Clinical Trial: NCT02103478 - My Cancer Genome

NCT02103478

Description:

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.

Related Conditions:

Myelodysplastic Syndromes

Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

URL:

https://clinicaltrials.gov/show/NCT02103478

Trial Eligibility

Document

Title

Brief Title: Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral Cytidine Deaminase Inhibitor (CDAi) in Patients With Myelodysplastic Syndromes (MDS)
Official Title: A Phase1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 With Oral Decitabine in Subjects With Myelodysplastic Syndromes (MDS)

Clinical Trial IDs

ORG STUDY ID: ASTX727-01
NCT ID: NCT02103478

Conditions

Myelodysplastic Syndrome
MDS

Interventions

Drug	Synonyms	Arms
ASTX727 Dose Escalation	cedazuridine (E7727), oral decitabine, IV decitabine	Phase 1 Dose Escalation
ASTX727 Dose Confirmation	ASTX727 oral (combination of oral E7727 and oral decitabine), IV decitabine	Phase 2 Dose Confirmation
ASTX727 Fixed-Dose Combination	ASTX727 oral (combination of oral E7727 and oral decitabine)	Phase 2 Fixed-Dose Combination

Purpose

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.

Detailed 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.

Trial Arms

Name	Type	Description	Interventions
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).	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.	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.	ASTX727 Fixed-Dose Combination

Eligibility Criteria

        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

Maximum Eligible Age:	N/A
Minimum Eligible Age:	18 Years
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1
Time Frame:	Day 5
Safety Issue:
Description:	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).

Secondary Outcome Measures

Measure:	Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer
Time Frame:	At specified timepoints from 0 to 24 hours post-dose
Safety Issue:
Description:	AUC is a measure of the plasma concentration of the drug over time (AUC0-8). PK parameters are reported for the dose escalation stage by cohort in Phase 1 and dose confirmation and fixed-dose combination stages in Phase 2.

Measure:	Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer
Time Frame:	At specific timepoints from 0 to 24 hours post-dose
Safety Issue:
Description:	Cmax is the maximum observed plasma concentration. PK parameters are reported for the dose escalation stage by cohort in Phase 1 and dose confirmation and fixed-dose combination stages in Phase 2.

Measure:	Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer
Time Frame:	At specific timepoints from 0 to 24 hours post-dose
Safety Issue:
Description:	Tmax is the time to maximum observed plasma concentration. PK parameters are reported for the dose escalation stage by cohort in Phase 1 and the dose confirmation and fixed-dose combination stages in Phase 2.

Measure:	Maximum Observed Plasma Concentration (Cmax) of Decitabine
Time Frame:	At specific timepoints from 0 to 24 hours post-dose
Safety Issue:
Description:	Cmax is the maximum observed plasma concentration. PK parameters for plasma decitabine are reported for the dose escalation stage by cohort in Phase 1 and dose confirmation and fixed-dose combination stages in Phase 2.

Measure:	Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2
Time Frame:	At specific timepoints from 0 to 24 hours post-dose
Safety Issue:
Description:	Tmax is the time to reach maximum plasma concentration for decitabine. PK parameters for plasma decitabine are reported for the dose confirmation and fixed-dose combination stages.

Measure:	Duration of Complete Response in Phase 1
Time Frame:	Up to 32 Months
Safety Issue:
Description:	Duration of response (in number of days) was calculated from the first time the response was observed to time of relapse or last time point in the study.

Measure:	Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate
Time Frame:	Up to approximately 29 months
Safety Issue:
Description:	Duration of response (in number of days) was calculated from the first time the response was observed to time of relapse or last time point in the study. Kaplan-Meier estimate for complete response is shown.

Measure:	Mean Maximum %LINE Demethylation in Phase 1
Time Frame:	Pre-dose to Day 28 in Course 2 (28 days per course)
Safety Issue:
Description:	Mean maximum % long interspread nuclear element-1 (LINE-1) demethylation decrease from baseline after oral decitabine + cedazuridine (E7727) or ASTX727 compared with IV decitabine 20 mg/m^2 in the dose escalation stage.

Measure:	Number of Participants With Overall Response in Phase 1
Time Frame:	Up to 32 months
Safety Issue:
Description:	The evaluation of response was based on International Working Group 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).

Measure:	Number of Participants With Adverse Events
Time Frame:	Up to 5 years
Safety Issue:
Description:	Number of participants with any treatment-emergent adverse event (AE) and any AE graded ≥3 using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Measure:	Number of Participants With Hematological Improvement
Time Frame:	Up to 32 months
Safety Issue:
Description:	Hematological improvement was calculated as defined by the IWG 2006 MDS Response Criteria.

Measure:	Number of Participants With Transfusion Independence
Time Frame:	Up to 32 months
Safety Issue:
Description:	Transfusion independence was calculated based on the number of transfusion-dependent participants at baseline who had no red blood cell or platelet transfusions for 56 consecutive days or more after treatment.

Measure:	Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death
Time Frame:	Up to 32 months
Safety Issue:
Description:	Number of participants to reach the event (AML or death), where time to reach AML was calculated as the number of days from the day the participant received the first dose of IV decitabine, oral decitabine + E7727, or the FDC tablet to the date of death or the date of MDS progression to AML as defined by ≥20% blasts in bone marrow or peripheral blood using the World Health Organization classification. Time to AML or death was censored on the last date of contact if a participant was lost to follow up prior to reaching a time-to-event endpoint.

Measure:	Number of Participants With Overall Survival
Time Frame:	Up to 32 months
Safety Issue:
Description:	Overall survival was defined as the number of days from the day the participant received the first dose of IV decitabine, oral decitabine + E7727, or the FDC tablet to the date of death, regardless of cause.

Details

Phase:	Phase 1/Phase 2
Primary Purpose:	Interventional
Overall Status:	Completed
Lead Sponsor:	Astex Pharmaceuticals, Inc.

Trial Keywords

Myelodysplastic Syndrome
MDS

Last Updated

December 23, 2020

Clinical Trials /

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