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Pharmacokinetics, Safety, and Efficacy of ASTX727 in Combination With Venetoclax in Acute Myeloid Leukemia (AML)

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ClinicalTrials.gov Identifier: NCT04657081
Recruitment Status : Recruiting
First Posted : December 8, 2020
Last Update Posted : August 2, 2021
Sponsor:
Information provided by (Responsible Party):
Astex Pharmaceuticals, Inc.

Brief Summary:
This is a single-arm, open-label, multicenter, non-randomized interventional study to evaluate the pharmacokinetic (PK) interaction, safety, and preliminary efficacy of ASTX727 when given in combination with venetoclax for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. The primary purpose of the study is to rule out drug-drug interactions between ASTX727 and venetoclax combination therapy by evaluating area under the curve (AUC) and maximum plasma concentration (Cmax) exposure.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Decitabine and Cedazuridine (ASTX727) Drug: Venetoclax Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single-Arm, Open-Label Pharmacokinetic, Safety, and Efficacy Study of ASTX727 in Combination With Venetoclax in Adult Patients With Acute Myeloid Leukemia
Actual Study Start Date : December 31, 2020
Estimated Primary Completion Date : September 30, 2022
Estimated Study Completion Date : July 31, 2024


Arm Intervention/treatment
Experimental: Oral administration of ASTX727 and venetoclax combination

Cycle 1: ASTX727 according to a prescribed dosing regimen and venetoclax on day 1 (100 mg daily), day 2 (200 mg daily), and days 3-28 (400 mg daily) of a 28-day cycle.

Cycle 2 and beyond: ASTX727 according to a prescribed dosing regimen and venetoclax on days 1-28 (400 mg daily) of a 28-day cycle.

Drug: Decitabine and Cedazuridine (ASTX727)
Route of administration: oral in the form of a tablet
Other Name: INQOVI

Drug: Venetoclax
Route of administration: oral in the form of a tablet
Other Name: Venclexta




Primary Outcome Measures :
  1. Pharmacokinetic parameter: AUC0-24 [ Time Frame: On Days 5 and 15 in Cycle 2 (28 days per cycle) ]
    Venetoclax area under the curve from time 0 to 24 hours (AUC0-24) with and without ASTX727.

  2. Pharmacokinetic parameter: Cmax [ Time Frame: On Days 5 and 15 in Cycle 2 (28 days per cycle) ]
    Venetoclax maximum observed concentration (Cmax) with and without ASTX727.


Secondary Outcome Measures :
  1. Pharmacokinetic parameter: AUC0-24 [ Time Frame: Days 1, 2 and 5 in Cycle 2 (28 days per cycle) ]
    Decitabine area under the curve from time 0 to 24 hours (AUC0-24).

  2. Pharmacokinetic parameter: Cmax [ Time Frame: Days 1, 2 and 5 in Cycle 2 (28 days per cycle) ]
    Decitabine and cedazuridine maximum observed concentration (Cmax).

  3. Pharmacokinetic parameter: AUC0-8 [ Time Frame: Days 1, 2 and 5 in Cycle 2 (28 days per cycle) ]
    Cedazuridine area under the curve from time 0 to 8 hours (AUC0-8).

  4. Pharmacokinetic parameter: 5-day AUC [ Time Frame: Days 1 to 5 in Cycle 2 (28 days per cycle) ]
    Decitabine 5-day cumulative AUC.

  5. Safety: Participants with TEAEs [ Time Frame: Up to 24 months ]
    Number of participants with treatment-emergent adverse events (TEAEs)

  6. Complete response (CR) [ Time Frame: Up to 24 months ]
    Number of participants with CR, CR + complete response with partial hematological recovery (CRh), and CR + incomplete blood count recovery (CRi).

  7. Time to Response [ Time Frame: Up to 24 months ]
    Number of days from the first dose to the first documented evidence of complete response or CRh.

  8. Duration of Response [ Time Frame: Up to 24 months ]
    Number of days from the start of response (CR or CRh) until disease progression, start of alternative antileukemia therapy, or death.

  9. Overall Response [ Time Frame: Up to 24 months ]
    Number of days from date of first dose until death due to any cause.



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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. Participant must be 18 years of age or older.
  2. Histological confirmation of newly diagnosed AML by World Health Organization (WHO) 2016 criteria.
  3. Projected life expectancy of at least 3 months.
  4. Participants must be considered ineligible for intensive induction chemotherapy defined by the following: a) Age 75 years or older, or b) Age 18 to 74 years with at least one of the following comorbidities: i) Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina), ii) Severe pulmonary disorder (eg, diffusing lung capacity for carbon monoxide DLCO ≤65% or forced expiratory volume in 1 second [FEV1] ≤65%), iii) Creatinine clearance ≥30 mL/min to <45 mL/min, iv) Moderate hepatic impairment with total bilirubin >1.5 to ≤3.0 × upper limit of normal (ULN).
  5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
  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.
  7. Participants and their partners with reproductive potential must agree to use at least 2 effective contraceptive measures during the study and for 3 months after the last dose of study treatment, including refraining from sperm donation. Effective contraception includes methods such as oral contraceptives or double-barrier method (eg, use of a condom AND diaphragm, with spermicide).
  8. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and protocol, and willing to participate in the study.

Exclusion Criteria:

  1. History of myeloproliferative neoplasm including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation.
  2. The following karyotype abnormalities: t(8;21), inv(16) or t(15;17), or other acute promyelocytic leukemia variants that remain sensitive to all-trans retinoic acid (ATRA) therapy.
  3. Known active central nervous system involvement from AML.
  4. Known human immunodeficiency virus (HIV) infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax). Human immunodeficiency virus testing will be performed at Screening, only if indicated per local guidelines or institutional standards.
  5. Known active hepatitis B or C infection (detectable viral load). Hepatitis B or C testing will be performed at Screening, only if indicated per local guidelines or institutional standards.
  6. Severe hepatic impairment defined as: bilirubin >1.5×upper limit of normal (ULN) for participants ≥75 years or >3×ULN for participants <75 years; or aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) >3×ULN (unless considered to be due to leukemic organ involvement).
  7. Severe renal impairment defined as: calculated creatinine clearance or glomerular filtration rate <30 mL/min.
  8. A malabsorption syndrome or other condition that precludes enteral route of administration.
  9. Cardiovascular disability status of New York Heart Association Class >2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.
  10. Chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition or known hypersensitivity to any of the study medications that in the opinion of the investigator would adversely affect his/her participating in this study.
  11. Clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal).
  12. History of other malignancies prior to study entry, with the exception of adequately treated in situ carcinoma of the breast or cervix uteri; localized basal cell carcinoma or squamous cell carcinoma of the skin; previous malignancy confined and surgically resected (or adequately treated and controlled with other modalities); and any early stage malignancy for which no definitive therapy is required.
  13. White blood cell (WBC) count >25,000/μL (Hydroxyurea treatment is permitted to meet this criterion).
  14. Treatment with the following: a) A hypomethylating agent (azacitidine or decitabine), or venetoclax including prior treatment for myelodysplastic syndrome (MDS), b) Chimeric Antigen Receptor (CAR)-T cell therapy, c) Investigational therapies for MDS or AML.
  15. Participants who cannot discontinue concomitant prophylactic antifungal therapy with CYP3A inhibitor activity or other concomitant medications with moderate or strong CYP3A inhibitor activity ≥7 days or 5 half-lives, whichever is greater, prior to cycle 1 day 1 (C1D1).
  16. Participants who cannot discontinue concomitant drugs that are strong CYP3A or P-gp inhibitors ≥7 days or 5 half-lives, whichever is greater, prior to C1D1.
  17. Participants who cannot avoid concomitant drugs known as moderate or strong CYP3A inducers.
  18. Current participation in another research or observational study.
  19. Known or suspected hypersensitivity to decitabine, cedazuridine, venetoclax, or any of their excipients.
  20. 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 noncompliance with the protocol.
  21. Patients who consume grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit ≤7 days prior to C1D1.

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): NCT04657081


Contacts
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Contact: Jacki Dillingham 925-560-0100 Jacki.Dillingham@astx.com

Locations
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United States, California
USC Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Casey O'Connell    323-865-3000      
Stanford University Recruiting
Palo Alto, California, United States, 94306
Contact: Gabriel Mannis    650-498-6000      
United States, Illinois
The University of Chicago Medical Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Olatoyosi Odenike    773-702-3354      
United States, New York
Roswell Park Comprehensive Cancer Center Recruiting
Buffalo, New York, United States, 14263
Contact: Elizabeth Griffiths, MD    716-845-7110      
Weill Cornell Medical College Recruiting
New York, New York, United States, 10065
Contact: Gail Roboz    646-962-2700    gar2001@med.cornell.edu   
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232-6307
Contact: Michael Savona       michael.savona@vumc.org   
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Courtney DiNardo    713-794-1141    cdinardo@mdanderson.org   
Sponsors and Collaborators
Astex Pharmaceuticals, Inc.
Investigators
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Study Director: Kim-Hien Dao, DO, PhD Astex Pharmaceuticals, Inc.
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Responsible Party: Astex Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT04657081    
Other Study ID Numbers: ASTX727-07
First Posted: December 8, 2020    Key Record Dates
Last Update Posted: August 2, 2021
Last Verified: July 2021
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
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Decitabine
Venetoclax
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors