TAK-243 for Leukemia

Recruiting at 3 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: OATP/BCRP inhibitors, CYP3A4/5 inducers

Disqualifiers: APL, Active infection, Cardiopulmonary disease, others

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

Compensation: Varies

Number of Visits: 6

Duration: 12 months

42 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of TAK-243 in treating patients with acute myeloid leukemia or myelodysplastic syndromes with increased blasts that has come back (relapsed) or that is not responding to treatment (refractory). TAK-243 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically organic anion transport protein (OATP) and BCRP inhibitors or strong inducers/inhibitors of cytochrome P450 (CYP)3A4/5, at least 14 days before starting TAK-243. It's important to discuss all your current medications with the study team to ensure there are no interactions.

What makes the drug TAK-243 unique for treating leukemia?

TAK-243 (MLN7243) is unique because it targets the ubiquitin-activating enzyme, which is a novel approach in leukemia treatment, potentially disrupting cancer cell survival pathways that are not addressed by existing therapies. ^{1 2 3 4 5}

Research Team

Guillaume Richard-Carpentier

Principal Investigator

University Health Network Princess Margaret Cancer Center LAO

Eligibility Criteria

This trial is for adults with acute myeloid leukemia or myelodysplastic syndromes that have relapsed or are not responding to treatment. Participants must meet specific health criteria, including a certain performance status and liver function. They should not have had recent chemotherapy or investigational therapy and cannot be allergic to the study drug TAK-243.

Inclusion Criteria

My condition worsened or didn't improve after at least one treatment.

I am following the required birth control measures.

Minimum life expectancy of 1 month

Exclusion Criteria

I do not have any severe infections or diseases.

Prolonged QTc interval

I have had major surgery recently.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive TAK-243 intravenously over 30 minutes on days 1, 4, 8, and 11 of each cycle. Cycles repeat every 21 days for up to 12 months.

12 months

4 visits per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• TAK-243

Trial Overview The trial is testing TAK-243, which may inhibit cancer cell growth by blocking enzymes needed for cell growth. It involves procedures like bone marrow aspiration/biopsy and heart function tests to determine the best dose of TAK-243 and its side effects in patients.

Participant Groups

Group I: Treatment (TAK-243) Experimental Treatment 6 Interventions

Patients receive TAK-243 IV over 30 minutes on days 1, 4, 8, and 11 of each cycle. Cycles repeats every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients undergo urine sample collection, bone marrow aspiration and bone marrow biopsy, MUGA and ECHO during screening and on study, and blood sample collection throughout the trial.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase 1b study involving 56 adults with CD123-positive acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), the combination of Tagraxofusp (TAG) with azacitidine (AZA) and the BCL-2 inhibitor venetoclax (VEN) showed promising efficacy, achieving a response rate of 69% in an expansion cohort of 26 patients, including a 39% complete remission rate.

The treatment was well-tolerated, with no increased toxicity observed from the combination therapy, and median overall survival was reported at 14 months, indicating that TAG-AZA-VEN is a safe and effective option for high-risk AML patients, including those with TP53 mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia. Lane, AA., Garcia, JS., Raulston, EG., et al.[2023]

TIM-3 is a surface antigen found on leukemic stem cells (LSCs) in most types of acute myelogenous leukemia (AML), making it a potential target for therapy, while it is absent on normal hematopoietic stem cells.

An anti-TIM-3 antibody demonstrated the ability to effectively eliminate AML LSCs in xenograft models without harming normal blood cell production, indicating its potential as a safe and effective treatment option for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TIM-3 as a novel therapeutic target for eradicating acute myelogenous leukemia stem cells. Kikushige, Y., Miyamoto, T.[2021]

Targeting the interleukin 3 receptor α chain (CD123) on leukemia stem cells has been explored as a treatment for various myeloid malignancies, but the success of these therapies has been limited, indicating a need for better patient selection criteria.

Understanding the patterns of CD123 expression and its biological significance is essential for improving the effectiveness of CD123-targeting therapies in hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting CD123 in hematologic malignancies: identifying suitable patients for targeted therapy. Patnaik, MM., Mughal, TI., Brooks, C., et al.[2021]

The t(4;11)(q21;q23) chromosomal translocation, leading to the MLL-AF4 fusion gene, is present in about 10% of newly diagnosed adult B-cell acute lymphoblastic leukemia (ALL) cases, marking it as a high-risk leukemia with distinct biological and clinical features.

Intensifying treatment with allogeneic hematopoietic stem cell transplantation (HSCT) during the first complete remission may improve prognosis for these patients, although existing literature presents conflicting data on its effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathogenetic, Clinical, and Prognostic Features of Adult t(4;11)(q21;q23)/MLL-AF4 Positive B-Cell Acute Lymphoblastic Leukemia. Marchesi, F., Girardi, K., Avvisati, G.[2021]

In a study involving 7 patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts, PR-104 demonstrated significantly greater efficacy against T-lineage ALL (T-ALL) compared to B-cell-precursor ALL (BCP-ALL), suggesting it may be a promising treatment for T-ALL.

The expression of the enzyme AKR1C3 was found to be a predictive biomarker for PR-104 sensitivity, as higher levels of AKR1C3 in T-ALL xenografts correlated with increased sensitivity to the drug, indicating that testing for AKR1C3 could help identify patients who would benefit most from PR-104 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia. Moradi Manesh, D., El-Hoss, J., Evans, K., et al.[2021]

References

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

Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia. [2023]

2. Japan pubmed.ncbi.nlm.nih.gov

TIM-3 as a novel therapeutic target for eradicating acute myelogenous leukemia stem cells. [2021]

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

Targeting CD123 in hematologic malignancies: identifying suitable patients for targeted therapy. [2021]

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

Pathogenetic, Clinical, and Prognostic Features of Adult t(4;11)(q21;q23)/MLL-AF4 Positive B-Cell Acute Lymphoblastic Leukemia. [2021]

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

AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia. [2021]