TAK-243 for Leukemia

Recruiting at 5 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests TAK-243 to determine the optimal dose and understand its side effects for individuals with certain types of leukemia (a blood cancer) or myelodysplastic syndromes (a bone marrow disorder) that have recurred or resisted other treatments. TAK-243 blocks enzymes that aid cancer cell growth. Suitable candidates have acute myeloid leukemia or myelodysplastic syndromes that have not improved with standard treatments. Participants will receive TAK-243 through an IV on specific days in 21-day cycles, for up to a year, unless the disease worsens or side effects become too severe. 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 treatment.

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.

Is there any evidence suggesting that TAK-243 is likely to be safe for humans?

Research shows that TAK-243 is being tested for safety in people. Earlier studies examined the side effects and optimal dose for patients with certain types of leukemia. As a Phase 1 trial, the primary goal is to assess how well patients tolerate the treatment and identify any side effects.

In early research, TAK-243 has been tested in various cancers, but specific safety information for leukemia remains limited. Phase 1 trials typically involve a small number of patients and represent the initial step in testing a new treatment in humans. This means the treatment is used in people for the first time, so they are closely monitored for adverse reactions.

While TAK-243 has shown promise in lab studies and other cancers, this trial is crucial to understand its effects in people with leukemia. Participants are carefully monitored to ensure their safety, and the trial aims to identify any potential side effects. If TAK-243 is well-tolerated, it may proceed to further testing with larger groups. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about TAK-243 for leukemia because it has a unique mechanism of action that sets it apart from standard treatments like chemotherapy and targeted therapies. Unlike most treatments, which often target specific cancer cell features or DNA, TAK-243 inhibits a cellular process crucial for protein degradation, potentially halting cancer cell growth more effectively. This novel approach could offer a new avenue for treating leukemia, especially in cases where other treatments have failed. Additionally, TAK-243 is administered intravenously, allowing for precise control over dosing and treatment schedule, which may improve patient outcomes and reduce side effects.

What evidence suggests that TAK-243 might be an effective treatment for leukemia?

Research shows that TAK-243, the investigational treatment in this trial, may help treat acute myeloid leukemia (AML) and myelodysplastic syndromes. Studies have found that TAK-243 can slow and reduce the growth of AML cells. Higher doses and prolonged use of TAK-243 enhance its ability to stop cancer cells from growing over time. TAK-243 blocks UBA1, an enzyme necessary for cancer cell growth. Early research in various cancer types, including blood cancers like AML, suggests that TAK-243 has strong anti-cancer effects. This makes TAK-243 a promising option for patients whose leukemia has returned or is not responding to other treatments. ^{1 2 3 6 7}

Who Is on the Research Team?

Guillaume Richard-Carpentier

Principal Investigator

University Health Network Princess Margaret Cancer Center LAO

Are You a Good Fit for This Trial?

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.

Minimum life expectancy of 1 month

I am following the required birth control measures.

Exclusion Criteria

Prolonged QTc interval

I do not have any severe infections or diseases.

I have had major surgery recently.

Timeline for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03816319?term=TAK-243&rank=2

TAK-243 in Treating Patients With Relapsed or Refractory ... 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 ...

2. ashpublications.org ashpublications.org/blood/article/130/Supplement%201/814/83481/TAK-243-Is-a-Selective-UBA1-Inhibitor-That

TAK-243 Is a Selective UBA1 Inhibitor That Displays ... TAK-243 reduced growth and viability of human AML cell lines (OCI-AML2, TEX, U937 and NB4) in a concentration- and time-dependent manner with IC ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10949913/

Activity of the Ubiquitin-activating Enzyme Inhibitor TAK- ... To date, TAK-243 has been shown to exhibit antiproliferative activity in various human cancer models, including blood cancers (acute myeloid ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0006497119813307

TAK-243 Is a Selective UBA1 Inhibitor That Displays ... TAK-243 reduced growth and viability of human AML cell lines (OCI-AML2, TEX, U937 and NB4) in a concentration- and time-dependent manner with IC ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03816319

TAK-243 in Treating Patients With Relapsed or Refractory ... 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 ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2019-00238

TAK-243 in Treating Patients with Relapsed or Refractory ... 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 ...

7. aacrjournals.org aacrjournals.org/mct/article/14/12_Supplement_2/A164/233351/Abstract-A164-The-small-molecule-UAE-inhibitor-TAK

Abstract A164: The small molecule UAE inhibitor TAK-243 ... The small molecule UAE inhibitor TAK-243 (MLN7243) prevents DNA damage repair and reduces cell viability/tumor growth when combined with ...