BTM-3566 for B-Cell Lymphoma

Overseen By Meghan Reynolds

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Bantam Pharmaceuticals

Disqualifiers: Primary CNS lymphoma, Neurologic disease, Second malignancy, others

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

Compensation: Varies

Number of Visits: 3

Duration: 24 months

24 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to learn if BMT-3566 can safety be given to adult patients with relapsed or refractory mature b cell lymphomas. It will also learn how well BTM-3566 works to treat relapsed or refractory mature b cell lymphomas. The main questions it aims to answer are: What are the side effects of BTM-3566 at different doses? What are the levels of BTM-3566 in the blood at different timepoints around dosing? What is the clinical benefit of BTM-3566 in treating cancer (i.e. how well does it slow or stop disease progression)? Participants will: Take BTM-3566 in 14-day periods with 7 days of dosing followed by 7 days of no dosing Visit the clinic regularly for checkups and tests Keep a diary of their dosing and weight

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. However, it does mention that you cannot have received any anti-cancer therapy within 28 days before starting the trial.

What safety data exists for BTM-3566 or similar treatments in humans?

Bruton's tyrosine kinase inhibitors, similar to BTM-3566, have been studied for safety in B-cell malignancies. New-generation inhibitors show fewer heart-related side effects but more blood and stomach issues compared to older ones. In a trial with a similar drug, M7583, common side effects included diarrhea, fatigue, and vomiting, but no severe dose-limiting toxicities were reported. ^{1 2 3 4 5}

How is the drug BTM-3566 different from other treatments for B-cell lymphoma?

BTM-3566 is unique because it targets the BCL6 protein, which is crucial for the survival of certain B-cell lymphomas. This approach is different from conventional treatments as it specifically inhibits BCL6, a protein involved in the development and maintenance of these cancer cells, offering a new strategy for treating lymphomas that rely on BCL6 for growth. ^{6 7 8 9 10}

Research Team

Zahid Bashir, MBBS

Principal Investigator

Bantam Pharmaceuticals

Eligibility Criteria

Adults over 18 with relapsed or refractory mature B cell lymphoma can join this trial. They should have measurable disease, be able to perform daily activities (ECOG PS 0-2), and likely live at least another 3 months. Participants must use birth control during the study and for 90 days after.

Inclusion Criteria

I am 18 years old or older.

Must have measurable disease per response evaluation criteria in lymphoma (Lugano classification)

Must have a predicted life expectancy of ≥3 months

Exclusion Criteria

Is pregnant or breastfeeding

I have been diagnosed with lymphoma in my brain or spinal cord.

I have side effects from cancer treatment that are mild or worse.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-3 weeks

Treatment

Participants receive BTM-3566 in 14-day cycles with 7 days of dosing followed by 7 days off

24 months

Regular clinic visits for checkups and tests

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Imaging every 3 months, then every 6 months

Treatment Details

Interventions

• BTM-3566

Trial Overview The trial is testing BTM-3566's safety and effectiveness in treating mature B cell lymphomas that have come back or didn't respond to treatment. It involves taking the drug for a week, then pausing for a week, while attending regular clinic visits and tracking dosing.

Participant Groups

Group I: BTM-3566 Treatment Experimental Treatment 1 Intervention

BTM-3566 Oral Solution

Who Is Running the Clinical Trial?

Bantam Pharmaceuticals

Lead Sponsor

Trials

1

Recruited

20+

Findings from Research

A systematic review of 55 studies found that first-generation BTK inhibitors had a significantly higher incidence of cardiovascular adverse events (20.8%) compared to second-generation BTK inhibitors (6.3%).

While second-generation BTK inhibitors showed lower cardiovascular risks, they were associated with higher rates of hematologic/oncologic (62.3% vs. 39.2%) and gastrointestinal side effects (36.9% vs. 28.9%) compared to first-generation inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of Bruton's tyrosine kinase inhibitors in B-cell malignancies: A systematic review. Arustamyan, M., Kibrik, P., Hatipoglu, D., et al.[2022]

The BCH-LBL-2003 treatment regimen, modified from the BFM-90 protocol, showed high efficacy in treating childhood lymphoblastic lymphoma, achieving a 100% overall response rate and a 5-year overall survival rate of 87% among 112 patients studied over a median follow-up of 29 months.

Despite the high effectiveness, all patients experienced significant hematological toxicity (grade 3-4), and certain factors such as lack of complete remission at the end of induction therapy and T-cell immunophenotype were identified as poor prognostic indicators.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical features and prognosis of children with lymphoblastic lymphoma]. Jin, L., Zhang, R., Huang, S., et al.[2018]

The modified B-NHL-BFM-90 protocol resulted in an 83% complete remission rate among 55 Chinese children and adolescents with Burkitt's lymphoma and large cell lymphoma, indicating high efficacy in treating these conditions.

The event-free survival rate was 85% at a median follow-up of 24 months, with manageable side effects like myelosuppression and mucositis, suggesting the treatment is both effective and tolerable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved treatment outcome in Chinese children and adolescents with Burkitt's lymphoma and large cell lymphoma by using the modified B-non-Hodgkin's lymphoma-Berlin-Frankfurt-Münster-90 protocol. Sun, XF., Zhen, ZJ., Lui, DG., et al.[2015]

New-generation Bruton tyrosine kinase inhibitors (BTKi) show a high overall response rate of 92% in treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), particularly benefiting younger patients and those receiving combination therapy.

While BTKi-based therapies are generally well-tolerated, they can lead to significant adverse events like cytopenia and hypertension, and zanubrutinib may offer better efficacy than acalabrutinib as a monotherapy for CLL/SLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of new-generation Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia/small lymphocytic lymphoma: a systematic review and meta-analysis. Yin, S., Zheng, X., Zhang, W., et al.[2023]

In a phase I trial involving 18 patients with advanced B-cell malignancies, the BTK inhibitor M7583 showed a 50% objective response rate and a 78% disease control rate, indicating promising efficacy for patients who had failed prior treatments.

The drug was well tolerated, with no dose-limiting toxicities reported, although 89% of patients experienced treatment-emergent adverse events, primarily diarrhea, fatigue, and vomiting, suggesting a favorable safety profile for further testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I, first-in-human trial of Bruton's tyrosine kinase inhibitor M7583 in patients with B-cell malignancies. Jurczak, W., Rule, S., Townsend, W., et al.[2021]

BCL6 is a key protein involved in the development of germinal centers and is often mutated in B cell non-Hodgkin lymphomas (B-NHL), making it a promising target for therapy.

Several agents that inhibit BCL6 have shown anti-lymphoma activity in preclinical models, and future clinical trials will be crucial to assess their efficacy in treating B-NHL, especially when used alongside other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCL6 as a therapeutic target for lymphoma. Leeman-Neill, RJ., Bhagat, G.[2018]

BCL6 is a crucial transcription factor in B-cell and T-cell functions, playing a significant role in various lymphomas, including diffuse large B-cell lymphoma (DLBCL), where it is linked to better treatment responses.

Recent development of BCL6 antagonists shows promise, as they can inhibit the survival of DLBCL cells that rely on BCL6, suggesting potential for new lymphoma treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of BCL6 in lymphomas and routes to therapy. Wagner, SD., Ahearne, M., Ko Ferrigno, P.[2016]

BCL6 rearrangements were identified in 35.5% of diffuse large cell lymphomas (DLLC), indicating a significant genetic alteration associated with this type of cancer.

This genetic change was most common in diffuse large cell lymphoma (45%) compared to other types of non-Hodgkin's lymphoma, suggesting that BCL6 could be a key factor in understanding the development and monitoring of DLLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin's lymphoma. Lo Coco, F., Ye, BH., Lista, F., et al.[2021]

Disulfide (DSF), especially in combination with copper (Cu), significantly inhibits the growth of diffuse large B-cell lymphoma (DLBCL) cells by inducing apoptosis and causing cell cycle arrest, as demonstrated in four DLBCL cell lines and primary cells from eight patients.

The mechanism of action involves the inhibition of the NF-κB signaling pathway and a reduction in BCL6 levels, suggesting that DSF has therapeutic potential for treating DLBCL, which is typically resistant to conventional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DSF/Cu induces antitumor effect against diffuse large B-cell lymphoma through suppressing NF-κB/BCL6 pathways. Zhu, Y., Lei, C., Jiang, Q., et al.[2022]

A novel B-cell lymphoma cell line, YM, was established from a patient with diffuse large cell lymphoma, showing rearrangements of the BCL2 and BCL6 genes, which are implicated in the development of non-Hodgkin's lymphoma.

The YM cells exhibited both t(2;18) and t(3;16) translocations, leading to deregulated overexpression of BCL2 and BCL6, suggesting a potential collaboration between these genes in the pathogenesis of B-cell non-Hodgkin's lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular features of a new human lymphoma cell line carrying both BCL2 and BCL6 gene rearrangements. Yonetani, N., Akasaka, T., Akasaka, H., et al.[2015]

References

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

The safety of Bruton's tyrosine kinase inhibitors in B-cell malignancies: A systematic review. [2022]

2. China pubmed.ncbi.nlm.nih.gov

[Clinical features and prognosis of children with lymphoblastic lymphoma]. [2018]

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

Improved treatment outcome in Chinese children and adolescents with Burkitt's lymphoma and large cell lymphoma by using the modified B-non-Hodgkin's lymphoma-Berlin-Frankfurt-Münster-90 protocol. [2015]

4. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of new-generation Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia/small lymphocytic lymphoma: a systematic review and meta-analysis. [2023]

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

Phase I, first-in-human trial of Bruton's tyrosine kinase inhibitor M7583 in patients with B-cell malignancies. [2021]

6. England pubmed.ncbi.nlm.nih.gov

BCL6 as a therapeutic target for lymphoma. [2018]

7. England pubmed.ncbi.nlm.nih.gov

The role of BCL6 in lymphomas and routes to therapy. [2016]

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

Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin's lymphoma. [2021]

9. England pubmed.ncbi.nlm.nih.gov

DSF/Cu induces antitumor effect against diffuse large B-cell lymphoma through suppressing NF-κB/BCL6 pathways. [2022]

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

Molecular features of a new human lymphoma cell line carrying both BCL2 and BCL6 gene rearrangements. [2015]