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
Overview
- Phase
- Phase 1
- Intervention
- TAS1553
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- Astex Pharmaceuticals, Inc.
- Enrollment
- 20
- Locations
- 10
- Primary Endpoint
- Safety: Number of participants with dose-limiting toxicities in Part 1
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
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).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Capable of giving signed informed consent.
- •Participant must be 18 years of age or older, at the time of signing the informed consent.
- •Life expectancy of at least 12 weeks as assessed by the investigator.
- •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.
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to
- •Have platelet count ≥10,000/μL (transfusions to achieve this level are allowed).
- •Have adequate renal function as demonstrated by a 24-hour urine measured creatinine clearance ≥60 mL/min.
- •Adequate hepatic function as evidenced by:
- •aspartate aminotransferase (AST) ≤3× upper limit of normal (ULN)
- •alanine aminotransferase (ALT) ≤3×ULN
Exclusion Criteria
- •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).
- •Participants with highly proliferative disease are excluded as follows:
- •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.
- •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.
- •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.
- •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.
- •Known clinically active central nervous system (CNS) leukemia.
- •Diagnosis of BCR-ABL-positive leukemia, acute promyelocytic leukemia (M3 AML or APML), or juvenile myelomonocytic leukemia (JMML).
- •Second malignancy requiring active systemic therapy, except breast or prostate cancer stable on or responding to endocrine therapy.
- •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).
Arms & Interventions
Part 1 (dose escalation)
Oral administration of TAS1553 once daily at specific time points.
Intervention: TAS1553
Part 2 (dose expansion)
Oral administration of TAS1553 once daily at specific time points.
Intervention: TAS1553
Outcomes
Primary Outcomes
Safety: Number of participants with dose-limiting toxicities in Part 1
Time Frame: Up to 12 months
Safety: Number of participants with treatment-emergent adverse events in Part 1
Time Frame: Up to 12 months
Response rate in Cohort 2 (other myeloid neoplasms): Number of participants with overall response rate (ORR) of CR + partial response (PR) in Part 2
Time Frame: Up to 33 months
Response rate in Cohort 1 (AML): Number of participants with complete response (CR) + complete response with partial hematological recovery (CRh), and with CR + incomplete blood count recovery (CRi) in Part 2
Time Frame: Up to 33 months
Secondary Outcomes
- Pharmacokinetic parameter: Maximum plasma concentration (Cmax)(At specific timepoints from predose up to Day 8 of Cycle 6 (28 days per cycle))
- Pharmacokinetic parameter: Minimum plasma concentration (Cmin)(At specific timepoints from predose up to Day 8 of Cycle 6 (28 days per cycle))
- Overall survival (OS): Number of days from date of first dose until death due to any cause(Up to 33 months)
- Safety: Number of participants with treatment-emergent adverse events in Part 2(Up to 33 months)
- Pharmacodynamic biomarker: Change from baseline in deoxyadenosine triphosphate (dATP) pool levels in peripheral blood mononuclear cells (PBMCs)(At specific timepoints from predose up to Day 2 of Cycle 2 (28 days per cycle))
- Pharmacodynamic biomarker: Change from baseline in phosphorylated checkpoint kinase 1 (pCHK1) levels in bone marrow(At specific timepoints from predose up to Day 2 of Cycle 2 (28 days per cycle))
- Pharmacokinetic parameter: Area under the curve (AUC)(At specific timepoints from predose up to Day 8 of Cycle 6 (28 days per cycle))
- Pharmacokinetic parameter: Half-life (t½)(At specific timepoints from predose up to Day 8 of Cycle 6 (28 days per cycle))
- Pharmacokinetic parameter: Time to reach maximum plasma concentration (Tmax)(At specific timepoints from predose up to Day 8 of Cycle 6 (28 days per cycle))
- Hematological improvement: Number of participants in Cohort 2 (other myeloid neoplasms) with hematological improvement in Part 2(Up to 33 months)
- Time to response (TTR): Number of days from the first dose to the first documented evidence of response(Up to 33 months)
- Duration of response (DOR): Number of days from the start of response until disease progression or relapse(Up to 33 months)