TAK-243 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Refractory Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of TAK-243 in treating patients with acute myeloid leukemia, or myelodysplastic syndrome, or chronic myelomonocytic leukemia that has come back or that is not responding to treatment. TAK-243 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To establish the recommended phase 2 dose (RP2D) of ubiquitin-activating enzyme (UAE) inhibitor TAK-243 (MLN7243 [TAK-243]) administered intravenously in a twice-weekly schedule in patients with acute myeloid leukemia (AML) or patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) refractory to hypomethylating agents (HMAs). SECONDARY OBJECTIVES: I. To assess the maximum tolerated dose (MTD) evaluated on the first cycle (Day 1 to 21) of MLN7243 (TAK-243), its safety profile, and dose limiting toxicities (DLT). II. To investigate preliminary anti-leukemic activity of MLN7243 (TAK-243) monotherapy in patients with AML, MDS and CMML. III. To relate responses to the molecular/cytogenetic abnormalities in the malignant cells or to pharmacokinetic (PK)/pharmacodynamic (PD) findings. IV. To describe the PK of MLN7243 (TAK-243). V. To describe the PD profile of MLN7243 (TAK-243) in the study population. VI. To establish the RP2D of MLN7243 (TAK-243) administered intravenously in a once-weekly schedule in patients with AML or patients with MDS or CMML refractory to HMAs. OUTLINE: This is a dose escalation, followed by a dose expansion, study. Patients are assigned to 1 of 2 groups. GROUP I: Patients receive UAE inhibitor TAK-243 intravenously (IV) over 10 minutes on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity. GROUP II: Patients receive UAE inhibitor TAK-243 IV over 10 minutes on days 1, 8, and 15. Treatment repeats every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days.

Official Title
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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

Conditions
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Myelodysplastic Syndrome, Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia, Refractory Chronic Myelomonocytic Leukemia, Refractory High Risk Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: UAE Inhibitor TAK-243


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of AML, MDS or CMML, according to local laboratory review, classified by the 2016 World Health Organization (WHO) criteria (Arber et al., 2016) (with the exception of acute promyelocytic leukemia [APL] or AML with a t[15;17] [q22;q12] cytogenetic abnormality). Concomitant treatment with organic anion transporting polypeptide (OATP) and breast cancer resistance protein (BCRP) inhibitors or strong inducers/inhibitors of cytochrome P450 (CYP)3A4/5 is not allowed; treatment with these agents must be discontinued at least 14 days prior to MLN7243 (TAK-243) dosing. No history of allergy to/intolerance of MLN7243 (TAK-243) or any other component in its formulation. 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. Because no dosing or adverse event data are currently available on the use of MLN7243 (TAK-243) in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%). Hemoglobin > 8 g/dL. Patients may be transfused to achieve this value. Elevated indirect bilirubin due to post-transfusion hemolysis is allowed. Serum bilirubin =< 2 × institutional upper limit of normal (ULN). 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 > 50 mL/min based on the Cockcroft-Gault equation. Documented normal cardiac function (>= 55%) by echocardiogram or multi-gated acquisition (MUGA) scan. Known human immunodeficiency virus (HIV) positive patients who meet the following criteria will be considered eligible: CD4 count > 350 cells/mm^3 Undetectable viral load Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections 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. Absence of other malignancy requiring active therapy. Absence 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. Absence of chronic graft-versus-host disease (GVHD) following allogeneic transplantation; does not require continued treatment with systemic immunosuppressive agents. Female patients who: Are postmenopausal (age-related amenorrhea >= 12 consecutive months or follicle-stimulating hormone > 40 mIU/mL), for at least 1 year before the screening visit, OR Are 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 subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.) Male patients, even if surgically sterilized (i.e., status postvasectomy), 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.) The effects of MLN7243 (TAK-243) on the developing human fetus are unknown. For this reason and because ubiquitin-activating enzyme inhibitors are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of MLN7243 (TAK-243) administration. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. Patients with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after central nervous system (CNS)-directed treatment, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT] scan) during the screening period. Patient should be on stable steroid doses and should be taking an anti-seizure medication that does not cause drug-drug interactions. Patients with a history of CNS disease (leukemia) at diagnosis who have no current CNS symptoms would also be eligible. Patients with new or progressive brain metastases or symptomatic CNS leukemia will not be eligible. Ability to understand and the willingness to sign a written informed consent document and comply with all requirements of study participation (including all study procedures) prior to any screening procedures. Patients should have a minimum life expectancy of 1 month. AML-SPECIFIC ELIGIBILITY CRITERIA: Refractoriness to at least one attempt at remission induction (including, but not limited to, 7+3, idarubicin, fludarabine, high-dose cytarabine and filgrastim [Ida-FLAG] and mitoxantrone, etoposide, and high-dose cytarabine [NOVE-HiDAC]). OR AML relapse following at least one induction regimen. Induction therapy may be followed by appropriate consolidation therapy and/or allogeneic stem cell transplantation and may include intrathecal chemotherapy as indicated. OR Patients (including those newly diagnosed) who are not considered candidates for aggressive induction or reinduction chemotherapy regimens. AML-SPECIFIC ELIGIBILITY CRITERIA: Absence of active CNS leukemia (patients with prior CNS leukemia who have negative CNS cytology and who receive periodic prophylactic intrathecal chemotherapy are eligible). MDS-SPECIFIC ELIGIBILITY CRITERIA: Patients with International Prognostic Scoring System (IPSS) intermediate-2 or high risk MDS that is refractory to treatment with HMA therapy at time of enrollment, defined as: progression to AML. failure to respond to HMA therapy. recurrence or progression of MDS following initial response to HMA therapy. intolerance to HMAs. CMML-SPECIFIC ELIGIBILITY CRITERIA: Patients with IPSS intermediate-2 or high risk CMML that is refractory to treatment with HMA therapy at time of enrollment, defined as: progression to AML. failure to respond to HMA therapy. recurrence or progression of CMML following initial response to HMA therapy. intolerance to HMAs. Exclusion Criteria: Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1). Patients who are receiving any other investigational agents. History of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN7243 (TAK-243). Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible, as CYP3A4 is the major cytochrome P450 isozyme contributing to the metabolism of MLN7243 (TAK-243). 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. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant and lactating/breast-feeding women are excluded from this study because MLN7243 (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 MLN7243 (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 MLN7243 (TAK-243). Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia. Major surgery within 14 days before the first dose of any study drug or a scheduled surgery during study period. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection. Life-threatening illness unrelated to cancer. Patients with uncontrolled coagulopathy or bleeding disorder. Known hepatic cirrhosis or severe pre-existing hepatic impairment. Known cardiopulmonary disease defined as: Unstable angina; Congestive heart failure (New York Heart Association [NYHA] class III or IV); Myocardial infarction (MI) within 6 months prior to first dose (patients who had ischemic heart disease such as a (acute coronary syndrome [ACS]), MI, and/or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll); Cardiomyopathy Symptomatic pulmonary hypertension. Known central nervous system (CNS) involvement. Treatment with clinically significant metabolic enzyme inducers within 14 days before the first dose of the study drug. Clinically significant metabolic enzyme inducers are not permitted during this study. Clinically significant arrhythmia: History of polymorphic ventricular fibrillation or torsade de pointes, Permanent atrial fibrillation (a fib), defined as continuous a fib for >= 6 months, Persistent a fib, defined as sustained a fib lasting > 7 days and/or requiring cardioversion in the 4 weeks before screening, Grade 3 a fib defined as symptomatic and incompletely controlled medically, or controlled with device (e.g., pacemaker) or ablation, and Patients with paroxysmal a fib or < grade 3 a fib for period of at least 6 months are permitted to enroll provided that their rate is controlled on a stable regimen. Uncontrolled high blood pressure (i.e., systolic blood pressure >180 mmHg, diastolic blood pressure > 95 mmHg). Prolonged rate corrected QT (QTc) interval >= 500 msec, calculated according to institutional guidelines. Known moderate to severe chronic obstructive pulmonary disease, interstitial lung disease, and 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (twice weekly UAE inhibitor TAK-243)<br>Patients receive UAE inhibitor TAK-243 IV over 10 minutes on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity. | Drug: UAE Inhibitor TAK-243<br>* Given IV<br>* Other names: TAK-243;|
| Experimental: Group II (once weekly UAE inhibitor TAK-243)<br>Patients receive UAE inhibitor TAK-243 IV over 10 minutes on days 1, 8, and 15. Treatment repeats every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. | Drug: UAE Inhibitor TAK-243<br>* Given IV<br>* Other names: TAK-243;|

What is the study measuring?
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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 | 
| 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. | 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 | 
| Overall response rate (ORR) 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 | 
| Progression-free survival (PFS) in patients with AML | 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 disease progression or death (of any cause), whichever occurs first; assessed at 6 months and 1 year | 
| 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), assessed at 6 months and 1 year | 
| Rate of CR in patients with myelodysplastic syndrome (MDS) | As defined by Cheson et al., 2006. 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 | As defined by Cheson et al., 2006. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level. | Up to 1 year | 
| Marrow response in patients with MDS | As defined by Cheson et al., 2006. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level. | Up to 1 year | 
| Hematological improvement in patients with MDS | As defined by Cheson et al., 2006. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level. | Up to 1 year | 
| ORR in patients with MDS | As defined by Cheson et al., 2006. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level. | Up to 1 year | 
| 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 disease progression or death (of any cause), whichever occurs first, assessed at 6 months and 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), assessed at 6 months and 1 year | 
| Rate of CR in patients with chronic myelomonocytic leukemia (CMML) | As defined by Savona et al., 2015. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level. | Up to 1 year | 
| Rate of cytogenic CR in patients with CMML | As defined by Savona et al., 2015. 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 CMML | As defined by Savona et al., 2015. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level. | Up to 1 year | 
| Marrow response in patients with CMML | As defined by Savona et al., 2015. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level. | Up to 1 year | 
| Clinical benefit in patients with CMML | As defined by Savona et al., 2015. Categorical endpoints (e.g., response) will be reported in terms of counts by dose level. | Up to 1 year | 
| PFS in patients with CMML | 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 disease progression or death (of any cause), whichever occurs first, assessed at 6 months and 1 year | 
| OS in patients with CMML | 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), assessed at 6 months and 1 year | 
| Pharmacokinetic measurements | Expressed as area under the curve (AUC), half-life (t1/2), and maximum concentration (Cmax). | Baseline up to 1 year | 
| Demonstration of UBA1-MLN7243 (TAK-243) engagement | Assayed by proprietary monoclonal antibody courtesy of Takeda, to determine target binding and inhibition. | Baseline up to 1 year | 
| Reductions (as measured by FK2 antibody) of protein mono- and poly ubiquitylation | Used as a functional marker of target inhibition. | Baseline up to 1 year |