Pharmacokinetic, Safety, and Efficacy Evaluation of ASTX727 and Venetoclax in Adult Patients with Acute Myeloid Leukemia
- Trial ID
- 2024-516294-78-00
- Protocol
- ASTX727-07
- Sponsor
- Taiho Oncology Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the potential of **drug-drug interactions** by assessing the effect of ASTX727 on the pharmacokinetics (PK) of venetoclax in patients with **Acute Myeloid Leukemia (AML)**. This is clinically relevant as understanding these interactions can optimize therapeutic strategies and improve patient outcomes by ensuring effective and safe drug administration.
Secondary objectives include:
- Evaluating the potential of drug-drug interactions: effect of venetoclax on the PK of ASTX727.
- Assessing the safety of ASTX727 and venetoclax combination therapy.
- Evaluating clinical response with the combination therapy.
- Assessing preliminary efficacy as determined by time-to-event endpoints with the combination therapy.
- Evaluating secondary PK parameters of venetoclax, decitabine, and cedazuridine.
- Evaluating composite clinical response rates with the combination therapy.
Participants
The clinical trial involves a total of **120 participants** diagnosed with **Acute Myeloid Leukemia (AML)**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including a histological confirmation of newly diagnosed AML according to the World Health Organization 2016 criteria. The trial targets individuals who are ineligible for intensive induction chemotherapy, either due to age (75 years or older) or the presence of significant comorbidities such as severe cardiac or pulmonary disorders, moderate hepatic impairment, or reduced creatinine clearance. The trial also considers the Eastern Cooperative Oncology Group (ECOG) Performance Status, with eligible participants having a status of 0-2 for Phase 1 and 0-3 for Phase 2. The study population is characterized by a projected life expectancy of at least three months and the capability to provide legally effective informed consent. Participants' lifestyle factors, such as diet and physical activity, are not specified in the available data. The trial includes a vulnerable population, indicating additional ethical considerations in the study design.
Plans and Procedures
The clinical trial is designed as a **single-arm, open-label** study to evaluate the pharmacokinetics, safety, and efficacy of the combination of **ASTX727** and **venetoclax** in adult patients diagnosed with **Acute Myeloid Leukemia (AML)**. The trial is structured into two phases: Phase I and Phase II, with the primary objective of assessing the potential drug-drug interaction effects of ASTX727 on the pharmacokinetics of venetoclax, as well as evaluating the clinical response to the combination therapy. The trial is expected to conclude by November 26, 2025, with recruitment having commenced on March 1, 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of AML, and ineligibility for intensive induction chemotherapy. The trial will include follow-up visits to monitor the pharmacokinetic parameters and clinical response, with the primary endpoints being the venetoclax area under the curve (AUC) and maximum concentration (Cmax) on specified days of the treatment cycle. Secondary endpoints will include the incidence and severity of adverse events, as well as other safety assessments.
The expected duration of participant involvement varies depending on the phase of the trial, with the maximum treatment period for ASTX727 being 112 days and for venetoclax being 630 days. Participants may be subject to early termination from the study if they experience severe adverse events, fail to comply with the study protocol, or withdraw consent. The study aims to provide valuable insights into the efficacy and safety of the combination therapy in treating AML, contributing to the broader understanding of potential treatment options for this condition.
Treatment
The clinical trial involves the administration of **ASTX727**, a combination of **decitabine** and **cedazuridine**, provided in tablet form. This experimental medication is administered orally. The maximum daily dose is 999 mg, with a total treatment period of up to 112 days. The active substances, decitabine and cedazuridine, are both of chemical origin. The primary objective of the trial is to evaluate the pharmacokinetic interactions and clinical response when combined with venetoclax in patients with acute myeloid leukemia.
**Venetoclax** is used as a non-experimental treatment in this study. It is available in film-coated tablet form and is administered orally. Venetoclax is provided in three different dosages: 10 mg, 50 mg, and 100 mg tablets, marketed under the name Venclyxto by AbbVie Deutschland GmbH & Co. KG. The maximum daily dose of venetoclax is 400 mg, with a total treatment period of up to 630 days. Venetoclax is also of chemical origin and is used to assess its interaction with ASTX727 and its efficacy in combination therapy.
Efficacy
The efficacy of the clinical trial involving the combination of ASTX727 and venetoclax in adult patients with **Acute Myeloid Leukemia** will be assessed through several primary and secondary endpoints. The primary endpoints include the evaluation of the venetoclax area under the curve (AUC0-24) and maximum concentration (Cmax) on Day 5 with ASTX727 and Day 15 without ASTX727 in Cycle 2 for Phase 1, as well as the complete remission (CR) rate for Phase 2 Parts A and B. Secondary endpoints encompass a range of pharmacokinetic and clinical response measures. These include the AUC0-24 and Cmax of decitabine and cedazuridine on Day 5 with venetoclax, the incidence and severity of adverse events, and additional clinical response rates such as CR+CRh and CR+CRi rates. Time to CR or CRh, duration of CR or CRh, and overall survival are also evaluated. Pharmacokinetic parameters such as Cmax, Cmin, Tmax, T1/2, and other secondary PK parameters are assessed for both phases. The efficacy assessments are scheduled at specific timepoints, including Days 1, 2, and 5 in Cycle 2, to ensure comprehensive data collection and analysis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be 18 years of age or older
- Histological confirmation of newly diagnosed AML by World Health Organization (WHO) 2016 criteria (Swerdlow et al 2017).
- Projected life expectancy of at least 3 months.
- 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 capacity of the lung 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 (subjects with ECOG ≥3 are not eligible); Phase 2: ECOG Performance Status of 2 or 3 (subjects with ECOG 4 are not eligible).
- For Phase 1, ECOG 0-2. For Phase 2, ECOG 0-3. Sex and Contraceptive Barrier Requirements
- Participant can be male or female. Due to section size limitations, please refer to Protocol Section 10.2 for contraception requirements.
- Capable of giving legally effective informed consent (as described in Appendix 1 [Section 10.1.3]), which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol, and willing to participate in the study.
Exclusion Criteria
- 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.
- 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
- Known active central nervous system involvement from AML.
- 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.
- 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.
- Severe hepatic impairment defined as: bilirubin >1.5×upper limit of normal (ULN) for subjects ≥75 years or >3×ULN for subjects <75 years; or aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) >3×ULN (unless abnormalities are considered to be due to leukemic organ involvement or bilirubinemia is due to known Gilbert's Syndrome).
- Severe renal impairment defined as: calculated creatinine clearance or glomerular filtration rate <30 mL/min.
- A malabsorption syndrome or other condition that precludes enteral route of administration
- 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.
- Significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular or pulmonary 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.
- Clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal).
- 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.
- WBC count >25,000/μL. (Hydroxyurea treatment is permitted to meet this criterion.)
- Treatment with the following: a) A hypomethylating agent (azacitidine or decitabine), or venetoclax including prior treatment for MDS. b) Chimeric Antigen Receptor (CAR)-T cell therapy. c) Investigational therapies for MDS or AML.
- 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 C1D1.
- 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.
- Participants who cannot avoid concomitant drugs known as moderate or strong CYP3A inducers
- Current participation in another research requiring interventions such as drug therapy or study procedures
- Known or suspected hypersensitivity to decitabine, cedazuridine, venetoclax, or any of their excipients
- 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 subject to high risk of noncompliance with the protocol.
- Patients who consume grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit ≤7 days prior to C1D1
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 01 Mar 2022 | 40 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ASTX727 | Test | TABLET | ORAL USE | 999 | 112 | PRD11224172 |
Venclyxto 50 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 400 | 630 | PRD6353830 |
Venclyxto 10 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 400 | 630 | PRD6353822 |
Venclyxto 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 400 | 630 | PRD6353842 |