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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)

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ClinicalTrials.gov Identifier: NCT04155580
Recruitment Status : Not yet recruiting
First Posted : November 7, 2019
Last Update Posted : November 8, 2019
Sponsor:
Information provided by (Responsible Party):
Astex Pharmaceuticals, Inc.

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
Acute Myeloid Leukemia Drug: ASTX660 Drug: ASTX727 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.


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Study Type : Interventional  (Clinical Trial)
Estimated 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)
Estimated Study Start Date : January 2020
Estimated Primary Completion Date : October 2021
Estimated Study Completion Date : October 2021


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 Name: 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 Name: 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 Name: cedazuridine + decitabine




Primary Outcome Measures :
  1. Safety Assessment: Number of participants with treatment-emergent adverse events (TEAEs) [ Time Frame: 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 [ Time Frame: Up to 30 months ]
  2. Time to response: Time from first dose to the first documented evidence of response [ Time Frame: Up to 30 months ]
  3. Duration of response: Time from the start of response until disease progression or relapse [ Time Frame: Up to 30 months ]
  4. Overall survival: Time since first dose until death due to any cause [ Time Frame: Up to 30 months ]
  5. Composite complete response: Number of participants (sum of CR+CRi) [ Time Frame: Up to 30 months ]
  6. Complete response with partial hematological recovery (CRh): Number of participants [ Time Frame: Up to Month 30 ]
  7. Pharmacokinetic parameter: Area under the curve (AUC) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: On Days 1, 5 and 6 of Cycle 1 and Day 1 of Cycle 2 (28 days per cycle) ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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:

    1. refractory to intensive induction chemotherapy OR
    2. relapsed after intensive induction chemotherapy or stem cell transplant OR
    3. relapsed after or refractory to treatment with molecularly targeted and/or low-intensity chemotherapeutic regimens.
  3. Have an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2.
  4. Have adequate renal function as demonstrated by measured or calculated creatinine clearance ≥60 mL/min.
  5. Have adequate liver function as demonstrated by:

    1. Aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (ULN)
    2. Alanine aminotransferase (ALT) ≤2.5 × ULN
    3. Bilirubin ≤1.5 × ULN - unless considered due to leukemic organ involvement.
  6. 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.
  15. Prior treatment with hypomethylating agent (ie, decitabine or azacitidine) for more than 2 cycles.
  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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04155580


Contacts
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Contact: Laksmi Wilson 925-560-2914 Laksmi.Wilson@astx.com

Sponsors and Collaborators
Astex Pharmaceuticals, Inc.
Investigators
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Study Director: Roberta Ferraldeschi, MD, PhD Astex Pharmaceuticals, Inc.

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Responsible Party: Astex Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT04155580     History of Changes
Other Study ID Numbers: ASTX660-02
First Posted: November 7, 2019    Key Record Dates
Last Update Posted: November 8, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors