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

Astex Pharmaceuticals

Status and phase: Completed; Phase 2; Phase 1

Conditions: MDS; Myelodysplastic Syndrome

Treatments: Drug: ASTX727 Dose Escalation; Drug: ASTX727 Fixed-Dose Combination; Drug: ASTX727 Dose Confirmation

Study type: Interventional

Funder types: Industry

Identifiers

NCT02103478

ASTX727-01

Details and patient eligibility

About

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.

Full description

The trial was designed to define daily doses of the individual components (cedazuridine [E7727] or decitabine) so that decitabine exposure after oral administration would be comparable to exposure after IV decitabine at the approved daily dose of 20 mg/m^2. The main objective of Phases 1 and 2 was to establish and confirm the doses of the 2 components to be used in the final fixed-dose combination (FDC) product (ASTX727) using mainly pharmacokinetics and pharmacodynamics as endpoints.

Enrollment: 130 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 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

Exclusion criteria

• 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

---

130 participants in 3 patient groups

Phase 1 Dose Escalation

Experimental group

Description:

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).

Treatment:

Drug: ASTX727 Dose Escalation

Phase 2 Dose Confirmation

Experimental group

Description:

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.

Treatment:

Drug: ASTX727 Dose Confirmation

Phase 2 Fixed-Dose Combination

Experimental group

Description:

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.

Treatment:

Drug: ASTX727 Fixed-Dose Combination