TAK-243 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes With Increased Blasts

A Phase 1 Study of TAK-243 for Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndromes With Increased Blasts

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.

Study Overview

• Status: Suspended
• Conditions: Recurrent Acute Myeloid Leukemia; Recurrent Myelodysplastic Syndrome; Refractory Acute Myeloid Leukemia; Refractory Myelodysplastic Syndrome; Myelodysplastic Syndrome With Excess Blasts; Recurrent Myelodysplastic Syndrome/Acute Myeloid Leukemia; Refractory Myelodysplastic Syndrome/Acute Myeloid Leukemia
• Intervention / Treatment: Procedure: Multigated Acquisition Scan; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Drug: UAE Inhibitor TAK-243; Procedure: Biospecimen Collection; Procedure: Echocardiography Test

Detailed Description

PRIMARY OBJECTIVE:

I. To establish the recommended phase 2 dose (RP2D) of UAE inhibitor TAK-243 (TAK-243) administered intravenously in a twice-weekly schedule in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).

SECONDARY OBJECTIVES:

I. To assess the maximum tolerated dose (MTD) evaluated on the first cycle (Day 1 to 21) of TAK-243, its safety profile, and dose limiting toxicities (DLT).

II. To investigate preliminary anti-leukemic activity of TAK-243 monotherapy in patients with AML or MDS.

III. To describe the pharmacokinetic (PK) profile of TAK-243. IV. To describe the pharmacodynamic (PD) effects of TAK-243.

EXPLORATORY OBJECTIVE:

I. To investigate associations between clinical responses and molecular/cytogenetic abnormalities in the leukemia cells or to the PK profile or PD effects of TAK-243.

OUTLINE: This is a dose-escalation study.

Patients receive TAK-243 intravenously (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, multigated acquisition scan (MUGA) and echocardiogram (ECHO) during screening and on study, and blood sample collection throughout the trial.

After completion of study treatment, patients are followed up at 30 days.

• Study Type: Interventional
• Enrollment (Estimated): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • University Health Network-Princess Margaret Hospital
• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
  • Virginia
    • Richmond, Virginia, United States, 23298
      • VCU Massey Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of AML or MDS with increased blasts (MDS-IB) assessed by local laboratory review according to the 2022 World Health Organization (WHO) criteria for myeloid neoplasms. Both patients with MDS-IB1 (5-9% bone marrow blasts) and MDS-IB2 (10-19% bone marrow blasts) are eligible.
• Patients must have relapsed or refractory disease after receiving at least one prior line of therapy
• AML-specific inclusion criteria: Patients with relapsed or refractory AML with >= 5% bone marrow blasts after receiving at least two courses of intensive induction chemotherapy (including, but not limited to, 7+3 regimen, fludarabine, cytarabine, idarubicin and filgrastim [FLAG-Ida] and mitoxantrone, etoposide, and cytarabine [MEC]) or 2 cycles of venetoclax-based lower intensity regimen (azacitidine plus venetoclax or low-dose cytarabine plus venetoclax), and without any other approved therapies available that would be more appropriate in the investigator's judgment. Patients who have received only one course of intensive induction chemotherapy but are not eligible for a second course because of decreased performance status or clear disease progression may be eligible for participation after discussion with the study principal investigator (PI). Patients with concomitant extramedullary disease relapse are eligible to participate, but not patients with isolated extramedullary relapse without bone marrow disease.
• MDS-specific inclusion criteria: Patients with relapsed or refractory MDS-IB with >= 5% bone marrow blasts after at least 4 cycles of hypomethylating agent (HMA)-based therapy or at least two courses of intensive induction chemotherapy and meet criteria for stable disease (SD), progressive disease (PD) or disease relapse according to the International Working Group 2023 response criteria for higher-risk MDS. Patients must not have access to any other approved therapies that would be more appropriate in the investigator's judgment. Patients who have received less than 4 cycles of HMA-based therapy may be eligible to participate after discussion with the study PI if there is clear evidence of progression or intolerance to HMA-based therapy that precludes its continuation.

• Patients must have recovered from the effects of any prior systemic therapy, radiotherapy or surgery:

  • Patients should not have received other investigational therapy within 2 weeks.
  • Patients should not have received standard chemotherapy within 1 week of administration of study drug; hydroxyurea administration (for leukocyte count control) is permitted.
• Age >=18 years. Because no dosing or adverse event data are currently available on the use of TAK-243 in patients <18 years of age, children are excluded from this study.
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%).

• Serum bilirubin =< 1.5 × institutional upper limit of normal (ULN).

  • Patients with a known history of Gilbert's syndrome may enroll.
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 × institutional ULN.
• Serum creatinine < 176 mcmol/L (2 mg/dL) OR
• Creatinine clearance > 60 mL/min based on the Cockcroft-Gault equation.
• Documented normal cardiac function (>= 50%) by echocardiogram or multi-gated acquisition (MUGA) scan.
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load withing 6 months are eligible for this trial.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

• The effects of TAK-243 on the developing human fetus are unknown and ubiquitin-activating enzyme inhibitors are known to be teratogenic. For this reason, female patients must be:

  • Postmenopausal (age-related amenorrhea >= 12 consecutive months or follicle-stimulating hormone > 40 mIU/mL), for at least 1 year before the screening visit, OR
  • Surgically sterile (i.e., who had undergone hysterectomy or bilateral oophorectomy), OR

If they are of childbearing potential:

• Agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), OR

• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.) Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

  • Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:
• Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug (female and male condoms should not be used together), OR

• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)

  • Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
  • Patients should have a minimum life expectancy of 1 month.

Exclusion Criteria:

• Patients with acute promyelocytic leukemia (APL) or AML with t(15;17)(q22;q12) - PML::RARA).
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1), except anemia, neutropenia or thrombocytopenia of any grade and grade 2 peripheral neuropathy.
• Presence of any other malignancy requiring active therapy.
• Patients who are receiving any other investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to TAK-243.
• Concomitant treatment with organic anion transport protein (OATP) and BCRP inhibitors or strong inducers/inhibitors of cytochrome P450 (CYP)3A4/5. Treatment with these agents must be discontinued at least 14 days prior to TAK-243 dosing. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Presence of an active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
• Presence of active graft-versus-host disease (GVHD) or continued treatment with systemic immunosuppressive agents following allogeneic hematopoietic stem cell transplantation (HSCT).
• Presence of any co-morbid condition that, in the opinion of the investigator, might compromise the patient's safety, might interfere with participation in the trial or might interfere with the interpretation of trial results.
• Pregnant and lactating/breast-feeding women are excluded from this study because TAK-243 is a UAE-inhibiting agent with the potential for teratogenic or abortifacient effects and there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with TAK-243. Females of child-bearing potential must have a negative serum pregnancy test within 7 days before enrollment and should not be lactating/breast-feeding. Breastfeeding should be discontinued if the mother is treated with TAK-243.
• Major surgery within 14 days before the first dose of any study drug or a scheduled surgery during study period.
• Patients with uncontrolled coagulopathy or bleeding disorder.
• Patients with known hepatic cirrhosis.

• Patients with known active cardiopulmonary disease defined as:

  • Unstable angina withing 3 months prior to first dose of TAK-243;
  • Myocardial infarction (MI) within 6 months prior to first dose of TAK-243 (patients who had MI and/or coronary revascularization more than 6 months before screening and who are without cardiac symptoms may enroll);
  • Congestive heart failure (New York Heart Association [NYHA] Class III or IV;
  • Cardiomyopathy with left ventricular ejection fraction (LVEF) < 50%;
  • Symptomatic pulmonary hypertension.
• Presence of active central nervous system (CNS) involvement (patients with prior CNS leukemia who have negative CNS cytology and who receive periodic prophylactic intrathecal chemotherapy are eligible).

• Patients with clinically significant arrhythmia:

  • History of ventricular fibrillation or torsade de pointes at any time,
  • Episode of grade >= 3 atrial fibrillation or flutter in the last 3 months, defined as symptomatic episode, requiring urgent intervention (cardioversion, pacemaker or ablation) or with life-threatening consequences.
• Uncontrolled high blood pressure (i.e., systolic blood pressure >180 mm Hg, diastolic blood pressure > 95 mm Hg).
• Prolonged rate corrected QT (QTc) interval >= 480 msec, calculated using the Fridericia method.
• Patients with known severe or very severe chronic obstructive pulmonary disease (defined as forced expiratory volume in one second (FEV1) less than 30% or less than 50% of predicted), interstitial lung disease, or pulmonary fibrosis.
• Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s).
• Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s).
• Patients with history of neutrophilic dermatosis (e.g. Sweet syndrome, pyoderma gangrenosum), relapsing polychondritis, polyarteritis nodosa and/or giant cell arteritis.
• Patients with VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome) or any other autoinflammatory disease.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (TAK-243); 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.

Procedure: Multigated Acquisition Scan; Undergo MUGA; Other Names: Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; MUGA; Radionuclide Ventriculography; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Gated Heart Pool Scan; RNV Scan; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy; Other Names: Biopsy of Bone Marrow; Biopsy, Bone Marrow; Drug: UAE Inhibitor TAK-243; Given IV; Other Names: AOB87172; MLN7243; TAK-243; Procedure: Biospecimen Collection; Undergo urine and blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Sample Collection; Procedure: Echocardiography Test; Undergo ECHO; Other Names: Echocardiography; EC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended phase II dose (RP2D)	RP2D will be identified based on maximum tolerated dose and additional safety data. Primary endpoint will be analyzed on the population assessable for safety of the phase 1 trial (escalation part).	At 21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Determined by clinical symptoms/signs, laboratory evaluation and imaging. Graded by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Will be recorded in terms of event type, severity, dates of beginning and end, reversibility and evolution. Data will be gathered in tables summarizing toxicities and side effects for each dose level and cycle.	Up to 30 days after the last dose of TAK-243
Incidence of serious adverse events	Determined by clinical symptoms/signs, laboratory evaluation and imaging. Graded by CTCAE version 5.0. Will be recorded in terms of event type, severity, dates of beginning and end, reversibility and evolution. Data will be gathered in tables summarizing toxicities and side effects for each dose level and cycle.	Up to 30 days after the last dose of TAK-243
Rate of complete response (CR) in patients with acute myeloid leukemia (AML)	As defined by European LeukemiaNet criteria. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	Up to 1 year
Rate of complete response with incomplete hematological recovery (CRi), in patients with AML	As defined by European LeukemiaNet criteria. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	Up to 1 year
Rate of partial response (PR) in patients with AML	As defined by European LeukemiaNet criteria. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	Up to 1 year
Rate of morphologic leukemia-free state (MLFS) in patients with AML	As defined by European LeukemiaNet criteria. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	Up to 1 year
Pharmacokinetic measurements	Expressed as area under the curve (AUC), half-life (t1/2), and maximum concentration (Cmax).	Baseline up to 1 year
Incidence of dose-limiting toxicities (DLTs)	DLT will be described in terms of number and incidence rates at each dose level. The number and percentage of patients who will have developed a DLT in each dose level will also be reported.	Within the first cycle (Up to 21 days)
Rate of CR with partial hematological recovery (CRh) in patients with AML	As defined by European LeukemiaNet criteria. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	Up to 1 year
Overall response rate (ORR) in patients with AML	Will include CR, CRi plus CRh. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	Up to 1 year
Time to response in patients with AML	Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	From study treatment initiation (Cycle 1 Day 1) to achievement of CR, CRi or CRh, assessed up to
Overall survival (OS) in patients with AML	OS rates will be reported. OS will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method.	From study treatment initiation to death (of any cause) or last follow-up, assessed at 6 months and 1 year
Relapse-free survival (RFS) in patients with AML	Will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method.	From CR, CRi or CRh to the first occurrence of disease relapse, death (of any cause) or last follow-up, whichever occurs first, assessed at 6 months and 1 year
Rate of CR in patients with myelodysplastic syndrome (MDS)	Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	Up to 1 year
Rate of CR equivalent in patients with MDS	Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	Up to 1 year
Rate of CR with limited count recovery (CRL) in patients with MDS	Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	Up to 1 year
Rate of CR with partial hematologic recovery (CRh) in patients with MDS	Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	Up to 1 year
Rate of marrow CR in patients with MDS	Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	Up to 1 year
Rate of PR in patients with MDS	Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	Up to 1 year
ORR in patients with MDS	Defined by the revised International Working Group 2023 response criteria for higher-risk MDS. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	Up to 1 year
Time to response in patients with MDS	Categorical endpoints (e.g., response) will be reported in terms of counts by dose level.	From study treatment initiation (Cycle 1 Day 1) to achievement of CR, CRL or CRh, assessed up to 1 year
OS in patients with MDS	OS rates will be reported. OS will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method.	From study treatment initiation to death (of any cause) or last follow-up, assessed at 6 months and 1 year
Progression-free survival (PFS) in patients with MDS	PFS rates will be reported. PFS will be analyzed using the Kaplan-Meier method. The median survival rates will be reported with a 95% confidence interval. Median follow-up will be calculated using the reverse Kaplan-Meier method.	From study treatment initiation to the first occurrence of progressive disease (PD), relapse from CR (or CR equivalent), death (of any cause), or last follow-up whichever occurs first, assessed at 6 months and 1 year
Demonstration of UBA1-TAK-243 engagement	Assayed by proprietary monoclonal antibody courtesy of Takeda, to determine target binding and inhibition.	Baseline up to 1 year
Reductions of protein mono- and poly ubiquitylation	Measured by FK2 antibody. Used as a functional marker of target inhibition.	Baseline up to 1 year

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Guillaume Richard-Carpentier, University Health Network Princess Margaret Cancer Center LAO

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2025
• Primary Completion (Estimated): October 24, 2026
• Study Completion (Estimated): October 24, 2026

Study Registration Dates

• First Submitted: January 24, 2019
• First Submitted That Met QC Criteria: January 24, 2019
• First Posted (Actual): January 25, 2019

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 15, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Anemia; Leukemia; Anemia, Refractory; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Anemia, Refractory, with Excess of Blasts; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Cytological Techniques; Cytodiagnosis; Diagnostic Techniques, Surgical; Biopsy; Specimen Handling; TAK-243
• Other Study ID Numbers: NCI-2019-00238 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA186644 (U.S. NIH Grant/Contract); 10237 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No