and venetoclax as per label; bexmarilimab 4 dose levels Q1W followed by Q2W; 28-day cycle

Group III: Phase 1 - Intermediate/high risk MDS, CMML 10-19%, MDS/CMML failure to HMA, r/r AML Experimental Treatment 2 Interventions

Standard of care azacitidine as per label; bexmarilimab 4 dose levels at once every week (Q1W) followed by once every 2 weeks (Q2W); 28-day cycle

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Faron Pharmaceuticals Ltd

Lead Sponsor

Trials

9

Recruited

780+

Findings from Research

In a Japanese subgroup of the phase 3 VIALE-A trial, venetoclax-azacitidine significantly improved overall survival rates compared to placebo-azacitidine, with 67% of patients alive at 12 months versus 46% in the placebo group.

The treatment also resulted in a high complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 67%, while maintaining a safety profile similar to the global study, indicating it is a viable first-line treatment for Japanese patients with acute myeloid leukemia ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Yamamoto, K., Shinagawa, A., DiNardo, CD., et al.[2023]

The combination of 225 Ac-lintuzumab and venetoclax showed a synergistic effect in killing tumor cells in venetoclax-resistant acute myeloid leukemia (AML) models, indicating a potential new treatment strategy.

This combination therapy not only induced DNA damage but also reduced MCL-1 protein levels, which is linked to resistance against venetoclax, leading to better tumor control and prolonged survival in preclinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. Garg, R., Allen, KJH., Dawicki, W., et al.[2021]

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

ASP1235, an antibody drug conjugate targeting FLT3, shows promising anti-tumor effects when combined with venetoclax and azacitidine in a preclinical model of acute myeloid leukemia (AML), particularly in THP-1 cells.

The combination treatment demonstrated superior efficacy compared to monotherapy and did not result in significant body weight loss, suggesting a favorable safety profile for this triple therapy in AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-tumor effect of antibody drug conjugate ASP1235 targeting Fms-like tyrosine kinase 3 with venetoclax plus azacitidine in an acute myeloid leukemia xenograft mouse model. Tsuzuki, H., Kawase, T., Nakazawa, T., et al.[2023]

In a study of nine AML patients with acquired resistance to venetoclax, the typical BCL2 mutation associated with resistance was not found, suggesting that this mutation is not necessary for developing resistance in AML.

The study identified that existing mutations, particularly the expansion of FLT3-ITD, were primarily responsible for venetoclax resistance, indicating that monitoring these mutations could help in developing strategies to prevent or overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. Zhang, X., Qian, J., Wang, H., et al.[2022]

In a study of 60 patients with acute myeloid leukemia (AML), the combination of venetoclax and azacitidine (Ven+AZA) demonstrated a high response rate, with 70.8% of previously untreated patients unfit for standard chemotherapy achieving complete remission (CR) or CR with incomplete hematological recovery (CRi) after one cycle.

Ven+AZA was found to be safe and tolerable, with some patients achieving minimal residual disease (MRD) negativity, particularly in those with favorable genetic mutations like NPM1, IDH1/IDH2, and TP53, indicating its potential effectiveness in specific patient subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. Yu, WJ., Jia, JS., Wang, J., et al.[2022]

In a study of 33 untreated acute myeloid leukemia (AML) patients receiving off-label venetoclax/azacitidine, the complete remission rate was 63.3%, which is lower than the 84.9% rate observed in a clinical trial cohort, although the difference was not statistically significant (P = .081).

The median overall survival for off-trial patients was 381 days, significantly shorter than the 880 days for trial patients (P = .041), indicating that while off-trial use is feasible, it may lead to inferior outcomes compared to clinical trial settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia. Winters, AC., Gutman, JA., Purev, E., et al.[2020]

In a phase II trial involving 209 patients with metastatic colorectal cancer, the addition of bevacizumab to fluorouracil and leucovorin (FU/LV) significantly improved median progression-free survival to 9.2 months compared to 5.5 months with placebo, indicating a strong therapeutic benefit.

While bevacizumab treatment was associated with a higher incidence of grade 3 hypertension (16% vs. 3% in the placebo group), this side effect was manageable with medication and did not lead to discontinuation of the treatment, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. Kabbinavar, FF., Schulz, J., McCleod, M., et al.[2022]

In a study of 409 patients with metastatic colorectal cancer, first-line treatment with XELOX plus bevacizumab (XELOX-Bev) resulted in a median overall survival of 25 months, compared to 20 months for FOLFIRI plus bevacizumab (FOLFIRI-Bev), indicating XELOX-Bev is more effective.

XELOX-Bev also demonstrated a higher response rate of 56.4% compared to 26.1% for FOLFIRI-Bev, along with a better safety profile, making it a preferable first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

XELOX plus bevacizumab vs. FOLFIRI plus bevacizumab treatment for first-line chemotherapy in metastatic colon cancer: a retrospective study of the Anatolian Society of Medical Oncology. Duran, AO., Karaca, H., Besiroglu, M., et al.[2020]

In a phase 2 clinical trial involving 133 patients with refractory metastatic colorectal cancer, the addition of atezolizumab to capecitabine and bevacizumab therapy resulted in a median progression-free survival (PFS) of 4.4 months compared to 3.6 months for the placebo group, indicating a potential benefit, although not clinically meaningful.

Patients with microsatellite-stable disease and those without liver metastasis showed greater benefits from the combination therapy, suggesting that specific patient characteristics may influence the efficacy of atezolizumab in this treatment context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Capecitabine and Bevacizumab With or Without Atezolizumab for the Treatment of Refractory Metastatic Colorectal Cancer: A Randomized Clinical Trial. Mettu, NB., Ou, FS., Zemla, TJ., et al.[2022]

In a study of 31 patients with metastatic colorectal cancer who had previously failed chemotherapy, 32.2% showed an objective response to bevacizumab combined with FOLFIRI or FOLFOX, indicating potential efficacy in chemorefractory cases.

The treatment resulted in a median progression-free survival of 9.7 months and an overall survival of 18.4 months, with acceptable tolerance, suggesting that bevacizumab can be a viable option for patients who have not previously received it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab plus FOLFIRI or FOLFOX in chemotherapy-refractory patients with metastatic colorectal cancer: a retrospective study. Lièvre, A., Samalin, E., Mitry, E., et al.[2021]

In a study of 198 Chinese patients with advanced non-small cell lung cancer (NSCLC), first-line treatment with bevacizumab combined with chemotherapy showed a high objective response rate of 68.8%, indicating its efficacy in this population.

The treatment was generally safe, with only 8 cases of severe adverse events related to bevacizumab and a low incidence of grade 3 adverse events (<9%), confirming that the safety profile aligns with previous studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of first-line bevacizumab combination therapy in Chinese population with advanced non-squamous NSCLC: data of subgroup analyses from MO19390 (SAiL) study. Zhou, CC., Bai, CX., Guan, ZZ., et al.[2022]

References

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

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. [2023]

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

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]

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

Anti-tumor effect of antibody drug conjugate ASP1235 targeting Fms-like tyrosine kinase 3 with venetoclax plus azacitidine in an acute myeloid leukemia xenograft mouse model. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. [2022]

6. China pubmed.ncbi.nlm.nih.gov

[Short-term efficacy of venetoclax combined with azacitidine in acute myeloid leukemia: a single-institution experience]. [2022]

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

Real-world experience of venetoclax with azacitidine for untreated patients with acute myeloid leukemia. [2020]

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

Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. [2022]

9. Thailand pubmed.ncbi.nlm.nih.gov

XELOX plus bevacizumab vs. FOLFIRI plus bevacizumab treatment for first-line chemotherapy in metastatic colon cancer: a retrospective study of the Anatolian Society of Medical Oncology. [2020]

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

Assessment of Capecitabine and Bevacizumab With or Without Atezolizumab for the Treatment of Refractory Metastatic Colorectal Cancer: A Randomized Clinical Trial. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Bevacizumab plus FOLFIRI or FOLFOX in chemotherapy-refractory patients with metastatic colorectal cancer: a retrospective study. [2021]

12. Italy pubmed.ncbi.nlm.nih.gov

Safety and efficacy of first-line bevacizumab combination therapy in Chinese population with advanced non-squamous NSCLC: data of subgroup analyses from MO19390 (SAiL) study. [2022]