Clinical Trials /

A Study of TAS1553 in Subjects With Relapsed or Refractory Acute Myeloid Leukemia (AML) and Other Myeloid Neoplasms

NCT04637009

Description:

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).

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic/Myeloproliferative Neoplasm
  • Myeloproliferative Neoplasm
  • Myeloproliferative Neoplasm, Unclassifiable
  • Secondary Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of TAS1553 in Subjects With Relapsed or Refractory Acute Myeloid Leukemia (AML) and Other Myeloid Neoplasms
  • Official Title: A Phase 1 Study of Safety, Pharmacokinetics and Preliminary Activity of TAS1553 in Subjects With Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) and Other Myeloid Neoplasms

Clinical Trial IDs

  • ORG STUDY ID: TAS1553-01
  • NCT ID: NCT04637009

Conditions

  • Acute Myeloid Leukemia
  • Myeloproliferative Neoplasm
  • Myelodysplastic/Myeloproliferative Neoplasm

Interventions

DrugSynonymsArms
TAS1553Part 1 (dose escalation)

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Part 1 (dose escalation)ExperimentalOral administration of TAS1553 once daily at specific time points.
  • TAS1553
Part 2 (dose expansion)ExperimentalOral administration of TAS1553 once daily at specific time points.
  • TAS1553

Eligibility Criteria

        Inclusion Criteria:

          1. Capable of giving signed informed consent.

          2. Participant must be 18 years of age or older, at the time of signing the informed
             consent.

          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.

        Exclusion Criteria:

          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
                  criterion.

               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
                  treatment.

          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
             permitted.

          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
             conditions:

               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
                  significant arrhythmias.

               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
             inducers.

         16. Inability to swallow oral medication.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety: Number of participants with treatment-emergent adverse events in Part 1
Time Frame:Up to 12 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Pharmacokinetic parameter: Area under the curve (AUC)
Time Frame:At specific timepoints from predose up to Day 8 of Cycle 6 (28 days per cycle)
Safety Issue:
Description:
Measure:Pharmacokinetic parameter: Maximum plasma concentration (Cmax)
Time Frame:At specific timepoints from predose up to Day 8 of Cycle 6 (28 days per cycle)
Safety Issue:
Description:
Measure:Pharmacokinetic parameter: Minimum plasma concentration (Cmin)
Time Frame:At specific timepoints from predose up to Day 8 of Cycle 6 (28 days per cycle)
Safety Issue:
Description:
Measure:Pharmacokinetic parameter: Time to reach maximum plasma concentration (Tmax)
Time Frame:At specific timepoints from predose up to Day 8 of Cycle 6 (28 days per cycle)
Safety Issue:
Description:
Measure:Pharmacokinetic parameter: Half-life (t½)
Time Frame:At specific timepoints from predose up to Day 8 of Cycle 6 (28 days per cycle)
Safety Issue:
Description:
Measure:Hematological improvement: Number of participants in Cohort 2 (other myeloid neoplasms) with hematological improvement in Part 2
Time Frame:Up to 33 months
Safety Issue:
Description:
Measure:Time to response (TTR): Number of days from the first dose to the first documented evidence of response
Time Frame:Up to 33 months
Safety Issue:
Description:
Measure:Duration of response (DOR): Number of days from the start of response until disease progression or relapse
Time Frame:Up to 33 months
Safety Issue:
Description:
Measure:Overall survival (OS): Number of days from date of first dose until death due to any cause
Time Frame:Up to 33 months
Safety Issue:
Description:
Measure:Safety: Number of participants with treatment-emergent adverse events in Part 2
Time Frame:Up to 33 months
Safety Issue:
Description:
Measure:Pharmacodynamic biomarker: Change from baseline in deoxyadenosine triphosphate (dATP) pool levels in peripheral blood mononuclear cells (PBMCs)
Time Frame:At specific timepoints from predose up to Day 2 of Cycle 2 (28 days per cycle)
Safety Issue:
Description:
Measure:Pharmacodynamic biomarker: Change from baseline in phosphorylated checkpoint kinase 1 (pCHK1) levels in bone marrow
Time Frame:At specific timepoints from predose up to Day 2 of Cycle 2 (28 days per cycle)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Astex Pharmaceuticals, Inc.

Trial Keywords

  • MDS/MPN, unclassifiable in chronic phase
  • Accelerated phase MPN
  • Chronic neutrophilic leukemia (CNL), accelerated phase
  • Polycythemia vera (PV), accelerated phase
  • Primary myelofibrosis (PMF), accelerated phase
  • Essential thrombocythemia (ET), accelerated phase
  • Chronic eosinophilic leukemia, not otherwise specified (NOS), accelerated phase
  • MPN, unclassifiable
  • MDS/MPN
  • Chronic myelomonocytic leukemia (CMML)
  • Atypical chronic myeloid leukemia (aCML), BCR-ABL1-negative
  • MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)
  • MDS/MPN, unclassifiable

Last Updated

January 13, 2021