Clinical Trials /

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

NCT04657081

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: ASTX727-07
  • NCT ID: NCT04657081

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Decitabine and Cedazuridine (ASTX727)INQOVIOral administration of ASTX727 and venetoclax combination
VenetoclaxVenclextaOral administration of ASTX727 and venetoclax combination

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Oral administration of ASTX727 and venetoclax combinationExperimentalCycle 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.
  • Decitabine and Cedazuridine (ASTX727)
  • Venetoclax

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pharmacokinetic parameter: AUC0-24
Time Frame:On Days 5 and 15 in Cycle 2 (28 days per cycle)
Safety Issue:
Description:Venetoclax area under the curve from time 0 to 24 hours (AUC0-24) with and without ASTX727.

Secondary Outcome Measures

Measure:Pharmacokinetic parameter: AUC0-24
Time Frame:Days 1, 2 and 5 in Cycle 2 (28 days per cycle)
Safety Issue:
Description:Decitabine area under the curve from time 0 to 24 hours (AUC0-24).
Measure:Pharmacokinetic parameter: Cmax
Time Frame:Days 1, 2 and 5 in Cycle 2 (28 days per cycle)
Safety Issue:
Description:Decitabine and cedazuridine maximum observed concentration (Cmax).
Measure:Pharmacokinetic parameter: AUC0-8
Time Frame:Days 1, 2 and 5 in Cycle 2 (28 days per cycle)
Safety Issue:
Description:Cedazuridine area under the curve from time 0 to 8 hours (AUC0-8).
Measure:Pharmacokinetic parameter: 5-day AUC
Time Frame:Days 1 to 5 in Cycle 2 (28 days per cycle)
Safety Issue:
Description:Decitabine 5-day cumulative AUC.
Measure:Safety: Participants with TEAEs
Time Frame:Up to 24 months
Safety Issue:
Description:Number of participants with treatment-emergent adverse events (TEAEs)
Measure:Complete response (CR)
Time Frame:Up to 24 months
Safety Issue:
Description:Number of participants with CR, CR + complete response with partial hematological recovery (CRh), and CR + incomplete blood count recovery (CRi).
Measure:Time to Response
Time Frame:Up to 24 months
Safety Issue:
Description:Number of days from the first dose to the first documented evidence of complete response or CRh.
Measure:Duration of Response
Time Frame:Up to 24 months
Safety Issue:
Description:Number of days from the start of response (CR or CRh) until disease progression, start of alternative antileukemia therapy, or death.
Measure:Overall Response
Time Frame:Up to 24 months
Safety Issue:
Description:Number of days from date of first dose until death due to any cause.

Details

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

Last Updated

March 25, 2021