A Multi-phase Study of ASTX030 (Azacitidine and Cedazuridine) in Myeloid Neoplasm Alone or in Combination With Venetoclax in AML (AZTOUND Study)

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)

Overview

Study ASTX030-01 is a multi-phase study comprising of Phases 1-3 Monotherapy arms, and Phase 1 and Phase 2 Combination Therapy arms. 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 treatment-naïve AML. Phase 2 Combination Therapy is an open-label, single arm, study evaluating the efficacy, safety, pharmacokinetics (PK), and drug interactions of ASTX030 in combination with venetoclax in participants with treatment-naïve AML. The duration of this multi-phase study is approximately 8 years.

Detailed description

The Phase 1 and Phase 2 Monotherapy arms have completed enrollment. The Phase 3 Monotherapy, Phase 1 Combination Therapy, and Phase 2 Combination Therapy arms are open for enrollment.

Interventions

• Drug Azacitidine
  Tablets/Capsules for oral administration and powder for reconstitution to aqueous suspension for SC administration.
• Drug ASTX030 (cedazuridine + azacitidine)
  FDC Capsules for oral administration.
• Drug Azacitidine
  Powder for reconstitution to aqueous suspension for SC administration.
• Drug ASTX030 (cedazuridine + azacitidine)
  Tablets/Capsules for oral administration.
• Drug Cedazuridine
  Tablets for oral administration.
• Drug Venetoclax
  Oral tablets.

Primary outcome measures

• Phase 1, 2 and 3 Monotherapy: Total Cycle Area Under the Curve (AUC) From 0 to 24 Hours (AUC0-24) Exposures [Time frame: Predose and at multiple timepoints post-dose up to 24 hours]
• Phase 1 Combination Therapy: Number of Participants with Treatment-emergent Adverse Events (TEAEs) [Time frame: Up to 24 months]
• Phase 1 and 2 Combination Therapy: Complete Response (CR) Rate as Assessed by the Investigator [Time frame: Up to 36 months]
• Phase 1 Combination Therapy: AUC0-24 of Venetoclax With ASTX030 [Time frame: Pre-dose and at multiple timepoints post-dose up to 24 hours on Day 7 (with ASTX030] of Cycle 1]
• Phase 1 Combination Therapy: AUC0-24 of Venetoclax Without ASTX030 [Time frame: Pre-dose and at multiple timepoints post-dose up to 24 hours on Day 14 (without ASTX030) of Cycle 1]
• Phase 1 Combination Therapy: Maximum Plasma Concentration (Cmax) of Venetoclax With ASTX030 [Time frame: Pre-dose and at multiple timepoints post-dose up to 24 hours on Day 7 (with ASTX030] of Cycle 1]
• Phase 1 Combination Therapy: Cmax of Venetoclax Without ASTX030 [Time frame: Pre-dose and at multiple timepoints post-dose up to 24 hours on Day 14 (without ASTX030) of Cycle 1]

Secondary outcome measures (12)

• Phase 1, 2 and 3 Monotherapy: Number of Participants with Treatment-emergent Adverse Events (TEAEs) [Time frame: Up to 36 months]
• Phase 1, 2 and 3 Monotherapy: Change in Deoxyribonucleic Acid (DNA) Methylation [Time frame: Baseline in Phase 1 to the end of Cycle 2 in Phase 3 (28 days per cycle)]
• Phase 1, 2 and 3 Monotherapy: Best CR Rate in Participants with MDS, CMML, or MDS/Myeloproliferative Neoplasms (MPN) [Time frame: Up to 36 months]
• Phase 1, 2 and 3 Monotherapy: AML-free Survival for Participants with MDS, CMML, or MDS/MPN [Time frame: Up to 36 months]
• Phase 1, 2 and 3 Monotherapy: Duration of Response [Time frame: Up to 36 months]
• Phase 1, 2 and 3 Monotherapy: Overall Survival [Time frame: Up to 36 months]
• Phase 1, 2 and 3 Monotherapy: Time to Response [Time frame: Up to 36 months]
• Phase 1, 2 and 3 Monotherapy: Red Blood Cell (RBC) Transfusion Independence (TI) [Time frame: Up to 36 months]
• Phase 1, 2 and 3 Monotherapy: Platelet Transfusion Independence (TI) [Time frame: Up to 36 months]
• Phase 1, 2 and 3 Monotherapy: AUC of Azacitidine, Cedazuridine and Cedazuridine-epimer [Time frame: Predose and at multiple timepoints post-dose on Days 1, 2 and 7 of Cycle 1 and Cycle 2 (cycle length=28 days)]
• Phase 1, 2 and 3 Monotherapy: Cmax of Azacitidine, Cedazuridine and Cedazuridine-epimer [Time frame: Predose and at multiple timepoints post-dose on Days 1, 2 and 7 of Cycle 1 and Cycle 2 (cycle length=28 days)]
• Phase 1, 2 and 3 Monotherapy: Time to Reach Cmax (Tmax) of Azacitidine, Cedazuridine and Cedazuridine-epimer [Time frame: Predose and at multiple timepoints post-dose on Days 1, 2 and 7 of Cycle 1 and Cycle 2 (cycle length=28 days)]

Eligibility criteria

Inclusion criteria

• Phase 2 Monotherapy:

1\. 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.

• Phase 3 Monotherapy:

• Has 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:

a) 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).

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Participants with adequate organ function.
• For participants with prior allogeneic stem cell transplant, no evidence of graft-versus-host disease (GVHD).
• Participants with no major surgery within 3 weeks before first study treatment.
• Participants with no cytotoxic chemotherapy (excluding hydroxyurea) within 4 weeks before first study treatment.
• Is able to swallow the number of tablets/capsules required for the treatment assignment within a 10-minute period and tolerate 4 hours of fasting.
• Participants with projected life expectancy of at least 12 weeks.
• Phase 1 and Phase 2 Combination Therapy:

• Has histological confirmation of newly diagnosed AML by World Health Organization (WHO) 2022 criteria (Phase 1) or 2016 criteria (Phase 2).
• Participants with projected life expectancy of at least 12 weeks.
• Must be considered ineligible for intensive induction chemotherapy defined by the following:

a. 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).

ii. 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).

v. ECOG Performance Status of 2 or 3.

• Has 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

• All Monotherapy Phases:

• Has an active uncontrolled gastric or duodenal ulcer.
• Has poor medical risk because of other conditions.
• Has known human immunodeficiency virus (HIV) infection.
• Is known to be positive for Hepatitis B or C infection.
• Has a life-threatening illness.
• Has 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.
• Participants with MDS/MPN including CMML who have clinical extramedullary disease including clinically palpable hepatomegaly or splenomegaly.
• Has previous treatment with more than 1 cycle of decitabine, azacitidine, or guadecitabine (Phases 2 and 3 only).
• Has 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.
• Has a known or suspected hypersensitivity to cedazuridine or azacitidine or any of their excipients.
• Cannot 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.
• Has a known or suspected hypersensitivity to cedazuridine or azacitidine or any of their excipients.
• Phase 1 and Phase 2 Combination Therapy:

• Has 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.
• Has the following karyotype abnormalities: t(15;17) or other acute promyelocytic leukemia variants that remain sensitive to all-trans retinoic acid (ATRA) therapy \[t(8;21) and inv(16) are excluded in Phase 2 only\].
• Has known active central nervous system involvement from AML.
• Has known human immunodeficiency virus (HIV) infection.
• Is known to be positive for Hepatitis B or C infection.
• Has severe hepatic impairment
• Has severe renal impairment
• Has a malabsorption syndrome or other condition that precludes enteral route of administration.
• Has a cardiovascular disability status of New York Heart Association Class >2.
• Has 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.
• Has clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal).
• Has 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.
• Has a WBC count >25,000/ microliters (μL) (hydroxyurea treatment is permitted to meet this criterion).
• Has received treatment with any of the following:

• A hypomethylating agent (azacitidine or decitabine) or venetoclax, including prior treatment for MDS.
• Chimeric Antigen Receptor (CAR)-T cell therapy.
• Investigational therapies for MDS or AML.
• Cannot discontinue treatment with any of the following:

• Prophylactic 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).
• Drugs that are strong CYP3A or P-gp inhibitors ≥7 days or 5 half-lives, whichever is greater, prior to C1D1.
• Cannot avoid concomitant drugs known as moderate or strong CYP3A inducers.
• Cannot 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.
• Is participating in another research study requiring interventions such as drug therapy or study procedures.
• Has a known or suspected hypersensitivity to cedazuridine, azacitidine, venetoclax, or any of their excipients.
• Has known significant mental illness or other conditions such as alcohol or other substance abuse or addictions
• Consumes grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit ≤7 days prior to C1D1.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 24 centers

• Keck School of Medicine of USC — Los Angeles
• UC Irvine Health - Chao Family Comprehensive Cancer Center — Orange
• Yale University — New Haven
• University of Miami - Sylvester Comprehensive Cancer Center — Miami
• University of Emory - Winship Cancer Institute — Atlanta
• Dana-Farber Cancer Institute — Boston
• John Theurer Cancer Center / Hackensack University — Hackensack
• Roswell Park Comprehensive Cancer Center — Buffalo
• … and 16 more centers

Spain · 16 centers

• Institut Català d'Oncologia Badalona — Badalona
• Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet) — L'Hospitalet de Llobregat
• Clinica Universidad de Navarra - Pamplona — Pamplona
• Hospital Universitario Central de Asturias — Oviedo
• Hospital Universitari Vall d'Hebrón — Barcelona
• Hospital Clinic de Barcelona — Barcelona
• Hospital San Pedro de Alcantara — Cáceres
• Institut Català d'Oncologia Girona (ICO Girona) — Girona
• … and 8 more centers

Italy · 9 centers

• Ospedale Santa Maria delle Croci di Ravenna — Ravenna
• Azienda Ospedaliero - Universitaria Careggi — Florence
• Azienda Ospedaliera Ordine Mauriziano di Torino — Torino
• Azienda Ospedaliero-Universitaria di Bologna - Policlinico Sant Orsola-Malpighi — Bologna
• Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico — Milan
• Azienda Ospedaliero-Universitaria Maggiore della Carità di Novara — Novara
• Fondazione PTV - Policlinico Tor Vergata — Roma
• Umberto I - Policlinico di Roma — Roma
• … and 1 more center

Germany · 4 centers

• Universitätsklinikum Freiburg — Freiburg im Breisgau
• Universitätsklinikum Heidelberg — Heidelberg
• Städtisches Klinikum Braunschweig — Braunschweig
• Universitätsklinikum Halle — Halle

Hungary · 4 centers

• Szent-Györgyi Albert Klinikai Központ, II. sz. Belgyógyászati Klinika és Kardiológiai Közp — Szeged
• Petz Aladár Győr-Moson-Sopron Vármegyei Egyetemi Oktató Kórház — Győr
• Debreceni Egyetem Klinikai Központ — Debrecen
• Semmelweis Egyetem Belgyógyászati és Hematológiai Klinika — Budapest

Czechia · 3 centers

• Fakultni Nemocnice Ostrava — Ostrava
• Fakultní Nemocnice Královské Vinohrady — Prague
• Vseobecna Fakultni Nemocnice v Praze — Prague

France · 3 centers

• Institut Universitaire du Cancer de Toulouse (IUCT) Oncopole — Toulouse
• Hôpital l'Archet — Nice
• Hôpital Saint-Louis — Paris

Poland · 3 centers

• Samodzielny Publiczny Szpital Kliniczny nr 1 w Lublinie — Lublin
• Wojewódzkie Wielospecjalistyczne Centrum — Lodz
• Szpitale Pomorskie Spółka Z Ograniczoną Odpowiedzialnością — Gdynia

United Kingdom · 3 centers

• King's College Hospital NHS Foundation Trust — London
• The Christie NHS Foundation Trust — Manchester
• University Hospital Southampton NHS Foundation Trust — Southampton

Canada · 2 centers

• Eastern Health - Health Sciences Centre — St. John's
• Princess Margaret Cancer Centre — Toronto

Identifiers

NCT: NCT04256317 · ASTX030-01 · 2024-515098-93

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗