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

Trial Summary

What is the purpose of this trial?

This is an open-label, dose escalation study to evaluate the safety, toxicity, and pharmacokinetics (PK) as well as preliminary efficacy of BTX-A51 capsules in participants with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). The study will be done in three parts. Part 1a (Monotherapy Dose Escalation) of this study is designed to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of orally administered BTX-A51 in up to 35 participants who are evaluable for toxicity. Once the MTD is determined, it is planned that an additional 15 participants will be enrolled in Part 1b (Monotherapy Cohort Expansion) of this study for additional experience with safety and efficacy, and to determine the recommended Phase 2 dose (RP2D) which may or may not be different from the MTD. After determination of MTD and RP2D from Part 1a, Part 1c (Azacitidine Combination Dose Escalation) will enroll up to 30 participants. Continued treatment will be available under this study protocol for up to eight 28-day cycles (Continued Treatment Phase) if the Investigator judges the benefit outweighs the risk. Once BTX-A51 treatment has completed, participants will be contacted by telephone every 3 months for up to 2 years after their last treatment for survival status and anticancer therapy (Overall Survival Follow-up).

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.

What data supports the effectiveness of the drug BTX-A51 for treating leukemia?

Research shows that inhibiting casein kinase enzymes, like those targeted by BTX-A51, can help kill leukemia cells by activating the p53 pathway, which is important for controlling cell growth and death. This approach has shown promise in preclinical studies for treating acute myeloid leukemia (AML) and other blood cancers. ^{1 2 3 4 5}

What makes the drug BTX-A51 unique for treating leukemia?

BTX-A51 is unique because it is a proteolysis-targeting chimera (PROTAC) that specifically targets and degrades Bruton's tyrosine kinase (BTK), which is involved in the growth and survival of leukemia cells. This approach is different from traditional inhibitors as it leads to the degradation of the target protein, potentially offering a more effective treatment for leukemia, especially in cases resistant to other therapies. ^{6 7 8 9 10}

Research Team

Zung Thai, MD

Principal Investigator

Edgewood Oncology Inc.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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 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]

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]

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]

References

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

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

2. Greece pubmed.ncbi.nlm.nih.gov

Synergistic anti-leukemic effects of CK2 inhibitors and pentabromobenzylisothioureas in vitro. [2014]

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

Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Targeting Casein Kinase 1 (CK1) in Hematological Cancers. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Mechanistic Basis for In Vivo Therapeutic Efficacy of CK2 Inhibitor CX-4945 in Acute Myeloid Leukemia. [2021]

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

Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models. [2023]

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

Bruton's tyrosine kinase is not essential for Bcr-Abl-mediated transformation of lymphoid or myeloid cells. [2018]

8. China pubmed.ncbi.nlm.nih.gov

[Effects of PCI-32765 and Dasatinib on the Acute Lymphoblastic Leukemic Cells and Their Mechanisms]. [2021]

9. United States 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. [2021]

10. England 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. [2019]