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Official Title

A Multi-phase, Pharmacokinetics, Safety, and Efficacy Study of ASTX030 (Azacitidine and Cedazuridine) as Monotherapy in Subjects With Myeloid Neoplasm or in Combination With Venetoclax in Subjects With AML (AZTOUND Study)

Phase
Phase 2/Phase 3
Sponsor
Taiho Oncology, Inc.
Enrollment
236
Timeline
May 2020 → May 2028
About This Study

Study ASTX030-01 is a multi-phase study comprising of Phases 1-3 Monotherapy arms and a Phase 1 Combination Therapy arm Phase 1 Monotherapy consists of an open-label Dose Escalation Stage (Stage A) using multiple cohorts at escalating dose levels of oral cedazuridine and azacitidine (only one study drug will be escalated at a time) followed by a Dose Expansion Stage (Stage B). Phase 2 Monotherapy is a randomized, open-label, crossover study to compare oral ASTX030 to subcutaneous (SC) azacitidine. Phase 3 Monotherapy is a randomized open-label crossover study comparing the final fixed dose of oral ASTX030 to SC azacitidine. Phase 1 Combination Therapy is an open-label, multicenter, randomized, exploratory study comparing ASTX030 and SC azacitidine in combination with venetoclax in participants with AML. The duration of this multi-phase study is approximately 7 years.

Eligibility Criteria

Inclusion Criteria

  • 1Phase 2 Monotherapy:
  • 21\. Has Confirmed MDS, CMML, or other MDS/MPN diagnosis who are candidates to receive and benefit from single agent azacitidine and as applicable according to local country approvals and/or local institution standard practice.
  • 3Phase 3 Monotherapy:
  • 4Has confirmed MDS or CMML and is a candidate to receive and benefit from single agent azacitidine as applicable according to local country approvals and/or local institution standard practice:
  • 5a) French-American-British myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and CMML or MDS with intermediate-2 or high risk MDS according to the International Prognostic Scoring System (IPSS).
  • 6Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
  • 7Participants with adequate organ function.
  • 8For participants with prior allogeneic stem cell transplant, no evidence of graft-versus-host disease (GVHD).
  • 9Participants with no major surgery within 3 weeks before first study treatment.
  • 10Participants with no cytotoxic chemotherapy (excluding hydroxyurea) within 4 weeks before first study treatment.
  • 11Is able to swallow the number of tablets/capsules required for the treatment assignment within a 10-minute period and tolerate 4 hours of fasting.
  • 12Participants with projected life expectancy of at least 12 weeks.
  • 13Phase 1 Combination Therapy:
  • 14Has histological confirmation of newly diagnosed AML by World Health Organization (WHO) 2022 criteria.
  • 15Participants with projected life expectancy of at least 12 weeks.
  • 16Must be considered ineligible for intensive induction chemotherapy defined by the following:
  • 17a. Aged 75 years or older, or b. Aged 18 to 74 years with at least one of the following comorbidities: i. Severe cardiac disorder (e.g., congestive heart failure requiring treatment, ejection fraction ≤50%, or chronic stable angina).
  • 18ii. Severe pulmonary disorder (e.g., 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).
  • 19v. ECOG Performance Status of 2 or 3.
  • 20Has an ECOG Performance Status of 0-2 for participants ≥75 years of age or 0-3 for participants 18 to 74 years of age.

Exclusion Criteria

  • 1All Monotherapy Phases:
  • 2Has an active uncontrolled gastric or duodenal ulcer.
  • 3Has poor medical risk because of other conditions.
  • 4Has known human immunodeficiency virus (HIV) infection.
  • 5Is known to be positive for Hepatitis B or C infection.
  • 6Has a life-threatening illness.
  • 7Has a 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.
  • 8Participants with MDS/MPN including CMML who have clinical extramedullary disease including clinically palpable hepatomegaly or splenomegaly.
  • 9Has previous treatment with more than 1 cycle of decitabine, azacitidine, or guadecitabine (Phases 2 and 3 only).
  • 10Has been treated with any investigational drug or therapy within 2 weeks, or 5 half-lives, whichever is longer, before the protocol-defined first dose of study treatment, or ongoing clinically significant adverse events from previous treatment with investigational drug or therapy.
  • 11Has a known or suspected hypersensitivity to cedazuridine or azacitidine or any of their excipients.
  • 12Cannot discontinue treatment with any drugs that delay gastric emptying such as glucagon-like peptide-1 (GLP-1) and/or gastric inhibitory polypeptide (GIP) agonists in Cycles 1 and 2 of the study.
  • 13Has a known or suspected hypersensitivity to cedazuridine or azacitidine or any of their excipients.
  • 14Phase 1 Combination Therapy:
  • 15Has a history of MPN including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia with or without BCR-ABL1 translocation, or AML with BCR-ABL1 translocation.
  • 16Has the following karyotype abnormalities: t(15;17) or other acute promyelocytic leukemia variants that remain sensitive to all-trans retinoic acid (ATRA) therapy.
  • 17Has known active central nervous system involvement from AML.
  • 18Has known human immunodeficiency virus (HIV) infection.
  • 19Is known to be positive for Hepatitis B or C infection.
  • 20Has severe hepatic impairment
  • 21Has severe renal impairment
  • 22Has a malabsorption syndrome or other condition that precludes enteral route of administration.
  • 23Has a cardiovascular disability status of New York Heart Association Class \>2.
  • 24Has significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular, or pulmonary disease; or any other medical condition that in the opinion of the investigator would adversely affect his/her participation in this study.
  • 25Has clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal).
  • 26Has a 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.
  • 27Has a WBC count \>25,000/ microliters (μL) (hydroxyurea treatment is permitted to meet this criterion).
  • 28Has received treatment with any of the following:
  • 29A hypomethylating agent (azacitidine or decitabine) or venetoclax, including prior treatment for MDS.
  • 30Chimeric Antigen Receptor (CAR)-T cell therapy.
  • 31Investigational therapies for MDS or AML.
  • 32Cannot discontinue treatment with any of the following:
  • 33Prophylactic antifungal therapy with CYP3A inhibitor activity or other concomitant medications with moderate or strong CYP3A inhibitor activity ≥7 days or 5 halflives, whichever is greater, prior to Cycle 1 Day 1 (C1D1).
  • 34Drugs that are strong CYP3A or P-gp inhibitors ≥7 days or 5 half-lives, whichever is greater, prior to C1D1.
  • 35Cannot avoid concomitant drugs known as moderate or strong CYP3A inducers.
  • 36Cannot discontinue treatment with any drugs that delay gastric emptying such as GLP-1 and/or GIP agonists in Cycles 1 and 2 of the study.
  • 37Is participating in another research study requiring interventions such as drug therapy or study procedures.
  • 38Has a known or suspected hypersensitivity to cedazuridine, azacitidine, venetoclax, or any of their excipients.
  • 39Has known significant mental illness or other conditions such as alcohol or other substance abuse or addictions
  • 40Consumes grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit ≤7 days prior to C1D1.

Locations

73 sites participating in this study

University of Emory - Winship Cancer Institute

Atlanta, Georgia 30322

Recruiting

Keck School of Medicine of USC

Los Angeles, California 90089

Recruiting

UC Irvine Health - Chao Family Comprehensive Cancer Center

Orange, California 92868

Recruiting
Data sourced from ClinicalTrials.govView on ClinicalTrials.gov →