A Study of TAS1440 With ATRA in Subjects With r/r AML

Study Overview
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Brief Summary
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This is a multicenter, 2-part, Phase 1 study to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of TAS1440 administered as a single agent and in combination with all-trans retinoic acid (ATRA) in participants with acute myeloid leukemia (AML) who have relapsed or are refractory (r/r) to prior treatment. The study duration is expected to be approximately 30 months.

Official Title
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A Phase 1 Study of Safety, Pharmacokinetics, and Preliminary Activity of TAS1440, as a Single Agent and in Combination With All-Trans Retinoic Acid (ATRA) in Subjects With Relapsed or Refractory (r/r) Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: TAS1440
* Drug: TAS1440 + ATRA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a projected life expectancy of at least 12 weeks and be in stable condition to complete 1 full cycle (4 weeks) of treatment. Have histological confirmation of AML by World Health Organization (WHO) 2016 criteria and who have failed all other available conventional therapies. Have a peripheral blood or bone marrow blast count >5% at the time of enrollment. Have disease that: is refractory to standard induction chemotherapy, including but not limited to anthracycline and cytarabine combination therapy, or has relapsed after anthracycline and cytarabine therapy or stem cell transplant (SCT), or is refractory to or has relapsed after a front-line regimen containing a hypomethylating agent, alone or in combination. Have an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 1. Have adequate renal function as demonstrated by a serum creatinine ≤1.5 × upper limit of normal (ULN) or calculated creatinine clearance (by the standard Cockcroft-Gault formula) of ≥60 mL/min. Have adequate liver function as demonstrated by the following: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <3 × upper limit of normal (ULN) AST and ALT <5 × ULN (if considered due to leukemic organ involvement). Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Exclusion Criteria: Known clinically active central nervous system leukemia. BCR-ABL-positive leukemia. Diagnosis of acute promyelocytic leukemia (M3 AML or APML or APL). Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy. Grade 3 or higher graft versus host disease (GVHD), or GVHD requiring treatment with either: a calcineurin inhibitor, or prednisone more than 5 mg/day (Note: Prednisone at any dose for other indications is allowed). Total serum bilirubin ≥1.5 × ULN (except for subjects with Gilbert's Syndrome for whom direct bilirubin is >2.5 × ULN), or liver cirrhosis, or chronic liver disease Child-Pugh Class B or C. Known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis titer being treated with antivirals is allowed. For subjects considered at risk of viral exposure, serologies should be used to establish negativity. Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the investigator, predisposes the subject to high risk of non-compliance with the protocol. Myocardial impairment of any cause (eg, cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, or congestive heart failure) resulting in heart failure by New York Heart Association (NYHA) Criteria (Class III or IV staging). Screening 12-lead echocardiogram with measurable QTc interval (according to either Fridericia's or Bazett's correction) of >480 milliseconds. Active, uncontrolled infection. Participants with an infection receiving treatment (antibiotic, antifungal, or antiviral treatment) must be afebrile and hemodynamically stable for ≥72 hours before enrollment. Non-AML-associated pulmonary disease requiring >2 liters per minute (LPM) oxygen. Proliferative AML with total white blood cells > 20,000/uL Any other condition that puts the participant at an imminent risk of death. Treated with any investigational therapy within 2 weeks of the first dose of study treatment. Inability to swallow oral medication. Known hypersensitivity to ATRA, any of its components, or other retinoids. Known sensitivity to parabens.

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: TAS1440<br>TAS1440 as a single agent administered once daily (QD) on specific days during each 28-day cycle in Part 1. | Drug: TAS1440<br>* Form: Capsule or Tablet Route of Administration: Oral<br>|
| Experimental: TAS1440 + ATRA<br>TAS1440 administered QD on specific days during each 28-day cycle in combination with ATRA twice daily (BID) in Part 2. | Drug: TAS1440 + ATRA<br>* Form: Capsule or Tablet Route of Administration: Oral<br>* Other names: Vesanoid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Number of participants with treatment-emergent adverse events (TEAEs) |  | Approximately 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate: Number of participants with complete remission (CR), complete remission with incomplete blood count recovery (CRi), partial remission (PR) and complete remission with partial hematological recovery (CRh) |  | Approximately 30 months | 
| Overall survival: Time from the date of the first dose until death due to any cause |  | Approximately 30 months | 
| Pharmacokinetic parameter: Area under the curve (AUC) |  | Up to Day 8 of Cycle 1 and Cycle 2 (28 days per cycle) | 
| Pharmacokinetic parameter: Maximum plasma concentration (Cmax) |  | Up to Day 8 of Cycle 1 and Cycle 2 (28 days per cycle) | 
| Pharmacokinetic parameter: Minimum plasma concentration (Cmin) |  | Up to Day 8 of Cycle 1 and Cycle 2 (28 days per cycle) | 
| Pharmacokinetic parameter: Time to reach maximum plasma concentration (Tmax) |  | Up to Day 8 of Cycle 1 and Cycle 2 (28 days per cycle) | 
| Pharmacokinetic parameter: Half-life (t1/2) |  | Up to Day 8 of Cycle 1 and Cycle 2 (28 days per cycle) |