BXCL701 for AML or MDS

Overseen By Eric S Winter, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Eric Stephen Winer, MD

Must not be taking: Gliptins, TKIs, others

Disqualifiers: Acute promyelocytic leukemia, active CNS involvement, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 12 months

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the safest and most effective dose of a new drug, BXCL701, for treating certain blood cancers—Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Participants will take BXCL701 twice daily in 28-day cycles. The trial targets individuals with AML who have either relapsed or didn't respond well to initial treatments, as well as those with a specific type of MDS that hasn't improved after other treatments. Those diagnosed with these conditions and for whom previous treatments haven't worked might be suitable candidates. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but it strongly encourages changing drugs that strongly affect CYP3A4 enzymes if possible. You cannot take certain diabetes medications (gliptins) during the trial.

Is there any evidence suggesting that BXCL701 is likely to be safe for humans?

In a previous study, researchers examined BXCL701, also known as talabostat, for treating various cancers. This oral drug affects the immune system and has been tested in conditions like lymphoma and melanoma, with no reports of serious safety concerns. However, as this study remains in an early trial phase, the full safety profile is still being determined. This phase primarily aims to find the optimal dose that patients can tolerate without major side effects. So far, findings have not revealed significant safety issues, but more data is needed for confirmation. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for AML or MDS?

Researchers are excited about BXCL701 for treating Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) because it offers a novel approach compared to existing treatments, like chemotherapy and targeted therapies. BXCL701 works by inhibiting the Dipeptidyl Peptidase (DPP) activity, which plays a role in cancer cell survival and immune evasion. This mechanism could potentially enhance the body's immune response against cancer cells, setting it apart from conventional treatments. Additionally, BXCL701 is administered orally, which may provide a more convenient option compared to traditional intravenous therapies.

What evidence suggests that BXCL701 might be an effective treatment for AML or MDS?

Research has shown that BXCL701, a new treatment under study in this trial, could be promising for treating Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). In studies with mice, BXCL701 helped shrink AML tumors and reduce leukemia cells. It blocks certain proteins, enabling the body's immune system to fight cancer cells more effectively. This treatment aims to activate the immune system to better locate and destroy cancer cells. Early results suggest it might be safe, but further research is needed to confirm its effectiveness in people. ^{3 6 7 8 9}

Who Is on the Research Team?

Eric S Winter, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS), who have specific blood and organ function levels, can join. Those with HIV or hepatitis must be on effective treatment with an undetectable viral load. Participants should not have other active cancers, CNS leukemia involvement, or recent treatments that could interfere.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

My organs are functioning well, and I understand the risks and consent.

My condition is either relapsed or refractory AML, or I have a type of MDS with excess blasts-2.

Exclusion Criteria

I have been diagnosed with Acute Promyelocytic Leukemia.

My acute myeloid leukemia has spread to my brain or spinal cord.

I am eligible for this trial regardless of my gender or ethnicity.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive BXCL701 in a dose escalation approach, taking the drug 2x daily during each 28-day cycle for up to 12 cycles

12 months

Disease assessment at baseline, cycle 1, 3, 8, 15, 22, and day 1 of every cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• BXCL701

Trial Overview The trial is testing the safety and effectiveness of a drug called BXCL701 for AML/MDS patients. It aims to determine the best dose by monitoring participants' reactions over time.

How Is the Trial Designed?

Group I: Dose Escalation BXCL701 Experimental Treatment 1 Intervention

Dose escalation will occur using a 3+3 dose escalation approach, evaluating 4 different dose levels of BXCL701. During each 28 day study cycle participants will take BXCL701 2x daily for up to 12 cycles.

BXCL701 is already approved in United States for the following indications:

Approved in United States as BXCL701 for:

• Acute Myeloid Leukemia (AML)
• Myelodysplastic Syndrome (MDS)
• Small Cell Neuroendocrine Prostate Cancer (SCNC)
• Pancreatic Cancer
• Stage IIb to IV Melanoma
• Soft Tissue Sarcoma

Who Is Running the Clinical Trial?

Eric Stephen Winer, MD

Lead Sponsor

Trials

1

Recruited

20+

Published Research Related to This Trial

The study evaluated various methods for detecting the MDR1 gene in acute myelogenous leukemia (AML), finding that RT-PCR was more sensitive than Northern blot analysis, but also more prone to contamination from normal cells.

A modified method for estimating total MDR1 mRNA in leukemic cell populations was developed, which could be useful for large clinical trials and revealed that certain leukemia subtypes, like FAB M3, were mostly MDR1 negative.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methods for detection of MDR1 mRNA expression on acute myelogenous leukemia cells. Sato, H., Oonishi, T., Wada, C.[2018]

In a study of 73 leukemia patients, 31 showed positive expression of the multidrug resistance gene MDR1, indicating a significant correlation between high MDR1 levels and chemotherapy resistance, particularly in relapsed acute leukemia and chronic myeloid leukemia (CML) in blast crisis.

Patients with MDR1+ expression had a much higher refractory rate to chemotherapy (75%) compared to those who were MDR1- (15%), suggesting that measuring MDR1 expression can help tailor more effective treatment plans for individual leukemia patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Analysis of the multidrug resistance MDR1 gene expression in clinical leukemia with RT-PCR]. Zhang, H., Shi, G., Wang, J.[2018]

The combination of the MDR1 blocker SDZ PSC-833 with mitoxantrone and etoposide showed tolerable antileukemic activity in patients with relapsed acute myelogenous leukemia, although it required a significant dose reduction of these drugs due to toxicity.

Despite the treatment leading to some clearance of leukemia cells in the blood and bone marrow, no patients achieved complete remission, highlighting the need for further research to improve outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia. Kornblau, SM., Estey, E., Madden, T., et al.[2017]

In a study of 74 patients with acute myelogenous leukaemia (AML), high levels of MDR1 gene expression were associated with difficulty in achieving remission and shorter remission durations after treatment.

The findings suggest that elevated MDR1 expression may contribute to the ineffectiveness of anthracycline-based treatments in some AML patients, indicating a potential mechanism for treatment resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MDR1 transcript levels as an indication of resistant disease in acute myelogenous leukaemia. Sato, H., Preisler, H., Day, R., et al.[2019]

Younger acute myeloid leukemia (AML) patients with the multidrug resistance gene-1 (MDR1) expression have a poor prognosis, indicating that MDR1 is a significant factor in predicting treatment response.

Elderly AML patients who are MDR1-negative can achieve high complete response rates (around 75%) with induction chemotherapy, suggesting they may have favorable outcomes despite their age, while MDR1-positive elderly patients are less likely to respond well to standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunophenotyping and cytogenetics in older adults with acute myeloid leukemia: significance of expression of the multidrug resistance gene-1 (MDR1). Willman, CL.[2013]

Citations

1. ash.confex.com ash.confex.com/ash/2023/webprogram/Paper186598.html

Paper: Phase 1 Study of BXCL701, a Dipeptidyl Peptidase ... Mouse model studies demonstrated a reduction in AML blasts and AML tumor size when treated with BXCL701. We hypothesize that BXCL701 can be safe ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8423358/

Dipeptidyl Peptidase 9 Sets a Threshold for CARD8 ... These data thus suggest that DPP8/9 inhibitors nevertheless induce CARD8 inflammasome activation via two separate mechanisms: 1) accelerated N-terminal ...

3. sciencedirect.com sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/talabostat

Talabostat - an overview | ScienceDirect Topics Talabostat is defined as a FAP-inhibitor that cancels the anti-immunogenic effect of fibroblast activation protein (FAP), thereby improving T-cell immunity ...

4. veri.larvol.com veri.larvol.com/news/talabostat-bxcl701/drug

News - talabostat (BXCL701) Phase 1 Study of BXCL701, a Dipeptidyl Peptidase Inhibitor, in Relapsed/Refractory Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome (ASH 2023).

5. researchgate.net researchgate.net/publication/322739999_Inhibition_of_Dpp89_Activates_the_Nlrp1b_Inflammasome

Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome Evidence has shown that in mouse myeloid cells, small molecular inhibitors of the serine dipeptidase Dpp8/9 can activate the caspase-1 signaling pathway via the ...

6. file.medchemexpress.com file.medchemexpress.com/batch_PDF/HY-13233A/Talabostat-mesylate-SDS-MedChemExpress.pdf

Talabostat mesylate-SDS-MedChemExpress OSHA: No component of this product present at a level equal to or greater than 0.1% is identified as a potential or confirmed carcinogen by OSHA. Reproductive ...

7. adisinsight.springer.com adisinsight.springer.com/drugs/800016264

Talabostat - BioXcel Therapeutics - AdisInsight - Springer Talabostat (also known an BXCL 701 or PT 100) is an orally available small molecule immunomodulator, being developed by OnkosXcel Therapeutics (a wholly ...

8. go.drugbank.com go.drugbank.com/drugs/DB06182

Talabostat: Uses, Interactions, Mechanism of Action Investigated for use/treatment in lymphoma (non-hodgkin's), leukemia (lymphoid), lung cancer, melanoma, and pancreatic cancer.

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6082709/

DPP8/9 inhibitor-induced pyroptosis for treatment of acute ... We further show that DPP8/9 inhibitors induce pyroptosis in the large majority of human acute myeloid leukemia (AML) cell lines and primary AML samples, but not ...