Clinical Trial 23556

• Overview

  Study Title:

  A Phase 1 Study of MLN7243 (TAK-243) for Either Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome/Chronic Myelomonocytic Leukemia Refractory to Hypomethylating Agents

  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.

  Objective:

  Primary Objectives: To establish the recommended phase 2 dose (RP2D) of TAK-243 administered intravenously in a twice-weekly schedule in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Secondary Objectives: 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). To investigate preliminary anti-leukemic activity of TAK-243 monotherapy in patients with AML or MDS. To describe the pharmacokinetic (PK) profile of TAK-243. To describe the pharmacodynamic (PD) effects of TAK-243.

• Treatments

  Therapies:

  Therapy (NOS)

• Inclusion Criteria

  Inclusion Criteria:
  • Diagnosis of Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (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.
  • Eastern Cooperative Oncology Group (ECOG) performance status == 50%).
  • 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.
  • Other criteria may apply.

• Exclusion Criteria

  Exclusion Criteria:
  • 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.
  • Uncontrolled high blood pressure.
  • 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.
  • Other criteria may apply.

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