Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral Cytidine Deaminase Inhibitor (CDAi) in Patients With Myelodysplastic Syndromes (MDS)

NCT02103478 | Completed Phase 1 Results DMC

• 1 other identifier: ASTX727-01
• Study Type: interventional
• Target: 130
• Locations: 2 countries
• Sites: 17

Brief Summary

This first-in-human, 3-stage, open-label study evaluated the safety and pharmacokinetics of ASTX727, as well as determined the dose for later stages.

Conditions

Myelodysplastic Syndrome; MDS

Keywords

Myelodysplastic Syndrome; MDS

Outcome Measures

Primary Outcomes (5)

• Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1

  Mean AUC0-t of oral decitabine given with cedazuridine (E7727) following IV decitabine 20 mg/m\^2 infusion on Day 5. AUCs were calculated by the linear up/log down method using the measured concentration-time values above the BQL (below the limit of quantification).

  Day 5

• Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2

  Decitabine 5-day AUC ratio following IV decitabine 20 mg/m\^2 infusion versus concomitant oral administration of decitabine + cedazuridine (E7727) or ASTX727 in the dose combination and fixed-dose combination stages, respectively. AUC0-t (the area under the concentration-time curve from time zero to the time of the last (tlast) quantifiable concentration (Ct)) by dose/cohort and course/days was used for estimating decitabine cumulative 5-day AUC0-t exposures.

  Pre-dose to Day 5

• Number of Participants With Dose-limiting Toxicity in Phase 1

  Number of participants with protocol-specified dose-limiting toxicities (DLTs) in the dose escalation stage. DLTs were defined using the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAEv4.0), specifically ≥ Grade 3 non-hematologic toxicity (except Grade 3 nausea, vomiting, or diarrhea that is controllable by anti-emetics or optimal therapy or related to underlying disease or disease progression), specific Grade 3 laboratory tests, related prolonged Grade 4 thrombocytopenia or neutropenia that was not present prior to dosing, does not resolve within 14 days, and is not related to underlying disease, or any toxicity related to study treatment that results in treatment delays of \>4 weeks after Day 28.

  Up to Day 28 in Course 1 (28 days per course)

• Mean Maximum %LINE Demethylation in Phase 2

  Mean maximum % long interspread nuclear element-1 (LINE-1) demethylation after oral decitabine + cedazuridine (E7727) or ASTX727 (Course 1 or Course 2 - Treatment) compared with IV decitabine 20 mg/m\^2 (Course 1 or Course 2 - IV Decitabine) in the dose confirmation and fixed-dose combination stages, respectively. Least squares mean of maximum %LINE-1 methylation change from baseline.

  Pre-dose to Day 28 in Course 2 (28 days per course)

• Number of Participants With Overall Response in Phase 2

  The evaluation of response was based on International Working Group (IWG) 2006 MDS Response Criteria, with overall response calculated as number of participants with complete response+partial response+marrow complete response+hematological improvement (CR+PR+mCR+HI).

  Up to approximately 29 months

Secondary Outcomes (14)

• Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer

  At specified timepoints from 0 to 24 hours post-dose

• Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer

  At specific timepoints from 0 to 24 hours post-dose

• Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer

  At specific timepoints from 0 to 24 hours post-dose

• Maximum Observed Plasma Concentration (Cmax) of Decitabine

  At specific timepoints from 0 to 24 hours post-dose

• Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2

  At specific timepoints from 0 to 24 hours post-dose

Study Arms (3)

Phase 1 Dose Escalation

EXPERIMENTAL

Starting cohort was administered 40 mg oral cedazuridine and 20 mg oral decitabine. Participants were enrolled into successive cohorts in which either the cedazuridine or decitabine oral dose was varied in Course 1 Day 2 through Course 1 Day 5 for comparison with a single dose of IV decitabine at 20 mg/m\^2 administered on Day 1 by continuous IV infusion over 1 hour (28 days per course).

Drug: ASTX727 Dose Escalation

Phase 2 Dose Confirmation

EXPERIMENTAL

Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (E7727) (100 mg) + decitabine (35 mg) capsules Dailyx5 in Course 1 followed by IV decitabine (20 mg/m\^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.

Drug: ASTX727 Dose Confirmation

Phase 2 Fixed-Dose Combination

EXPERIMENTAL

Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine (E7727)/35 mg decitabine) Dailyx5 in Course 1 followed by IV decitabine (20 mg/m\^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, all participants received the FDC tablet Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.

Drug: ASTX727 Fixed-Dose Combination

Interventions

ASTX727 Dose Escalation DRUG

Oral investigational product and approved IV decitabine

Also known as: cedazuridine (E7727), oral decitabine, IV decitabine

Phase 1 Dose Escalation

ASTX727 Dose Confirmation DRUG

Randomization cross over design for courses 1 and 2

Also known as: ASTX727 oral (combination of oral E7727 and oral decitabine), IV decitabine

Phase 2 Dose Confirmation

ASTX727 Fixed-Dose Combination DRUG

Fixed-dose investigational product

Also known as: ASTX727 oral (combination of oral E7727 and oral decitabine)

Phase 2 Fixed-Dose Combination

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• International Prognostic Scoring System (IPSS) low, intermediate -1, intermediate-2, or high risk MDS (including chronic myelomonocytic leukemia; CMML) in Dose Escalation and Dose Confirmation-Randomization; only intermediate-2, or high risk MDS in Dose Confirmation-Open Label
• Eastern Cooperative Oncology Group (ECOG) 0 to 2
• No major surgery within 2 weeks of starting study treatment
• No cytotoxic chemotherapy within 2 weeks of starting study treatment
• Able to swallow pills

You may not qualify if:

• Previous treatment with 2 or more courses of decitabine (all stages) or azacitidine (Dose Confirmation stage only)
• Treatment with investigational therapy within 2 weeks of study treatment
• Uncontrolled medical disease(s) or active, uncontrolled infection
• Diagnosed with acute myeloid leukemia (AML)
• Active uncontrolled gastric or duodenal ulcer
• Known history of HIV or hepatitis C or B

Sponsors & Collaborators

• Astex Pharmaceuticals, Inc.: lead

Study Sites (17)

Mayo Clinic

Phoenix, Arizona, 85054, United States

Location

University of Southern California

Los Angeles, California, 90024, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Horizon Oncology

Lafayette, Indiana, 47905, United States

Location

Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

John Theurer Cancer Center/ Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Weill Cornell Medical College - New York Presbyterian Hospital

New York, New York, 10021, United States

Location

Vanderbilt Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

M. D. Anderson

Houston, Texas, 77030, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

University of Alberta Hospital

Edmonton, Alberta, T6G 2G3, Canada

Location

Sunnybrook Health Sciences Centre, Odette Cancer Centre

Toronto, Ontario, M4N 3M5, Canada

Location

Princess Margaret Cancer Center

Toronto, Ontario, M5G 2M9, Canada

Location

Hôpital Maisonneuve-Rosemont

Montreal, Quebec, H1T 2M4, Canada

Location

Related Publications (2)

• Garcia-Manero G, Griffiths EA, Steensma DP, Roboz GJ, Wells R, McCloskey J, Odenike O, DeZern AE, Yee K, Busque L, O'Connell C, Michaelis LC, Brandwein J, Kantarjian H, Oganesian A, Azab M, Savona MR. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020 Aug 6;136(6):674-683. doi: 10.1182/blood.2019004143.

  PMID: 32285126 DERIVED

• Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, Faderl S, Harb W, Kantarjian H, Lowder J, Oganesian A, Azab M, Garcia-Manero G. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019 Apr;6(4):e194-e203. doi: 10.1016/S2352-3026(19)30030-4.

  PMID: 30926081 DERIVED

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

cedazuridine; Decitabine; decitabine and cedazuridine drug combination

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Taiho Central
• Organization: Taiho Oncology, Inc.

clinicaltrialinfo@taihooncology.com

609-250-7336

Study Officials

• Mohammad Azab, MD

  Astex Pharmaceuticals, Inc.

  STUDY DIRECTOR

• James Lowder, MD

  Astex Pharmaceuticals, Inc.

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 20, 2014
• First Posted: April 4, 2014
• Study Start: October 28, 2014
• Primary Completion: June 5, 2018
• Study Completion: December 4, 2019
• Last Updated: August 27, 2024
• Results First Posted: October 19, 2020

Record last verified: 2024-07

Locations

CA (4); US (13)