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Pharmacokinetics, Safety, and Efficacy of ASTX727 in Combination With Venetoclax in Acute Myeloid Leukemia (AML)
Trial ID: NCT04657081
The Phase 1 portion of this study is a single-arm, open-label, multicenter, non-randomized interventional study to evaluate the pharmacokinetic (PK) interaction, safety, and 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. The Phase 2 portion of the study is to assess the efficacy of ASTX727 and venetoclax when given in combination and to evaluate potential PK interactions. Phase 2 will follow the same overall study design as Phase 1 and has two parts, Part A and Part B.
A Single-Arm, Open-Label Pharmacokinetic, Safety, and Efficacy Study of ASTX727 in Combination With Venetoclax in Adult Patients With Acute Myeloid Leukemia
1. Participant must be 18 years of age or older.
2. Histological confirmation of newly diagnosed AML by World Health Organization (WHO)
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), v) Phase 1: Eastern Cooperative Oncology Group
(ECOG) Performance Status of 2 (participants with ECOG ≥3 are not eligible); Phase 2,
Parts A and B: ECOG Performance Status of 2 or 3 (participants with ECOG 4 are not
5. Phase 1: ECOG Performance Status of 0-2; Phase 2, Parts A and B: ECOG 0-3.
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 a highly
effective contraceptive measure 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 legally effective 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.
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
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
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
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
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
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
18. Current participation in another research study requiring interventions such as drug
therapy or study procedures.
19. Known or suspected hypersensitivity to decitabine, cedazuridine, venetoclax, or any of
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. Participants who consume grapefruit, grapefruit products, Seville oranges (including
marmalade containing Seville oranges) or starfruit ≤7 days prior to C1D1.
drug: Decitabine and Cedazuridine (ASTX727)