Clinical Trial Results:
A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727 (Cedazuridine and Decitabine Fixed-Dose Combination) versus IV Decitabine in Subjects with Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), and Acute Myeloid Leukemia (AML)
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Summary
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EudraCT number |
2018-003395-12 |
Trial protocol |
ES GB CZ HU AT IT |
Global end of trial date |
25 May 2023
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Results information
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Results version number |
v1(current) |
This version publication date |
26 Apr 2024
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First version publication date |
26 Apr 2024
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ASTX727-02
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03306264 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Astex Pharmaceuticals, Inc.
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Sponsor organisation address |
4420 Rosewood Drive, Suite 200, Pleasanton, CA, United States, 94588
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Public contact |
Karen Mosher, Astex Pharmaceuticals, Inc., KMosher@taihooncology.com
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Scientific contact |
Karen Mosher, Astex Pharmaceuticals, Inc., KMosher@taihooncology.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
25 May 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
25 May 2023
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The overall aim of the ASTX727-02 study is to establish the safety and effectiveness of ASTX727 in adult subjects with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) using a pharmacokinetics (PK) bridging approach.
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Protection of trial subjects |
All study subjects were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
15 Feb 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 110
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Country: Number of subjects enrolled |
Canada: 28
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Country: Number of subjects enrolled |
Spain: 20
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Country: Number of subjects enrolled |
United Kingdom: 1
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Country: Number of subjects enrolled |
Austria: 8
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Country: Number of subjects enrolled |
Czechia: 15
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Country: Number of subjects enrolled |
France: 3
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Country: Number of subjects enrolled |
Germany: 18
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Country: Number of subjects enrolled |
Hungary: 10
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Country: Number of subjects enrolled |
Italy: 7
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Worldwide total number of subjects |
220
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EEA total number of subjects |
81
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
39
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From 65 to 84 years |
168
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85 years and over |
13
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Recruitment
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Recruitment details |
A total of 227 subjects took part in the study from 15 February 2018 to 25 May 2023. 138 subjects with a diagnosis of MDS or CMML took part from the United States and Canada. 89 participants with a diagnosis of AML took part from Austria, Canada, Czech Republic, France, Germany, Hungary, Italy, Spain, and United Kingdom. | |||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Total 138 subjects with MDS/CMML were enrolled & randomised in 1:1 ratio to receive ASTX727/decitabine in crossover manner. Total 89 subjects with AML were enrolled & randomised in 1:1 ratio to receive ASTX727/decitabine in crossover manner. Out of 227 subjects, 220 subjects received study treatment for which data has been reported in this study. | |||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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MDS or CMML: ASTX727 or IV Decitabine | |||||||||||||||||||||||||||
Arm description |
Subjects with MDS or CMML received ASTX727 tablet, containing the fixed-dose combination of 35 milligrams (mg) decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days), followed by intravenous (IV) infusion of decitabine 20 mg/meter per square (m^2), once daily, on Days 1 to 5 in cycle 2 or the converse. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all subjects enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, treatment discontinuation for other reasons, or withdrawal from the study. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Decitabine
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Investigational medicinal product code |
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Other name |
Dacogen
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
20 milligrams per square meters (mg/m2) 1-hour IV infusion daily.
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Investigational medicinal product name |
ASTX727
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Investigational medicinal product code |
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Other name |
Decitabine + Cedazuridine
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
ASTX727 tablet administered orally daily ×5
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Arm title
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AML: ASTX727 or IV Decitabine | |||||||||||||||||||||||||||
Arm description |
Subjects with AML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days), followed by IV infusion of decitabine 20 mg/m^2, once daily, on Days 1 to 5 in cycle 2 or the converse. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all subjects enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, participant discontinued treatment, or was withdrawn from the study. | |||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||
Investigational medicinal product name |
Decitabine
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Investigational medicinal product code |
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Other name |
Dacogen
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
20 milligrams per square meters (mg/m2) 1-hour IV infusion daily.
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Investigational medicinal product name |
ASTX727
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Investigational medicinal product code |
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Other name |
Decitabine + Cedazuridine
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
ASTX727 tablet administered orally daily ×5
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Baseline characteristics reporting groups
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Reporting group title |
MDS or CMML: ASTX727 or IV Decitabine
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Reporting group description |
Subjects with MDS or CMML received ASTX727 tablet, containing the fixed-dose combination of 35 milligrams (mg) decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days), followed by intravenous (IV) infusion of decitabine 20 mg/meter per square (m^2), once daily, on Days 1 to 5 in cycle 2 or the converse. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all subjects enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, treatment discontinuation for other reasons, or withdrawal from the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AML: ASTX727 or IV Decitabine
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Reporting group description |
Subjects with AML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days), followed by IV infusion of decitabine 20 mg/m^2, once daily, on Days 1 to 5 in cycle 2 or the converse. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all subjects enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, participant discontinued treatment, or was withdrawn from the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
MDS or CMML: ASTX727 or IV Decitabine
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Reporting group description |
Subjects with MDS or CMML received ASTX727 tablet, containing the fixed-dose combination of 35 milligrams (mg) decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days), followed by intravenous (IV) infusion of decitabine 20 mg/meter per square (m^2), once daily, on Days 1 to 5 in cycle 2 or the converse. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all subjects enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, treatment discontinuation for other reasons, or withdrawal from the study. | ||
Reporting group title |
AML: ASTX727 or IV Decitabine
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Reporting group description |
Subjects with AML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days), followed by IV infusion of decitabine 20 mg/m^2, once daily, on Days 1 to 5 in cycle 2 or the converse. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all subjects enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, participant discontinued treatment, or was withdrawn from the study. | ||
Subject analysis set title |
MDS or CMML: IV Decitabine
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects with MDS or CMML received decitabine 20 mg/m^2 IV injection, once daily, on Days 1 to 5 in cycle 1 or 2 (each cycle = 28 days).
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Subject analysis set title |
MDS or CMML: ASTX727
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects with MDS or CMML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, given by mouth, once daily, on Days 1 to 5 in cycle 1 or 2 (each cycle = 28 days). From cycle 3, subjects received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, treatment discontinuation for other reasons, or withdrawal from the study.
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Subject analysis set title |
AML: IV Decitabine
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects with AML received decitabine 20 mg/m^2 IV injection, once daily, on Days 1 to 5 in cycle 1 or 2 (each cycle = 28 days).
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Subject analysis set title |
AML: ASTX727
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects with AML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, given by mouth, once daily, on Days 1 to 5 in cycle 1 or 2 (each cycle = 28 days). From cycle 3, subjects received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, treatment discontinuation for other reasons, or withdrawal from the study.
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Subject analysis set title |
Arm: AML: ASTX727 or IV Decitabine
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Subjects with AML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (each cycle = 28 days), followed by IV infusion of decitabine 20 mg/m^2, once daily, on Days 1 to 5 in cycle 2 or the converse. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all subjects enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, treatment discontinuation for other reasons, or withdrawal from the study.
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End point title |
Total 5-day Area Under the Curve From 0 to 24 Hours (AUC0-24) After Treatment With ASTX727 Versus IV Decitabine [1] | ||||||||||||
End point description |
Primary Endpoint Pharmacokinetics (PK) Analysis Set included subjects who received full dose of ASTX727 within 3 hours of the intended dosing time, and no vomiting within 6 hours of dosing and had at least 2 days of evaluable decitabine (AUC0-24) measurements in the ASTX727 cycle, i.e, Day 1 and either Day 2 or Day 5 and received the full IV decitabine dose as a 1-hour infusion.
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End point type |
Primary
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End point timeframe |
ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this outcome measure. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
MDS/CMML: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) [2] | ||||||
End point description |
An AE is defined as any untoward medical occurrence in a clinical investigation subjects administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. Safety Analysis Set included all subjects who received any amount of study treatment.
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End point type |
Secondary
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End point timeframe |
From randomisation up to 30 days after last dose of study treatment (up to approximately 2.7 years)
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| Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Descriptive data was planned to be reported for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
AML: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) [3] | ||||||
End point description |
An AE is defined as any untoward medical occurrence in a clinical investigation subjects administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. Safety Analysis Set included all subjects who received any amount of study treatment.
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End point type |
Secondary
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End point timeframe |
From randomisation up to 30 days after last dose of study treatment (up to approximately 2.4 years)
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| Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the AML arm was applicable for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
MDS/CMML: Number of Subjects With Grade 3 or Higher TEAEs [4] | ||||||
End point description |
TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. Severity of AEs were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. Safety Analysis Set included all subjects who received any amount of study treatment.
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End point type |
Secondary
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End point timeframe |
From randomisation up to 30 days after last dose of study treatment (up to approximately 2.7 years)
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| Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the MDS/CMML arm was applicable for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
AML: Number of Subjects With Grade 3 or Higher TEAEs [5] | ||||||
End point description |
TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. Severity of AEs were graded using CTCAE version 4.03. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. Safety Analysis Set included all subjects who received any amount of study treatment.
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End point type |
Secondary
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End point timeframe |
From randomisation up to 30 days after last dose of study treatment (up to approximately 2.4 years)
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| Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the AML arm was applicable for this endpoint. |
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| No statistical analyses for this end point | |||||||
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End point title |
Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation | ||||||||||||||||||||||||||||||
End point description |
Pharmacodynamic (PD) LINE-1 Analysis Set included subjects who received any amount of study treatment and have LINE-1 methylation data at baseline (Day 1) of Cycle 1 or 2 and on either Day 8 or Day 15 of the respective cycle. Number of Subjects analysed signifies those who were evaluable for this endpoint. 'n' signifies those subjects who were evaluable for this endpoint at specified time point.
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End point type |
Secondary
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End point timeframe |
Pre-dose on Day 1 of Cycles 1 and 2 (as Baseline), and Days 8, 15 and 22 of Cycles 1 and 2 (each cycle= 28 days)
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Total 5-day Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 Versus IV Decitabine | ||||||||||||
End point description |
Overall PK Analysis Set included subjects who may not have been included in the Primary Endpoint PK Analysis Set and who received any amount of study treatment, complied with the protocol sufficiently to ensure PK samples were collected as intended and provided sufficient samples to measure available plasma concentrations for decitabine. Number of Subjects analysed signifies those who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Total 5-day Area Under the Curve From 0 to Last Quantifiable Concentration (AUC0-last) After Treatment With ASTX727 Versus IV Decitabine | ||||||||||||
End point description |
Overall PK Analysis Set included subjects who may not have been included in the Primary Endpoint PK Analysis Set and received any amount of study treatment, complied with the protocol sufficiently to ensure PK samples were collected as intended and provided sufficient samples to measure available plasma concentrations for decitabine. Number of Subjects analysed signifies those who were evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Total 5-day Area Under the Curve From 0 to 8 Hours (AUC0-8) After Treatment With ASTX727 Versus IV Decitabine | ||||||||||||
End point description |
Overall PK Analysis Set included subjects who may not have been included in the Primary Endpoint PK Analysis Set and received any amount of study treatment, complied with the protocol sufficiently to ensure PK samples were collected as intended and provided sufficient samples to measure available plasma concentrations for decitabine. Number of Subjects analysed signifies those who were evaluable for this endpoint
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End point type |
Secondary
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End point timeframe |
ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 Versus IV Decitabine | |||||||||||||||||||||||||||||||||||
End point description |
Overall PK Analysis Set included subjects not included in Primary Endpoint PK Analysis Set, received any amount of study treatment, complied with protocol sufficiently to ensure PK samples were collected, provided sufficient samples to measure available plasma concentrations for decitabine. Number of Subjects analysed signifies those who were evaluable for this endpoint. 'n' signifies those subjects who were evaluable for this endpoint at specified time point. '9999' indicates that the geomentric mean and geometric coefficient of variation was not estimable as no subjects were analysed for the given category.
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|||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||
End point timeframe |
ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
|
|||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Summarized data of Cmax on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of Cmax on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine. Overall PK Analysis Set included subjects who may not have been included in the Primary Endpoint PK Analysis Set and received any amount of study treatment, complied with the protocol sufficiently to ensure PK samples were collected as intended and provided sufficient samples to measure available plasma concentrations for decitabine, cedazuridine, and cedazuridine-epimer. Number of Subjects analysed signifies those who were evaluable for this endpoint. 'n' signifies those subjects who were evaluable for this endpoint at specified time point. '9999' indicates that the geomentric mean and geometric coefficient of variation was not estimable as no subjects were analysed for the given category.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine and Cedazuridine-epimer | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Summarized data of Tmax on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of Tmax on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine. Overall PK Analysis Set included subjects who may not have been included in the Primary Endpoint PK Analysis Set and received any amount of study treatment, complied with the protocol sufficiently to ensure PK samples were collected as intended and provided sufficient samples to measure available plasma concentrations for decitabine, cedazuridine, and cedazuridine-epimer. Number of Subjects analysed signifies those who were evaluable for this endpoint. 'n' signifies those subjects who were evaluable for this endpoint at specified time point. '9999' indicates that the geomentric mean and geometric coefficient of variation was not estimable as no subjects were analysed for the given category.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine | ||||||||||||||||||||||||
End point description |
Oral CL/F for oral decitabine was measured only on Day 1 and oral CL/F for oral cedazuridine was measured on Days 1, 2 and 5. Summarized data of Oral CL/F for oral decitabine on Day 1 for Cycle 1 and 2 and for oral cedazuridine on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Overall PK Analysis Set included subjects who may not have been included in the Primary Endpoint PK Analysis Set and received any amount of study treatment, complied with the protocol sufficiently to ensure PK samples were collected as intended and provided sufficient samples to measure available plasma concentrations for decitabine, and cedazuridine. Number of Subjects analysed signifies those who were evaluable for this endpoint. 'n' signifies those subjects who were evaluable for this endpoint at specified time point. '99999' indicates that geometric coefficient of variation could not be calculated as data for only one subject was available for analysis.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2 (each cycle= 28 days)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine and Cedazuridine-epimer | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Summarized data of t1/2 on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727 and on Day 1 and 5 respectively for Cycle 1 and 2 for IV Decitabine. Overall PK Analysis Set included subjects who may not have been included in the Primary Endpoint PK Analysis Set and received any amount of study treatment, complied with the protocol sufficiently to ensure PK samples were collected as intended and provided sufficient samples to measure available plasma concentrations for decitabine, cedazuridine, and cedazuridine-epimer. Number of Subjects analysed signifies those who were evaluable for this endpoint. 'n' signifies those subjects who were evaluable for this endpoint at specified time point. '9999' indicates that geomentric mean & geometric coefficient of variation was not estimable as no subjects were analysed for given category. '99999' indicates that geometric coefficient of variation could not be calculated as data for only 1 subject was available for analysis.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine | ||||||||||||||||||||||||||||||
End point description |
Summarized data of Vz/F on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Overall PK Analysis Set included subjects who may not have been included in the Primary Endpoint PK Analysis Set and received any amount of study treatment, complied with the protocol sufficiently to ensure PK samples were collected as intended and provided sufficient samples to measure available plasma concentrations for decitabine, and cedazuridine. Number of Subjects analysed signifies those who were evaluable for this endpoint. 'n' signifies those subjects who were evaluable for this endpoint at specified time point. '99999' indicates that geometric coefficient of variation could not be calculated as data for only one subject was available for analysis.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2 (each cycle= 28 days)
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||
End point title |
MDS/CMML: Percentage of Subjects With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria [6] | ||||||||||||||||||||
End point description |
CR:normal peripheral,persistent granulocyte count≥1.0x10^9/liter(L),platelet≥100x10^9/L,Hemoglobin(Hgb)≥11g/dL,normal bone marrow with persistent marrow blasts≤5%.mCR:reduction of bone marrow blasts to≤5%,decrease by 50% or more with/without normalization of peripheral counts.PR:normal peripheral counts,granulocyte count ≥1.0x10^9/L,platelet count≥100x10^9/L,Hgb≥11 g/dL,normal bone marrow,marrow blasts>5%,reduced by 50% or more for atleast 4 weeks.HI: HI-E:Hb increase≥1.5 g/dL in absence of RBC transfusions.HI-P:Absolute increase of platelet count from<20 to>20X10^9/L by at least 100%,if more than 20x10^9/L,by absolute increase of at least 30x10^9/L in absence of platelet transfusions.HI-N:granulocyte increase≥100%,by an absolute increase≥0.5x10^9/L for atleast 8 weeks.Efficacy Analysis Set included all subjects who received any amount of study treatment.'9999' indicates that number and CI 95% were not analysed as no subjects were analysed for given category.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Up to approximately 2.7 years
|
||||||||||||||||||||
| Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the MDS/CMML arm was applicable for this endpoint. |
|||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||
End point title |
AML: Percentage of Subjects With CR, CR With Incomplete Platelet Recovery (CRp), CR Plus CRp, and CR With Incomplete Blood Count Recovery (CRi) Based on IWG 2003 AML Response Criteria | ||||||||||||||||
End point description |
CR was defined as absolute neutrophil content (ANC) ≥1000/ microliter (μL), platelets ≥100,000/μL, independence from red blood cell (RBC) and platelet transfusions over the past week, no leukemic blasts and <5% leukemic blasts. CRp was defined as CR criteria except platelets <100,000/μL.and platelet transfusion over the past week. CRi was defined as CR criteria except ANC <1000/μL or platelets <100,000/μL. Percentage of subjects with CR, CRi, CRp, and CR Plus CRp based on IWG 2003 AML response criteria are reported. Intent-to-Treat (ITT) Analysis Set included data from all subjects who were randomised.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to approximately 2.4 years
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||
End point title |
AML: Percentage of Subjects With CR With Partial Hematologic Recovery (CRh) Based on IWG 2003 AML Response Criteria [7] | ||||||||
End point description |
CRh was defined as <5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/μL and ANC >500/μL), independence from RBC and platelet transfusions within 7 days of bone marrow evaluation, and peripheral blast ≤1%. Percentage of subjects with CRh based on IWG 2003 AML response criteria are reported. Efficacy Analysis Set included all subjects who received any amount of study treatment.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Day 1 of Cycle 3 up to approximately 2.4 years (each cycle= 28 days)
|
||||||||
| Notes [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the AML arm was applicable for this endpoint. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||
End point title |
AML: Time to First Response, Best Response and Complete Response Based on IWG 2003 AML Response Criteria [8] | ||||||||||||||
End point description |
Time to first response: Time in months from date of first treatment to first date when any response is achieved. Time to best response: Months from date of first treatment to first date when a subject’s best response,in the order of CR,CRi(or CRp or CRh), orPR,was achieved. Time to CR: Months from date of first treatment to first date when CR is achieved. CR:ANC ≥1000/ microliter (μL),platelets ≥100,000/μL, independence from RBC and platelet transfusions over past week,no leukemic blasts,and <5% leukemic blasts.CRp: CR criteria except ANC ≥1000/μL, platelets < 100,000/μL.and platelet transfusion over the past week. CRi:CR criteria except ANC <1000/μL or platelets <100,000/μL.CRh: <5% of blasts in the bone marrow,platelets >50,000/μL and ANC >500/μL, independence from RBC and platelet transfusions within 7 days and peripheral blast ≤1%. PR: CR criteria except decrease of ≥50% in leukemic blasts. Efficacy Analysis Set included all participants who received any amount of study treatment.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Up to approximately 2.4 years
|
||||||||||||||
| Notes [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the AML arm was applicable for this endpoint. |
|||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||
End point title |
AML: Duration of Complete Response and Combined CR and CRh Based on IWG 2003 AML Response Criteria [9] | ||||||||||||
End point description |
Duration of CR was defined as the time interval from the first CR to time of relapse. Duration of combined CR and CRh was defined as the time interval from the first CR or CRh to time of relapse. Duration of CR and combined CR and CRh was presented using a Kaplan-Meier estimate. Efficacy Analysis Set included all subjects who received any amount of study treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to approximately 2.4 years
|
||||||||||||
| Notes [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the AML arm was applicable for this endpoint. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||
End point title |
MDS/CMML: Percentage of Subjects With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) [10] | ||||||||||||||||||||
End point description |
Transfusion independence was defined as no transfusion for 56 consecutive days or more (84 and 112 days) after the first dose of study treatment while maintaining hemoglobin ≥8 grams/deciliter (g/dL) (RBC TI) or maintaining platelets ≥20×109/L (platelet TI). Efficacy Analysis Set included all subjects who received any amount of study treatment. Number of Subjects analysed signifies those who were evaluable for this endpoint. 'n' signifies those subjects who were evaluable for this endpoint in specified category.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Up to approximately 2.7 years
|
||||||||||||||||||||
| Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the MDS/CMML arm was applicable for this endpoint. |
|||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||||||||||
End point title |
AML: Percentage of Subjects With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI) [11] | ||||||||||||||||
End point description |
Transfusion independence was defined as no transfusion for 56 consecutive days or more (112 days) after the first dose of study treatment while maintaining hemoglobin ≥8 grams/deciliter (g/dL) (RBC TI) or maintaining platelets ≥20×109/L (platelet TI). Efficacy Analysis Set included all subjects who received any amount of study treatment. Number of Subjects analysed signifies those who were evaluable for this endpoint. 'n' signifies those subjects who were evaluable for this endpoint at specified time point.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to approximately 2.4 years
|
||||||||||||||||
| Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the AML arm was applicable for this endpoint. |
|||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||
End point title |
MDS/CMML: Leukemia-free Survival (LFS) [12] | ||||||||
End point description |
LFS was defined as time from the date of randomisation to the date when bone marrow or peripheral blood blasts reach ≥20%, or death from any cause. Subjects who hadn't reached AML at the time of the analysis were censored at the date of the last follow-up. Leukemia-free survival was presented using a Kaplan-Meier estimate. Efficacy Analysis Set included all subjects who received any amount of study treatment. Number of Subjects analysed signifies those who were evaluable for this endpoint. '9999999' indicates that the upper limit of the 95% Confidence Interval (CI) was not reached at time of data cut-off due to insufficient number of participants with an event.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From randomisation up to approximately 2.7 years
|
||||||||
| Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the MDS/CMML arm was applicable for this endpoint. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
MDS/CMML: Overall Survival (OS) [13] | ||||||||
End point description |
OS was defined as time from the date of randomisation to the date of death from any cause. Subjects without documented death at the time of the analysis were censored at the date of the last follow-up. Overall survival was presented using a Kaplan-Meier estimate. Efficacy Analysis Set included all subjects who received any amount of study treatment. Number of Subjects analysed signifies those who were evaluable for this endpoint. '9999999' indicates that the upper limit of the 95% CI was not reached at time of data cut-off due to insufficient number of participants with an event.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From randomisation up to approximately 2.7 years
|
||||||||
| Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the MDS/CMML arm was applicable for this endpoint. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
AML: Overall Survival (OS) [14] | ||||||||
End point description |
OS was defined as time from the date of randomisation to the date of death from any cause. Subjects without documented death at the time of the analysis were censored at the date of the last follow-up. Overall survival was presented using a Kaplan-Meier estimate. Efficacy Analysis Set included all subjects who received any amount of study treatment. Number of Subjects analysed signifies those who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From randomisation up to approximately 2.4 years
|
||||||||
| Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the AML arm was applicable for this endpoint. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||
End point title |
AML: Survival Rates at 6 Months, 1 Year, and 2 Years [15] | ||||||||||||||
End point description |
One-year survival rate was defined as the survival rate at the end of the first year from the date of randomisation. The survival rates at 6 months and at 2 years were calculated similarly. Efficacy Analysis Set included all subjects who received any amount of study treatment.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Month 6, Years 1 and 2
|
||||||||||||||
| Notes [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the AML arm was applicable for this endpoint. |
|||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||
End point title |
AML: Event-free Survival (EFS) [16] | ||||||||
End point description |
EFS was defined as time from the date of randomisation to the date of treatment failure [disease progression/relapse (due to confirmed reappearance of leukemic blasts in peripheral blood or ≥5% leukemic blasts in bone marrow (including relapse), discontinue treatment due to disease progression or treatment-related AE, or alternative anti-leukemia therapy except for HCT] or death from any cause, whichever occurs first. Subjects without documented treatment failure at the time of the analysis were censored at the date of the last follow-up. Event-free survival was presented using a Kaplan-Meier estimate. Efficacy Analysis Set included all subjects who received any amount of study treatment. Number of Subjects analysed signifies those who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From randomisation up to approximately 2.4 years
|
||||||||
| Notes [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the AML arm was applicable for this endpoint. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
AML: Progression-free Survival (PFS) [17] | ||||||||
End point description |
PFS was defined as time from the date of randomisation to the date disease progression due to confirmed reappearance of leukemic blasts in peripheral blood or ≥5% leukemic blasts in bone marrow (including relapse) or death from any cause, whichever occurs first. Participants without documented disease progression/relapse or death at the time of the analysis were censored at the date of the last follow-up. Progression-free survival was presented using a Kaplan-Meier estimate. Efficacy Analysis Set included all subjects who received any amount of study treatment. Number of Subjects analysed signifies those who were evaluable for this endpoint
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
From randomization up to approximately 2.4 years
|
||||||||
| Notes [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only the AML arm was applicable for this endpoint. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
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Adverse events information
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Timeframe for reporting adverse events |
CMML: From randomisation up to 2.7 years; AML: From randomisation up to 2.4 years
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Adverse event reporting additional description |
Safety Analysis Set included all subjects who received any amount of study treatment.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.0
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Reporting groups
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Reporting group title |
MDS or CMML: ASTX727 or IV Decitabine
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Reporting group description |
Subjects with MDS or CMML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (1 cycle = 28 days), followed by IV infusion of decitabine 20 mg/m^2, once daily, on Days 1 to 5 in cycle 2 or the converse. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all subjects enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, treatment discontinuation for other reasons, or withdrawal from the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AML: ASTX727 or IV Decitabine
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects with AML received ASTX727 tablet, containing the fixed-dose combination of 35 mg decitabine and 100 mg cedazuridine, orally, once daily, on Days 1 to 5 in cycle 1 (1 cycle = 28 days), followed by IV infusion of decitabine 20 mg/m^2, once daily, on Days 1 to 5 in cycle 2 or the converse. A washout period of 23 days was maintained between the 2 cycles. From cycle 3, all subjects enrolled in cycles 1 and 2 received ASTX727 tablet, once daily, on Days 1 to 5 of each 28-day cycle until disease progression, unacceptable toxicity, participant discontinued treatment, or was withdrawn from the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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20 Jan 2021 |
The following changes were made as part of Amendment 2: 1.Addition of information on marketing approval of ASTX727 as INQOVI® (35 mg decitabine/100 mg cedazuridine). 2.Addition of language describing modifications to study conduct implemented due to current coronavirus disease 2019 (COVID-19) health emergency. 3.Removal of restriction on ingestion of medication that may affect gastric pH for 4 hours before and 4 hours after ASTX727 dosing because PK results have shown this is not required. 4.Description of informed consent is changed from “written informed consent” to “legally effective informed consent.” 5.Further details and guidance on antibiotic prophylaxis are provided at request of health authority. 6.Exclusion criterion for “Hypersensitivity to decitabine, cedazuridine, or any of the excipients in ASTX727 tablets or IV decitabine” is added at request of health authority. 7.Brief summary of PK results from MDS subjects in this study is added at request of health authority. 8.Paragraph emphasizing importance of multiple cycles of treatment after completion of Cycles 1 and 2 is added at request of health authority. 9.An explanation that assessment of efficacy and safety is independent of PK endpoints is added at request of health authority. 10.Instructions regarding what to do in event of vomited dose are added at request of health authority. 11.Instructions that dosing should be delayed in presence of certain non-hematologic toxicities are added at request of health authority. 12. Prohibition of nucleosides or drugs metabolized by cytidine deaminase (CDA) is extended from days that ASTX727 is administered to entire duration of study treatment at request of health authority. 13.ASTX727 is identified as genotoxic, based on current INQOVI Prescribing Information. 14.Description of AE reporting is updated to align with current practice. 15.SAE reporting requirements are updated to align with current practice. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
