This is a Phase 1, 2-part, open-label, multicenter, first-in-human (FIH) study to assess the
safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of
TAS1553 administered orally to participants ≥18 years of age with relapsed or refractory
(R/R) acute myeloid leukemia (AML) or other myeloid neoplasms where approved therapies have
failed or for whom known life-prolonging therapies are not available. The AML population
includes de novo AML, secondary AML, and myelodysplastic syndrome (MDS)-transformed into AML.
Other myeloid neoplasms include accelerated phase myeloproliferative neoplasms (MPN), and
chronic or accelerated phase MPN-unclassifiable (MPN-U) and MDS-MPN. Blast crisis phase of
MPNs are considered secondary AML and will be included in the AML cohort.
Part 1 is a multicenter, sequential group treatment feasibility study with 1 treatment arm
and no masking (dose escalation). Part 2 is a multicenter, two-stage, multiple group, dose
confirmation study with 1 treatment arm and no masking (exploratory dose expansion).
1. Capable of giving signed informed consent.
2. Participant must be 18 years of age or older, at the time of signing the informed
3. Life expectancy of at least 12 weeks as assessed by the investigator.
4. Participants with R/R AML or other myeloid neoplasms where approved therapies have
failed or for whom known life-prolonging therapies are not available. The AML
population includes de novo AML, secondary AML, and MDS transformed into AML. Other
myeloid neoplasms include accelerated phase MPN, and chronic or accelerated phase
MPN-U and MDS-MPN. Blast crisis phase of MPN, MPN-U, and MDS-MPN are considered
secondary AML and will be included in the AML cohort.
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
6. Have platelet count ≥10,000/μL (transfusions to achieve this level are allowed).
7. Have adequate renal function as demonstrated by a 24-hour urine measured creatinine
clearance ≥60 mL/min.
8. Adequate hepatic function as evidenced by:
1. aspartate aminotransferase (AST) ≤3× upper limit of normal (ULN)
2. alanine aminotransferase (ALT) ≤3×ULN
3. total bilirubin ≤1.5×ULN.
9. Participants must be amenable to serial bone marrow biopsies, peripheral blood
sampling, and urine sampling during the study.
10. 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.
1. Participants who have MPN, MPN-U, or MDS/MPN and display hypoplastic bone marrow and
would also not ordinarily benefit from cytoreductive therapy such as hydroxyurea (HU).
2. Participants with highly proliferative disease are excluded as follows:
1. Part 1/AML: white blood cells (WBC) >20,000/μL and >50% blasts in blood. Measures
to reduce WBC, such as HU treatment within the last 2 weeks and cytotoxic
chemotherapy within the last 4 weeks are not allowed to meet this eligibility
2. Part 1/other myeloid neoplasms: WBC >20,000/μL. A short course of HU may be used
to meet this eligibility criterion, as long as HU is discontinued 96 hours and
any encountered drug-related toxicity must be resolved to Grade ≤1 before the
first dose of study treatment.
3. Part 2/Cohort 1, AML: WBC>20,000/μL and >50% blasts in blood. A short course of
HU may be used to meet this eligibility criterion, as long as HU is discontinued
96 hours, and any encountered drug-related toxicity must be resolved to Grade ≤1
before the first dose of study treatment.
4. Part 2/Cohort 2, other myeloid neoplasms: Specific WBC exclusion criterion not
defined. A short course of HU may be used to reduce WBC if judged to be necessary
by the investigator, as long as HU is discontinued 96 hours and any encountered
drug-related toxicity must be resolved to Grade ≤1 before the first dose of study
3. Known clinically active central nervous system (CNS) leukemia.
4. Diagnosis of BCR-ABL-positive leukemia, acute promyelocytic leukemia (M3 AML or APML),
or juvenile myelomonocytic leukemia (JMML).
5. Second malignancy requiring active systemic therapy, except breast or prostate cancer
stable on or responding to endocrine therapy.
6. Ongoing Grade ≥3 Graft Versus Host Disease (GVHD), or any grade GVHD requiring active
treatment (for example, calcineurin inhibitors, ≥5mg/day prednisone or other steroid
equivalent, or other immunosuppressive agents). (Note: Prednisone at any dose for
other indications is allowed).
7. Advanced human immunodeficiency virus (HIV) infection, active hepatitis B virus (HBV)
or hepatitis C virus (HCV) infection; Inactive hepatitis carrier status and
participants with laboratory evidence of no active replication and participants on
antiviral medication(s) who have a viral load below limit of detection will be
8. 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
participant to high risk of non-compliance with the protocol.
9. Active infection resistant to antibiotics; or non-leukemia-associated pulmonary
disease requiring >2 liters per minute oxygen or any other condition that puts the
participant at an imminent risk of death.
10. 24-hour urinary protein excretion ≥1g or urinalysis of 2+proteinuria.
11. History of, or at risk for, cardiac disease, as evidenced by any of the following
1. Abnormal left ventricular ejection fraction (LVEF; <50%) on echocardiogram (ECHO)
or multiple-gated acquisition (MUGA) scan at Screening.
2. Congestive cardiac failure of Class ≥III severity according to New York Heart
Association (NYHA) functional classification defined as patients with marked
limitation of activity and who are comfortable at rest, while Class IV patients
have symptoms of heart failure at rest.
3. Unstable cardiac disease including unstable angina or hypertension as defined by
the need for overnight hospital admission within the last 3 months (90 days).
4. Ventricular arrhythmias including ventricular bigeminy, clinically significant
brady arrhythmias such as sick sinus syndrome, third-degree atrioventricular (AV)
block, presence of cardiac pacemaker or defibrillator, or other clinically
5. Screening 12-lead electrocardiogram (ECG) with measurable QTcF interval of ≥470
msec (Fridericia's formula should be used).
12. Known hypersensitivity to TAS1553 or any of its components.
13. Allogenic hematopoietic stem cell transplantation (HSCT) within 180 days of the first
dose of TAS1553, or participants on immunosuppressive therapy post HSCT at the time of
screening (calcineurin inhibitors or similar must be discontinued ≥4 weeks prior to
the time of study drug initiation).
14. Treated with any systemic anticancer therapy within 2 weeks of the first dose of study
treatment. Any encountered treatment-related toxicities (excepting alopecia) must be
resolved to Grade 1 or less.
15. Phase 1 Part 1 only: participants who require concomitant use of strong CYP3A4
16. Inability to swallow oral medication.