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A Study of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (AML)

Sponsor
Astex Pharmaceuticals, Inc. (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT04155580
Collaborator
(none)
68
Enrollment
15
Locations
3
Arms
22.6
Anticipated Duration (Months)
4.5
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To evaluate the safety, pharmacokinetics (PK), and efficacy of ASTX660 when given alone and in combination with ASTX727 in participants with relapsed/refractory (R/R) acute myeloid leukemia (AML). The duration of the study is expected to be approximately 30 months.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

This is a three-part dose escalation and dose expansion Phase 1 study of ASTX660 alone and in combination with ASTX727 in adults with R/R AML.

Part 1 is an open-label, single arm, dose escalation with ASTX660 in combination with ASTX727 at the standard fixed dose combination (FDC).

Part 2 is an open-label, randomized, dose escalation intended to evaluate ASTX660 as a monotherapy and ASTX660 in combination with ASTX727 FDC.

Part 3 is an exploratory single arm dose expansion to further expand the number of participants treated with ASTX660 in combination with ASTX727 FDC.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
68 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1, Parallel, Open-Label Study of the Safety and Tolerability, Pharmacokinetics, and Antileukemic Activity of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)
Actual Study Start Date :
Jun 12, 2020
Anticipated Primary Completion Date :
Apr 30, 2022
Anticipated Study Completion Date :
Apr 30, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Part 1

ASTX660 once daily (Days 1-7 and 15-21 per 28-day cycle) + ASTX727 FDC once daily (Days 1-5 per 28-day cycle)

Drug: ASTX660
Capsule for oral administration

Drug: ASTX727
Tablet for oral administration
Other Names:
  • cedazuridine + decitabine

    		•
    Experimental: Part 2

    ASTX660 once daily (Days 1-7 and 15-21 per 28-day cycle) as a single agent or in combination with ASTX727 FDC once daily (Days 1-5 per 28-day cycle)

    Drug: ASTX660
    Capsule for oral administration

    Drug: ASTX727
    Tablet for oral administration
    Other Names:
  • cedazuridine + decitabine

    		•
    Experimental: Part 3

    ASTX660 at the recommended dose for expansion identified in Part 2 + ASTX727 FDC once daily (Days 1-5 per 28-day cycle)

    Drug: ASTX660
    Capsule for oral administration

    Drug: ASTX727
    Tablet for oral administration
    Other Names:
  • cedazuridine + decitabine

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Safety Assessment: Number of participants with treatment-emergent adverse events (TEAEs) [Up to 30 months]

    Secondary Outcome Measures

    1. Response rate: Number of participants achieving complete response (CR), complete response with incomplete hematological recovery (CRi), and partial response (PR) as determined by the European LeukemiaNet (ELN) 2017 response criteria for AML [Up to 30 months]

    2. Time to response: Time from first dose to the first documented evidence of response [Up to 30 months]

    3. Duration of response: Time from the start of response until disease progression or relapse [Up to 30 months]

    4. Overall survival: Time since first dose until death due to any cause [Up to 30 months]

    5. Composite complete response: Number of participants (sum of CR+CRi) [Up to 30 months]

    6. Complete response with partial hematological recovery (CRh): Number of participants [Up to Month 30]

    7. Pharmacokinetic parameter: Area under the curve (AUC) [On Days 1, 5 and 6 of Cycle 1 and Day 1 of Cycle 2 (28 days per cycle)]

    8. Pharmacokinetic parameter: Maximum plasma concentration (Cmax) [On Days 1, 5 and 6 of Cycle 1 and Day 1 of Cycle 2 (28 days per cycle)]

    9. Pharmacokinetic parameter: Minimum plasma concentration (Cmin) [On Days 1, 5 and 6 of Cycle 1 and Day 1 of Cycle 2 (28 days per cycle)]

    10. Pharmacokinetic parameter: Time to reach maximum plasma concentration (Tmax) [On Days 1, 5 and 6 of Cycle 1 and Day 1 of Cycle 2 (28 days per cycle)]

    11. Pharmacokinetic parameter: Half-life (t½) [On Days 1, 5 and 6 of Cycle 1 and Day 1 of Cycle 2 (28 days per cycle)]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Have a projected life expectancy of at least 12 weeks, as assessed by the Investigator.

    2. Have histological confirmation of AML by World Health Organization (WHO) 2016 criteria and are either:

    3. refractory to intensive induction chemotherapy OR

    4. relapsed after intensive induction chemotherapy or stem cell transplant OR

    5. relapsed after or refractory to treatment with molecularly targeted and/or low-intensity chemotherapeutic regimens.

    6. Have an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2.

    7. Have adequate renal function as demonstrated by measured or calculated creatinine clearance ≥60 mL/min.

    8. Have adequate liver function as demonstrated by:

    9. Aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (ULN)

    10. Alanine aminotransferase (ALT) ≤2.5 × ULN

    11. Bilirubin ≤1.5 × ULN - unless considered due to leukemic organ involvement.

    12. 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. Poor medical risk in the investigator's opinion because of systemic diseases in addition to the cancer under study, for example, uncontrolled infections.

    2. Known clinically active central nervous system (CNS) leukemia.

    3. BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).

    4. Diagnosis of acute promyelocytic leukemia (M3 AML or APML).

    5. Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy.

    6. Graft Versus Host Disease (GVHD), or any GVHD requiring treatment with immunosuppression. Any GVHD treatment (including calcineurin inhibitors) must be discontinued at least 28 days prior to Day 1 of study treatment.

    7. Presence of persistent toxicities of Grade >1 from prior treatment including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, and surgery (except for alopecia).

    8. Hypersensitivity to decitabine, ASTX727, ASTX660, or any of their excipients.

    9. Liver cirrhosis, or chronic liver disease Child-Pugh Class B or C.

    10. Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator's opinion, could compromise participant safety, or the integrity of study outcomes, or interfere with the absorption or metabolism of ASTX660 or ASTX727.

    11. History of, or at risk for, cardiac disease.

    12. Known human immunodeficiency virus (HIV), active hepatitis B virus (HBV), or active hepatitis C virus (HCV) infection (participants with laboratory evidence of no active replication will be permitted).

    13. Known significant mental illness or other conditions, such as active alcohol or other substance abuse that, in the opinion of the investigator, predispose the participant to high risk of noncompliance with the protocol treatment or assessments.

    14. Treated with any investigational therapy within 2 weeks of the first dose of study treatment or treatment with a myelosuppressive therapy within 4 weeks of the first dose of study treatment.

    15. In Parts 1 and 2, prior treatment with decitabine for more than 2 cycles. In Part 3, any treatment with an HMA (azacitidine or decitabine, for more than one cycle).

    16. Inability to swallow oral medication or inability or unwillingness to comply with the administration requirements related to ASTX660-02 (Note: G-tube administration is not allowed).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of California San Francisco San Francisco California United States 94143
    2 Smilow Cancer Hospital New Haven Connecticut United States 06510
    3 Sylvester Comprehensive Cancer Center Miami Florida United States 33136
    4 Northside Hospital - The Blood and Marrow Transplant Group of Georgia Atlanta Georgia United States 30342
    5 The University of Chicago Medical Center Chicago Illinois United States 60637
    6 Franciscan Health Indianapolis (Blood and Marrow Transplantation) Indianapolis Indiana United States 46237
    7 The University of Kansas Clinical Research Center Fairway Kansas United States 66205
    8 Mayo Clinic Rochester Minnesota United States 55905
    9 Roswell Park Comprehensive Cancer Center Buffalo New York United States 14263
    10 New York University Langone Health New York New York United States 10016
    11 Mount Sinai Medical Center New York New York United States 10029
    12 Lineberger Comprehensive Cancer Center Chapel Hill North Carolina United States 27599
    13 Ohio State University Comprehensive Cancer Center Columbus Ohio United States 43210
    14 Vanderbilt - Ingram Cancer Center Nashville Tennessee United States 37232
    15 The University of Texas MD Anderson Cancer Center Houston Texas United States 77030

    Sponsors and Collaborators

    • Astex Pharmaceuticals, Inc.

    Investigators

    None specified.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Astex Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT04155580
    Other Study ID Numbers:
    • ASTX660-02
    First Posted:
    Nov 7, 2019
    Last Update Posted:
    Jan 25, 2022
    Last Verified:
    Jan 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Astex Pharmaceuticals, Inc.
    AML
    Bone marrow
    CMML
    MDS
    ASTX727
    ASTX660
    cIAP1
    Cellular inhibitor of apoptosis protein
    XIAP
    CDAi
    Cytidine deaminase inhibitor
    Cedazuridine
    Decitabine
    Acute myeloid leukemia
    Chronic myelomonocytic leukemia
    Myelodysplastic syndrome
    Additional relevant MeSH terms:
    Leukemia
    Leukemia, Myeloid
    Leukemia, Myeloid, Acute
    Decitabine

    Study Results

    No Results Posted as of Jan 25, 2022