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

NCT ID: NCT03816319

Last Updated: 2026-01-23

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-03-12
• Study Completion Date: 2026-10-24

Brief Summary

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.

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.

Conditions

Myelodysplastic Syndrome With Excess Blasts; Recurrent Acute Myeloid Leukemia; Recurrent Myelodysplastic Syndrome; Recurrent Myelodysplastic Syndrome/Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Refractory Myelodysplastic Syndrome; Refractory Myelodysplastic Syndrome/Acute Myeloid Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Biospecimen Collection

Intervention Type: PROCEDURE

Undergo urine and blood sample collection

Bone Marrow Aspiration

Intervention Type: PROCEDURE

Undergo bone marrow aspiration

Bone Marrow Biopsy

Intervention Type: PROCEDURE

Undergo bone marrow biopsy

Echocardiography Test

Intervention Type: PROCEDURE

Undergo ECHO

Multigated Acquisition Scan

Intervention Type: PROCEDURE

Undergo MUGA

UAE Inhibitor TAK-243

Intervention Type: DRUG

Given IV

Interventions

Biospecimen Collection

Undergo urine and blood sample collection

Intervention Type: PROCEDURE

Bone Marrow Aspiration

Undergo bone marrow aspiration

Intervention Type: PROCEDURE

Bone Marrow Biopsy

Undergo bone marrow biopsy

Intervention Type: PROCEDURE

Echocardiography Test

Undergo ECHO

Intervention Type: PROCEDURE

Multigated Acquisition Scan

Undergo MUGA

Intervention Type: PROCEDURE

UAE Inhibitor TAK-243

Given IV

Intervention Type: DRUG

Other Intervention Names

RNV Scan; RNVG; SYMA Scanning; Synchronized Multigated Acquisition Scanning; AOB87172; MLN7243; TAK-243; Biological Sample Collection; Biospecimen Collected; Specimen Collection; Biopsy of Bone Marrow; Biopsy, Bone Marrow; EC; Echocardiography; Blood Pool Scan; Equilibrium Radionuclide Angiography; Gated Blood Pool Imaging; Gated Heart Pool Scan; MUGA; MUGA Scan; Multi-Gated Acquisition Scan; Radionuclide Ventriculogram Scan; Radionuclide Ventriculography

Eligibility Criteria

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
• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Guillaume Richard-Carpentier

Role: PRINCIPAL_INVESTIGATOR

University Health Network Princess Margaret Cancer Center LAO

Locations

Moffitt Cancer Center

Tampa, Florida, United States

Site Status: RECRUITING

Northwestern University

Chicago, Illinois, United States

Site Status: RECRUITING

VCU Massey Comprehensive Cancer Center

Richmond, Virginia, United States

Site Status: RECRUITING

University Health Network-Princess Margaret Hospital

Toronto, Ontario, Canada

Site Status: RECRUITING

Countries

United States; Canada

Facility Contacts

Site Public Contact

Role: primary

ClinicalTrials@moffitt.org

800-679-0775

Site Public Contact

Role: primary

cancer@northwestern.edu

312-695-1301

Site Public Contact

Role: primary

CTOclinops@vcu.edu

804-628-6430

Site Public Contact

Role: primary

clinical.trials@uhn.on.ca

416-946-4501

Other Identifiers

NCI-2019-00238

Identifier Type: REGISTRY

Identifier Source: secondary_id

10237

Identifier Type: OTHER

Identifier Source: secondary_id

10237

Identifier Type: OTHER

Identifier Source: secondary_id

UM1CA186644

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2019-00238

Identifier Type: -

Identifier Source: org_study_id