BTX-A51 for Leukemia

Recruiting at 2 trial locations

Overseen By Zung Thai, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Edgewood Oncology Inc.

Must not be taking: Immunosuppressants, High-dose steroids

Disqualifiers: Acute promyelocytic leukemia, High WBC, others

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

Compensation: Varies

Number of Visits: 3

80 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called BTX-A51, a casein kinase inhibitor, for challenging cases of acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). The main goals are to assess the treatment's safety, identify potential side effects, and evaluate its effectiveness. Initially, the trial will determine the optimal dose, then examine its efficacy alone and in combination with azacitidine. Individuals who have not responded to other treatments and still face these conditions might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you cannot have received cancer chemotherapy (other than hydroxyurea) within 2 weeks before starting the study drug. It's best to discuss your current medications with the study team.

Is there any evidence suggesting that BTX-A51 is likely to be safe for humans?

Research has shown that BTX-A51, when used alone, is generally safe for people with relapsed or hard-to-treat acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Earlier studies found that most side effects were manageable.

When combined with azacitidine, studies suggest BTX-A51 remains generally safe. While some side effects may occur, they usually aren't severe enough to halt treatment.

This trial is in an early stage, focusing on assessing the treatment's safety and potential side effects. Researchers will closely monitor participants to ensure their safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for leukemia, such as chemotherapy and targeted therapies, focus on killing rapidly dividing cells. However, BTX-A51 is unique because it targets specific proteins involved in leukemia cell survival and growth, potentially offering a more precise approach. Researchers are excited because this mechanism could minimize damage to healthy cells, potentially reducing side effects compared to traditional chemotherapy. Furthermore, BTX-A51 is being tested both on its own and in combination with azacitidine, which may enhance its effectiveness, offering a promising new option for patients with leukemia.

What evidence suggests that BTX-A51 might be an effective treatment for leukemia?

Research has shown that BTX-A51, a new treatment tested in this trial for leukemia, may help combat acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). BTX-A51 blocks certain enzymes that aid cancer cell growth. Studies suggest it can stabilize and activate a protein called p53, which controls cell growth. Early results are promising, indicating that the treatment is safe and has led to positive responses in patients with specific types of leukemia. Participants in this trial may receive BTX-A51 as a monotherapy or combined with azacitidine, depending on the study arm. While more data is needed, this treatment could offer hope for those with difficult-to-treat forms of leukemia. ^{1 2 3 5 6}

Who Is on the Research Team?

Zung Thai, MD

Principal Investigator

Edgewood Oncology Inc.

Are You a Good Fit for This Trial?

Adults (18+) with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), who have no other standard treatment options. Participants must be able to understand the study and consent, have a life expectancy of at least 6 weeks, and adequate organ function. Women must not be pregnant and agree to contraception; men must use barrier birth control.

Inclusion Criteria

I can care for myself and doctors expect me to live more than 6 weeks.

I have AML or high-risk MDS that is not responding to standard treatments.

I am not pregnant and will avoid pregnancy or use effective birth control during and up to 3 months after treatment.

Exclusion Criteria

I am experiencing severe complications from leukemia, like uncontrolled bleeding or serious infections.

White blood cell count > 20 x 10^9/L

I am not pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monotherapy Dose Escalation

Participants receive escalating doses of BTX-A51 to determine dose-limiting toxicities and maximum tolerated dose

28 days (one cycle)

Multiple visits for dose administration and monitoring

Monotherapy Cohort Expansion

Additional participants receive BTX-A51 at the maximum tolerated dose to gather more safety and efficacy data

28 days (one cycle)

Multiple visits for dose administration and monitoring

Azacitidine Combination Dose Escalation

Participants receive BTX-A51 combined with azacitidine to evaluate safety and determine the recommended Phase 2 dose

28 days (one cycle)

Multiple visits for dose administration and monitoring

Continued Treatment Phase

Participants continue treatment for up to eight 28-day cycles if the benefit outweighs the risk

Up to 224 days

Overall Survival Follow-up

Participants are contacted every 3 months for up to 2 years after their last treatment to assess survival status and anticancer therapy

Up to 2 years

Telephone contact every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• BTX-A51

Trial Overview The trial is testing BTX-A51 capsules for safety, toxicity, pharmacokinetics, and preliminary efficacy in two phases: dose escalation to find the maximum tolerated dose and a continuation phase for further safety and efficacy data. Patients may receive up to eight cycles of treatment.

How Is the Trial Designed?

Group I: Part 1c (Azacitidine Combination Dose Escalation) Experimental Treatment 2 Interventions

After determination of MTD and RP2D from Part 1a, combination dose escalation in Part 1c may begin. Patients with AML will receive BTX-A51 combined with azacitidine in escalating BTX-A51 dose cohorts. Dosing in this stage of the study consists of the first cycle of therapy (i.e., 28 days). The starting dose of BTX-A51 will be RP2D. Part 1c will follow a BOIN design as described for Part 1a. The numbers of patients and actual doses administered will be determined in response to DLTs a. There will be at least 3 patients per cohort.

Group II: Part 1b (Monotherapy Cohort Expansion) Experimental Treatment 1 Intervention

Dosing in this phase of the study consists of the first cycle of therapy (i.e., 28 days consisting of 3 weeks of treatment followed by 1 week with no study drug). Part 1b will continue at the MTD or the highest dose achieved in Phase 1a.

Group III: Part 1a (Monotherapy Cohort Escalation) Experimental Treatment 1 Intervention

Dosing in this phase of the study consists of the first cycle of therapy (i.e., 28 days consisting of 3 weeks of treatment followed by 1 week with no study drug). The BTX-A51 starting dose for Cohort 1 is 1 mg, to be given 5 days per week (maximum weekly dose of 5 mg). Beginning with Cohort 2, doses are intended to be administered 3 days per week. Barring dose-limiting toxicity (DLT), sequential dose escalation of BTX-A51 is planned with up to a total of eight dose levels to a maximum of 21 mg (63 mg/week); on the basis of these an MTD will be identified. The numbers of participants and actual doses administered will be determined using a Bayesian optimal interval (BOIN) design to determine the DLTs and MTD of BTX-A51.

Who Is Running the Clinical Trial?

Edgewood Oncology Inc.

Lead Sponsor

Trials

3

Recruited

200+

BioTheryX, Inc.

Lead Sponsor

Trials

3

Recruited

200+

Published Research Related to This Trial

Csnk1a1 is crucial for the survival of acute myeloid leukemia (AML) cells, and its knockdown leads to increased p53 activity and myeloid differentiation, which are detrimental to leukemia cells but less harmful to normal hematopoietic stem and progenitor cells (HSPCs).

The casein kinase 1 inhibitor D4476 selectively kills leukemia stem cells while sparing normal HSPCs, suggesting that targeting Csnk1a1 could be a promising therapeutic strategy for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. Järås, M., Miller, PG., Chu, LP., et al.[2021]

CK1 enzymes play a crucial role in regulating pathways involved in cancer development, particularly in hematological malignancies like chronic lymphocytic leukemia (CLL) and multiple myeloma (MM).

Inhibitors targeting CK1 isoforms, such as umbralisib, are currently being tested in clinical trials, showing potential to block cancer progression by affecting key pathways like WNT and p53.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Casein Kinase 1 (CK1) in Hematological Cancers. Janovská, P., Normant, E., Miskin, H., et al.[2021]

The study demonstrates that the tumor suppressor Ikaros functions by repressing genes involved in the cell cycle and the PI3 kinase pathway, which are crucial for the development of high-risk B-cell acute lymphoblastic leukemia (B-ALL).

Pharmacologic inhibition of casein kinase 2 (CK2) can reactivate Ikaros' tumor suppressor activity, offering a potential therapeutic strategy to eradicate B-ALL in high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Restoring Ikaros's wings to solve a leukemia maze. Lobry, C.[2021]

A series of novel compounds were developed as dual inhibitors of Btk and PI3Kδ kinases, showing effectiveness in suppressing leukemia cell proliferation at low micromolar concentrations in vitro.

Among these compounds, 16b demonstrated the strongest inhibitory activity against Btk and PI3Kδ, with IC50 values of 139 nM and 275 nM respectively, indicating its potential as a promising candidate for further development in leukemia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and synthesis of benzofuro[3,2-b]pyridin-2(1H)-one derivatives as anti-leukemia agents by inhibiting Btk and PI3Kδ. Liu, L., Shi, B., Li, X., et al.[2019]

The study found that CK2 inhibitors (DMAT, MPT, AEAT) combined with pentabromobenzylisothioureas (ZKK-3, ZKK-9, ZKK-13) produced a synergistic pro-apoptotic effect against the KG-1 acute myelogenous leukemia cell line, indicating a promising treatment strategy.

Among the CK2 inhibitors tested, AEAT showed the highest apoptotic activity, suggesting it may be the most effective option for targeting leukemia cells in this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic anti-leukemic effects of CK2 inhibitors and pentabromobenzylisothioureas in vitro. Koronkiewicz, M., Chilmonczyk, Z., Kazimierczuk, Z.[2014]

UBX-382, a novel proteolysis-targeting chimera (PROTAC), effectively degrades both wild-type and mutant Bruton tyrosine kinase (BTK) proteins, showing strong potential for treating B-cell lymphomas with a half-maximal degradation concentration in the single-digit nanomolar range.

In murine xenograft models, UBX-382 led to complete tumor regression after less than 2 weeks of oral dosing, outperforming other BTK inhibitors like ibrutinib, indicating its promising efficacy in targeting B-cell-related blood cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models. Lim, YS., Yoo, SM., Patil, V., et al.[2023]

A new series of imidazole group-substituted arylaminopyrimidines (IAAPs) were developed as potent inhibitors of Bruton's tyrosine kinase (BTK), showing IC50 values between 13.10 to 42.40 nM, indicating strong potential for treating hematological malignancies.

Compounds 11a and 11b demonstrated superior antiproliferative effects against acute myeloid leukemia (AML) and B lymphomas compared to the existing BTK inhibitor ibrutinib, while also exhibiting low toxicity to normal cells, making them promising candidates for further preclinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and biological activity of imidazole group-substituted arylaminopyrimidines (IAAPs) as potent BTK inhibitors against B-cell lymphoma and AML. Li, S., Wu, B., Zheng, X., et al.[2021]

Inhibiting Bruton's tyrosine kinase (BTK) in Bcr-Abl-positive cells did not improve cell viability or proliferation, suggesting that BTK is not a critical factor in the transformation caused by Bcr-Abl in chronic myeloid leukemia (CML).

The study found that reducing BTK levels or inhibiting its activity with small molecule inhibitors did not change the response to imatinib or affect Bcr-Abl's ability to transform hematopoietic cells, indicating that targeting BTK may not be an effective therapeutic strategy for Bcr-Abl-mediated leukemias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bruton's tyrosine kinase is not essential for Bcr-Abl-mediated transformation of lymphoid or myeloid cells. MacPartlin, M., Smith, AM., Druker, BJ., et al.[2018]

The CK2 inhibitor CX-4945 shows strong therapeutic effects in preclinical models of Acute Myeloid Leukemia (AML), demonstrating in vivo efficacy and potential as a treatment option.

CX-4945 works by restoring the function of the IKAROS tumor suppressor, which CK2 normally phosphorylates to inhibit its activity, leading to increased apoptosis in AML cells when combined with the chemotherapy drug daunorubicin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanistic Basis for In Vivo Therapeutic Efficacy of CK2 Inhibitor CX-4945 in Acute Myeloid Leukemia. Klink, M., Rahman, MA., Song, C., et al.[2021]

The Btk inhibitor PCI-32765 effectively inhibits the proliferation of acute lymphoblastic leukemia (ALL) cell lines, with Sup-B15 cells being more sensitive than RS4;11 cells, showing IC50 values of 3 µmol/L and 8 µmol/L respectively.

Both PCI-32765 and Dasatinib induce apoptosis in ALL cells and their combination enhances this effect, likely by blocking the B cell receptor (BCR) signaling pathway, which is crucial for cell proliferation and survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of PCI-32765 and Dasatinib on the Acute Lymphoblastic Leukemic Cells and Their Mechanisms]. Deng, Y., Tao, SD., Zhang, X., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40665325/

Phase I first-in-human dose escalation study of the oral casein ... Here, we report on the results of the phase 1 clinical trial of BTX A51 in patients with relapsed or refractory AML and MDS.

2. jhoonline.biomedcentral.com jhoonline.biomedcentral.com/articles/10.1186/s13045-025-01724-z

Phase I first-in-human dose escalation study of the oral casein ... Treatment of AML cells with BTX A51 robustly stabilizes and activates the p53 protein via a combined action of CK1α inhibition and shutdown of ...

3. targetedonc.com targetedonc.com/view/btx-a51-demonstrates-tolerability-and-manageable-safety-profile-in-patients-with-r-r-aml-mds

BTX A51 Demonstrates Tolerability and Manageable ... The oral casein kinase 1α and cyclin dependent kinase 7/9 inhibitor BTX A51 revealed a manageable safety profile in relapsed or refractory ...

4. bloodcancerstoday.com bloodcancerstoday.com/post/btx-a51-produces-early-signal-in-relapsed-aml-and-mds

BTX A51 Produces Early Signal in Relapsed AML and MDS First-in-human trial of BTX A51 demonstrates safety, on-target activity, and encouraging responses in RUNX1-mutant AML and MDS.

5. mdsf.sparkcures.com mdsf.sparkcures.com/trial/1527/NCT04243785

BTX-A51 - Myelodysplastic Syndrome Clinical Trials In this FIH study, monotherapy BTX-A51 demonstrated an acceptable safety profile and promising antileukemic activity in pts with heavily pretreated R/R AML.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11527261/

Phase I First-in-Human Dose Escalation Study of the oral ... Treatment of AML cells with BTX-A51 robustly stabilizes and activates the p53 protein via a combined action of CK1α inhibition and shutdown of MDM2 expression, ...