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

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ClinicalTrials.gov Identifier: NCT02103478
Recruitment Status : Completed
First Posted : April 4, 2014
Results First Posted : October 19, 2020
Last Update Posted : October 19, 2020
Sponsor:
Information provided by (Responsible Party):
Astex Pharmaceuticals, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Myelodysplastic Syndrome
MDS
Interventions Drug: ASTX727 Dose Escalation
Drug: ASTX727 Dose Confirmation
Drug: ASTX727 Fixed-Dose Combination
Enrollment 130
Recruitment Details In Phase 1, 127 participants were screened and 44 were randomized and received at least one treatment. In Phase 2, a total of 138 were screened, 86 were randomized, and 80 received at least one treatment.
Pre-assignment Details Data for Phase 1 participants as of 01 June 2017 data cut and Phase 2 participants as of 05 June 2018 data cut are included. Median follow up in Phase 1 was 710.5 days (range: 566-1008) and 729 days in Phase 2 (range: 365-876). As of the Phase 1 and Phase 2 data cuts, 3 and 13 participants were still on treatment, respectively.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Sequence A Phase 2 Dose Confirmation Sequence B Phase 2 Fixed-Dose Combination Sequence A Phase 2 Fixed-Dose Combination Sequence B
Hide Arm/Group Description Cohort 1 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). Cohort 2 was administered 60 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). Cohort 3 was administered 100 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). Cohort 4 was administered 100 mg oral cedazuridine and 40 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). Cohort 5 was administered 100 mg oral cedazuridine and 30 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). Participants were randomized in a 1:1 ratio to receive oral cedazuridine (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) in Sequence A. In Courses ≥ 3, all participants received cedazuridine and decitabine Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study. Participants were randomized in a 1:1 ratio to receive IV decibatine (20 mg/m^2) Dailyx5 in Course 1 followed by oral cedazuridine (100 mg) + decitabine (35 mg) capsules Dailyx5 in Course 2 (28 days per course) in Sequence B. In Courses ≥ 3, all participants received cedazuridine and decitabine Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study. Participants were randomized in a 1:1 ratio to receive oral cedazuridine (100 mg) + decitabine (35 mg) tablets Dailyx5 in Course 1 followed by IV decitabine (20 mg/m^2) Dailyx5 in Course 2 (28 days per course) in Sequence A. In Courses ≥ 3, all participants received cedazuridine and decitabine Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study. Participants were randomized in a 1:1 ratio to receive IV decibatine (20 mg/m^2) Dailyx5 in Course 1 followed by oral cedazuridine (100 mg) + decitabine (35 mg) tablets Dailyx5 in Course 2 (28 days per course) in Sequence B. In Courses ≥ 3, all participants received cedazuridine and decitabine Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Period Title: Overall Study
Started 7 6 6 6 19 25 25 16 14
Completed 2 2 0 0 2 5 4 2 2
Not Completed 5 4 6 6 17 20 21 14 12
Reason Not Completed
Adverse Event             0             0             1             2             1             1             2             2             1
Death             1             0             0             0             3             3             3             3             3
Progressive Disease             2             1             2             1             10             7             7             3             4
Bone Marrow/Stem Cell Transplant             1             2             1             0             2             5             2             3             2
Withdrawal by Subject             0             0             1             3             0             2             2             1             0
Other             1             1             1             0             1             2             5             2             2
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination Total
Hide Arm/Group Description Cohort 1 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). Cohort 2 was administered 60 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). Cohort 3 was administered 100 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). Cohort 4 was administered 100 mg oral cedazuridine and 40 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). Cohort 5 was administered 100 mg oral cedazuridine and 30 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). Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study. Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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. Total of all reporting groups
Overall Number of Baseline Participants 7 6 6 6 19 50 30 124
Hide Baseline Analysis Population Description
Demographic and baseline characteristics are shown for participants who received at least one dose of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 7 participants 6 participants 6 participants 6 participants 19 participants 50 participants 30 participants 124 participants
69.6  (8.1) 72  (6.2) 74  (4.8) 75.2  (7.1) 71.6  (8.8) 69.7  (10.72) 69.6  (10.57) 70.6  (9.67)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 6 participants 6 participants 6 participants 19 participants 50 participants 30 participants 124 participants
Female
4
  57.1%
1
  16.7%
3
  50.0%
2
  33.3%
4
  21.1%
9
  18.0%
10
  33.3%
33
  26.6%
Male
3
  42.9%
5
  83.3%
3
  50.0%
4
  66.7%
15
  78.9%
41
  82.0%
20
  66.7%
91
  73.4%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 6 participants 6 participants 6 participants 19 participants 50 participants 30 participants 124 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
1
  16.7%
0
   0.0%
2
   4.0%
3
  10.0%
6
   4.8%
Not Hispanic or Latino
7
 100.0%
6
 100.0%
5
  83.3%
5
  83.3%
18
  94.7%
46
  92.0%
26
  86.7%
113
  91.1%
Unknown or Not Reported
0
   0.0%
0
   0.0%
1
  16.7%
0
   0.0%
1
   5.3%
2
   4.0%
1
   3.3%
5
   4.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 6 participants 6 participants 6 participants 19 participants 50 participants 30 participants 124 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   2.0%
0
   0.0%
1
   0.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
  14.3%
0
   0.0%
0
   0.0%
1
  16.7%
1
   5.3%
2
   4.0%
0
   0.0%
5
   4.0%
White
6
  85.7%
6
 100.0%
5
  83.3%
5
  83.3%
18
  94.7%
46
  92.0%
28
  93.3%
114
  91.9%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
1
  16.7%
0
   0.0%
0
   0.0%
1
   2.0%
2
   6.7%
4
   3.2%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 7 participants 6 participants 6 participants 6 participants 19 participants 50 participants 30 participants 124 participants
Canada 0 0 0 0 0 8 8 16
United States 7 6 6 6 19 42 22 108
1.Primary Outcome
Title Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1
Hide 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).
Time Frame Day 5
Hide Outcome Measure Data
Hide Analysis Population Description
Participants who were successfully dosed according to criteria for both ASTX727 and IV decitabine dosing and with evaluable pharmacokinetic (PK) measurements are included.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5
Hide Arm/Group Description:
Cohort 1 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).
Cohort 2 was administered 60 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).
Cohort 3 was administered 100 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).
Cohort 4 was administered 100 mg oral cedazuridine and 40 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).
Cohort 5 was administered 100 mg oral cedazuridine and 30 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).
Overall Number of Participants Analyzed 5 6 6 6 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
53.6
(40%)
68.9
(44%)
94.8
(46%)
221
(74%)
146
(50%)
2.Primary Outcome
Title Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2
Hide Description 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.
Time Frame Pre-dose to Day 5
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with evaluable PK measurements are included. Phase 2 crossover design was used to compare AUC ratio for oral and IV administration.
Arm/Group Title Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/Group Description:
Participants were randomized in a 1:1 ratio to receive either Sequence A: Oral cedazuridine (100 mg) + decitabine (35 mg) capsules Dailyx5 in Course 1 followed by IV decitabine (20 mg/m^2) Dailyx5 in Course 2; or Sequence B: IV decitabine (20 mg/m^2) Dailyx5 in Course 1 followed by cedazuridine + decitabine capsules Dailyx5 in Course 2 (28 days per course). In Courses ≥ 3, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 40 24
Geometric Least Squares Mean (80% Confidence Interval)
Unit of Measure: Ratio of Geometric LSM
93.52
(82.10 to 106.50)
97.59
(80.48 to 118.30)
3.Primary Outcome
Title Number of Participants With Dose-limiting Toxicity in Phase 1
Hide Description 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.
Time Frame Up to Day 28 in Course 1 (28 days per course)
Hide Outcome Measure Data
Hide Analysis Population Description
The safety population includes participants in Phase 1 who received at least one dose of study drug.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5
Hide Arm/Group Description:
Cohort 1 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).
Cohort 2 was administered 60 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).
Cohort 3 was administered 100 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).
Cohort 4 was administered 100 mg oral cedazuridine and 40 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).
Cohort 5 was administered 100 mg oral cedazuridine and 30 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).
Overall Number of Participants Analyzed 7 6 6 6 19
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   5.3%
4.Primary Outcome
Title Mean Maximum %LINE Demethylation in Phase 2
Hide Description 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.
Time Frame Pre-dose to Day 28 in Course 2 (28 days per Course)
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacodynamic population includes all participants with evaluable data who received at least one dose of investigational product.
Arm/Group Title Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/Group Description:
Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 48 30
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percent
Course 1 - Treatment Number Analyzed 24 participants 16 participants
11.159
(9.023 to 13.294)
10.077
(7.696 to 12.459)
Course 1 - IV Decitabine Number Analyzed 24 participants 14 participants
11.303
(9.167 to 13.439)
12.665
(10.12 to 15.211)
Course 2 - Treatment Number Analyzed 22 participants 9 participants
9.833
(7.446 to 12.219)
8.134
(4.438 to 11.830)
Course 2 - IV Decitabine Number Analyzed 22 participants 11 participants
9.920
(7.534 to 12.307)
8.230
(4.887 to 11.574)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Phase 2 Dose Confirmation
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments The 95% confidence intervals for the difference (oral - IV) were generated using an ANOVA model separately for Course 1 and Course 2.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.144
Confidence Interval (2-Sided) 95%
-3.165 to 2.876
Estimation Comments Course 1
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Phase 2 Dose Confirmation
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments The 95% confidence intervals for the difference (oral - IV) were generated using an ANOVA model separately for Course 1 and Course 2.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.087
Confidence Interval (2-Sided) 95%
-3.463 to 3.288
Estimation Comments Course 2
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Phase 2 Fixed-Dose Combination
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments The 95% confidence intervals for the difference (oral - IV) were generated using an ANOVA model separately for Course 1 and Course 2.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.588
Confidence Interval (2-Sided) 95%
-6.074 to 0.899
Estimation Comments Course 1
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Phase 2 Fixed-Dose Combination
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments The 95% confidence intervals for the difference (oral - IV) were generated using an ANOVA model separately for Course 1 and Course 2.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.096
Confidence Interval (2-Sided) 95%
-5.080 to 4.888
Estimation Comments Course 2
5.Primary Outcome
Title Number of Participants With Overall Response in Phase 2
Hide Description 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).
Time Frame Up to approximately 29 months (data for Phase 2 participants as of 05 June 2018 data cut-off)
Hide Outcome Measure Data
Hide Analysis Population Description
The efficacy population includes all participants in Phase 2 who received at least one dose of investigational product.
Arm/Group Title Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/Group Description:
Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 50 30
Measure Type: Count of Participants
Unit of Measure: Participants
29
  58.0%
19
  63.3%
6.Secondary Outcome
Title Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer
Hide 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.
Time Frame At specified timepoints from 0 to 24 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with evaluable PK measurements are included.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/Group Description:
Cohort 1 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).
Cohort 2 was administered 60 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).
Cohort 3 was administered 100 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).
Cohort 4 was administered 100 mg oral cedazuridine and 40 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).
Cohort 5 was administered 100 mg oral cedazuridine and 30 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).
Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 6 6 6 6 19 37 19
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
Cedazuridine Number Analyzed 6 participants 6 participants 6 participants 6 participants 19 participants 32 participants 14 participants
1650
(43%)
1990
(64%)
3190
(53%)
4830
(51%)
3490
(46%)
2370
(56.8%)
1510
(49.4%)
Cedazuridine-epimer Number Analyzed 6 participants 6 participants 5 participants 3 participants 12 participants 37 participants 19 participants
503
(20%)
917
(64%)
1670
(48%)
2180
(34%)
1560
(56%)
1190
(48.3%)
710
(38%)
7.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer
Hide 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.
Time Frame At specific timepoints from 0 to 24 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with evaluable PK measurements are included.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/Group Description:
Cohort 1 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).
Cohort 2 was administered 60 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).
Cohort 3 was administered 100 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).
Cohort 4 was administered 100 mg oral cedazuridine and 40 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).
Cohort 5 was administered 100 mg oral cedazuridine and 30 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).
Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 6 6 6 6 19 47 29
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
Cedazuridine
309
(50%)
376
(67%)
636
(50%)
697
(75%)
570
(51%)
451
(51.4%)
293
(43.1%)
Cedazuridine-epimer
96
(22%)
184
(70%)
343
(44%)
321
(47%)
291
(54%)
235
(49%)
154
(44.6%)
8.Secondary Outcome
Title Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer
Hide 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.
Time Frame At specific timepoints from 0 to 24 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with evaluable PK measurements are included.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/Group Description:
Cohort 1 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).
Cohort 2 was administered 60 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).
Cohort 3 was administered 100 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).
Cohort 4 was administered 100 mg oral cedazuridine and 40 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).
Cohort 5 was administered 100 mg oral cedazuridine and 30 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).
Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 6 6 6 6 19 47 30
Median (Full Range)
Unit of Measure: hours
Cedazuridine Number Analyzed 6 participants 6 participants 6 participants 6 participants 19 participants 47 participants 29 participants
3
(2 to 4)
3
(2 to 4)
3
(3 to 4)
3
(2 to 6)
3
(2 to 6)
3
(1.50 to 4.08)
3
(2.00 to 7.18)
Cedazuridine-epimer Number Analyzed 6 participants 6 participants 6 participants 6 participants 19 participants 47 participants 29 participants
3
(2 to 4)
3
(2 to 3)
3
(3 to 4)
3
(2 to 6)
3
(2 to 6)
3
(1.50 to 6.17)
3.05
(2.00 to 7.20)
9.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of Decitabine
Hide 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.
Time Frame At specific timepoints from 0 to 24 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with evaluable PK measurements are included.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/Group Description:
Cohort 1 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).
Cohort 2 was administered 60 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).
Cohort 3 was administered 100 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).
Cohort 4 was administered 100 mg oral cedazuridine and 40 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).
Cohort 5 was administered 100 mg oral cedazuridine and 30 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).
Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 6 6 6 6 19 47 29
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
54.0
(36%)
76.5
(42%)
80.9
(41%)
161
(51%)
138
(55%)
126
(70.9%)
126
(76.2%)
10.Secondary Outcome
Title Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2
Hide 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.
Time Frame At specific timepoints from 0 to 24 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Participants with evaluable PK measurements are included.
Arm/Group Title Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/Group Description:
Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 49 29
Median (Full Range)
Unit of Measure: hours
1.00
(0.47 to 3.00)
0.95
(0.47 to 2.12)
11.Secondary Outcome
Title Duration of Complete Response in Phase 1
Hide 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.
Time Frame Up to 32 Months
Hide Outcome Measure Data
Hide Analysis Population Description
The efficacy population includes all participants in Phase 1 who received at least one dose of investigational product.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5
Hide Arm/Group Description:
Cohort 1 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).
Cohort 2 was administered 60 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).
Cohort 3 was administered 100 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).
Cohort 4 was administered 100 mg oral cedazuridine and 40 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).
Cohort 5 was administered 100 mg oral cedazuridine and 30 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).
Overall Number of Participants Analyzed 7 6 6 6 19
Median (Full Range)
Unit of Measure: days
546.00
(546.0 to 546.0)
364.00
(56.0 to 672.0)
470.00
(470.0 to 470.0)
29.00
(29.0 to 29.0)
399.0
(202.0 to 420.0)
12.Secondary Outcome
Title Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate
Hide 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.
Time Frame Up to approximately 29 months (data for Phase 2 participants as of 05 June 2018 data cut-off)
Hide Outcome Measure Data
Hide Analysis Population Description
The efficacy population includes all participants in Phase 2 who received at least one dose of investigational product.
Arm/Group Title Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/Group Description:
Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 50 30
Median (95% Confidence Interval)
Unit of Measure: days
399.0
(202.0 to 420.0)
175.0 [1] 
(112.0 to NA)
[1]
Not estimable at the time of data cut
13.Secondary Outcome
Title Mean Maximum %LINE Demethylation in Phase 1
Hide 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.
Time Frame Pre-dose to Day 28 in Course 2 (28 days per Course)
Hide Outcome Measure Data
Hide Analysis Population Description
The pharmacodynamic population includes all participants in Phase 1 with evaluable data who received at least one dose of investigational product.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5
Hide Arm/Group Description:
Cohort 1 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).
Cohort 2 was administered 60 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).
Cohort 3 was administered 100 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).
Cohort 4 was administered 100 mg oral cedazuridine and 40 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).
Cohort 5 was administered 100 mg oral cedazuridine and 30 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).
Overall Number of Participants Analyzed 6 6 6 6 18
Mean (Standard Deviation)
Unit of Measure: Percent change
Course 1 -8.3  (5.28) -9.2  (5.84) -10.5  (7.55) -12.1  (7.82) -11.7  (5.67)
Course 2 -8.0  (3.56) -7.1  (2.92) -8.9  (5.42) -8.6  (3.24) -7.5  (5.47)
14.Secondary Outcome
Title Number of Participants With Overall Response in Phase 1
Hide 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).
Time Frame Up to 32 months
Hide Outcome Measure Data
Hide Analysis Population Description
The efficacy population includes all participants in Phase 1 who received at least one dose of investigational product.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5
Hide Arm/Group Description:
Cohort 1 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).
Cohort 2 was administered 60 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).
Cohort 3 was administered 100 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).
Cohort 4 was administered 100 mg oral cedazuridine and 40 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).
Cohort 5 was administered 100 mg oral cedazuridine and 30 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).
Overall Number of Participants Analyzed 7 6 6 6 19
Measure Type: Count of Participants
Unit of Measure: Participants
4
  57.1%
3
  50.0%
2
  33.3%
1
  16.7%
3
  15.8%
15.Secondary Outcome
Title Number of Participants With Adverse Events
Hide 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.
Time Frame Up to 32 months
Hide Outcome Measure Data
Hide Analysis Population Description
The safety population includes all participants in Phase 1 and Phase 2 who received at least one dose of investigational product.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/Group Description:
Cohort 1 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).
Cohort 2 was administered 60 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).
Cohort 3 was administered 100 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).
Cohort 4 was administered 100 mg oral cedazuridine and 40 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).
Cohort 5 was administered 100 mg oral cedazuridine and 30 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).
Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 7 6 6 6 19 49 29
Measure Type: Count of Participants
Unit of Measure: Participants
Any Adverse Event
6
  85.7%
6
 100.0%
6
 100.0%
5
  83.3%
19
 100.0%
47
  95.9%
28
  96.6%
Any Grade ≥3 Adverse Event
5
  71.4%
6
 100.0%
5
  83.3%
5
  83.3%
18
  94.7%
43
  87.8%
22
  75.9%
16.Secondary Outcome
Title Number of Participants With Hematological Improvement
Hide Description Hematological improvement was calculated as defined by the IWG 2006 MDS Response Criteria.
Time Frame Up to 32 months
Hide Outcome Measure Data
Hide Analysis Population Description
The efficacy population includes all participants in Phase 1 and Phase 2 who received at least one dose of investigational product.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/Group Description:

Cohort 1 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: Oral investigational product and approved IV decitabine

Cohort 2 was administered 60 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: Oral investigational product and approved IV decitabine

Cohort 3 was administered 100 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: Oral investigational product and approved IV decitabine

Cohort 4 was administered 100 mg oral cedazuridine and 40 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: Oral investigational product and approved IV decitabine

Cohort 5 was administered 100 mg oral cedazuridine and 30 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: Oral investigational product and approved IV decitabine

Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 7 6 6 6 19 50 30
Measure Type: Count of Participants
Unit of Measure: Participants
4
  57.1%
3
  50.0%
2
  33.3%
0
   0.0%
3
  15.8%
6
  12.0%
7
  23.3%
17.Secondary Outcome
Title Number of Participants With Transfusion Independence
Hide 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.
Time Frame Up to 32 months
Hide Outcome Measure Data
Hide Analysis Population Description
The efficacy population includes all participants in Phase 1 and Phase 2 who received at least one dose of investigational product and were transfusion-dependent at baseline. Number analyzed is the number of participants who were transfusion-dependent at baseline.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/Group Description:
Cohort 1 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).
Cohort 2 was administered 60 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).
Cohort 3 was administered 100 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).
Cohort 4 was administered 100 mg oral cedazuridine and 40 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).
Cohort 1 was administered 100 mg oral cedazuridine and 30 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).
Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 4 2 6 5 12 29 21
Measure Type: Count of Participants
Unit of Measure: Participants
Red Blood Cell Number Analyzed 4 participants 2 participants 5 participants 4 participants 8 participants 22 participants 16 participants
2
  50.0%
0
   0.0%
3
  60.0%
0
   0.0%
2
  25.0%
11
  50.0%
8
  50.0%
Platelet Number Analyzed 0 participants 0 participants 1 participants 1 participants 4 participants 7 participants 5 participants
0 0
1
 100.0%
0
   0.0%
1
  25.0%
3
  42.9%
3
  60.0%
18.Secondary Outcome
Title Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death
Hide 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.
Time Frame Up to 32 months
Hide Outcome Measure Data
Hide Analysis Population Description
The efficacy population includes all participants in Phase 1 and Phase 2 who received at least one dose of investigational product.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/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).
Starting cohort was administered 60 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).
Starting cohort was administered 100 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).
Starting cohort was administered 100 mg oral cedazuridine and 40 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).
Starting cohort was administered 100 mg oral cedazuridine and 30 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).
Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 7 6 6 6 19 50 30
Measure Type: Count of Participants
Unit of Measure: Participants
Censored
4
  57.1%
5
  83.3%
6
 100.0%
5
  83.3%
11
  57.9%
22
  44.0%
11
  36.7%
Event
3
  42.9%
1
  16.7%
0
   0.0%
1
  16.7%
8
  42.1%
28
  56.0%
19
  63.3%
19.Secondary Outcome
Title Number of Participants With Overall Survival
Hide 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.
Time Frame Up to 32 months
Hide Outcome Measure Data
Hide Analysis Population Description
The efficacy population includes all participants in Phase 1 and Phase 2 who received at least one dose of investigational product.
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/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).
Starting cohort was administered 60 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).
Starting cohort was administered 100 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).
Starting cohort was administered 100 mg oral cedazuridine and 40 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).
Starting cohort was administered 100 mg oral cedazuridine and 30 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).
Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
Overall Number of Participants Analyzed 7 6 6 6 19 50 30
Measure Type: Count of Participants
Unit of Measure: Participants
Censored
6
  85.7%
5
  83.3%
6
 100.0%
5
  83.3%
15
  78.9%
26
  52.0%
14
  46.7%
Event
1
  14.3%
1
  16.7%
0
   0.0%
1
  16.7%
4
  21.1%
24
  48.0%
16
  53.3%
Time Frame Up to 3.5 years
Adverse Event Reporting Description Treatment-emergent adverse events were recorded from the start of study treatment until 30 days after the last dose of study treatment.
 
Arm/Group Title Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Hide Arm/Group Description Cohort 1 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). Cohort 2 was administered 60 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). Cohort 3 was administered 100 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). Cohort 4 was administered 100 mg oral cedazuridine and 40 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). Cohort 1 was administered 100 mg oral cedazuridine and 30 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). Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (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, all participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study. Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine/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.
All-Cause Mortality
Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/7 (14.29%)      1/6 (16.67%)      0/6 (0.00%)      1/6 (16.67%)      4/19 (21.05%)      24/50 (48.00%)      16/30 (53.33%)    
Hide Serious Adverse Events
Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/7 (28.57%)      4/6 (66.67%)      2/6 (33.33%)      5/6 (83.33%)      13/19 (68.42%)      37/50 (74.00%)      23/30 (76.67%)    
Blood and lymphatic system disorders               
Febrile neutropenia * 1  1/7 (14.29%)  5 1/6 (16.67%)  1 1/6 (16.67%)  1 2/6 (33.33%)  8 3/19 (15.79%)  3 17/50 (34.00%)  30 7/30 (23.33%)  10
Anemia * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Cardiac disorders               
Cardiac arrest * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 1/30 (3.33%)  1
Cardiogenic shock * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Tachycardia * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Myocarditis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Palpitations * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Sinus tachycardia * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Gastrointestinal disorders               
Abdominal pain * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 1/30 (3.33%)  1
Gastrointestinal hemorrhage * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/19 (0.00%)  0 2/50 (4.00%)  3 1/30 (3.33%)  1
Colonic obstruction * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Diarrhea * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Malena * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 1/30 (3.33%)  1
Nausea * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 2/50 (4.00%)  2 0/30 (0.00%)  0
Pancreatitis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Anal fissure * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 1/30 (3.33%)  1
General disorders               
Edema peripheral * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 1/30 (3.33%)  1
Multiple organ dysfunction syndrome * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Pyrexia * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 3/50 (6.00%)  3 1/30 (3.33%)  1
Sudden death * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 1/30 (3.33%)  1
Fatigue * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  2 0/30 (0.00%)  0
Immune system disorders               
Hypersensitivity * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Infections and infestations               
Pneumonia * 1  0/7 (0.00%)  0 1/6 (16.67%)  2 0/6 (0.00%)  0 2/6 (33.33%)  2 3/19 (15.79%)  3 7/50 (14.00%)  7 4/30 (13.33%)  5
Bacteremia * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 1/19 (5.26%)  1 3/50 (6.00%)  3 0/30 (0.00%)  0
Cellulitis * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 3/50 (6.00%)  3 1/30 (3.33%)  1
Sepsis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 2/19 (10.53%)  2 4/50 (8.00%)  4 5/30 (16.67%)  5
Tooth infection * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Atypical mycobacterial infection * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Clostridium difficile colitis * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Clostridium difficile infection * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Diverticulitis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Influenza * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 1/50 (2.00%)  1 1/30 (3.33%)  1
Respiratory syncytial virus infection * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Staphylococcal sepsis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Upper respiratory tract infection * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 1/50 (2.00%)  1 1/30 (3.33%)  1
Urinary tract infection * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 2/50 (4.00%)  2 2/30 (6.67%)  2
Septic shock * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 2/30 (6.67%)  2
Bacterial infection * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Candida sepsis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Endocarditis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Escherichia infection * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Oral infection * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Pharyngitis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Subcutaneous abscess * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Atypical pneumonia * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 1/30 (3.33%)  1
Pseudomonal sepsis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 1/30 (3.33%)  1
Anal abscess * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Pyomyositis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Soft tissue infection * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Injury, poisoning and procedural complications               
Cervical vertebral fracture * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Facial bones fracture * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Upper limb fracture * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Fall * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Subdural hemorrhage * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 1/30 (3.33%)  1
Investigations               
Liver function test increased * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Metabolism and nutrition disorders               
Failure to thrive * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 1/50 (2.00%)  1 1/30 (3.33%)  1
Dehydration * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 1/30 (3.33%)  1
Gout * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Musculoskeletal and connective tissue disorders               
Arthralgia * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Back pain * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 2/50 (4.00%)  2 0/30 (0.00%)  0
Bursitis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Joint stiffness * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Muscular weakness * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 2/50 (4.00%)  3 0/30 (0.00%)  0
Musculoskeletal stiffness * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Neck pain * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Squamous cell carcinoma * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Small cell lung cancer * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 1/30 (3.33%)  1
Nervous system disorders               
Vertebral artery dissection * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Syncope * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 2/30 (6.67%)  2
Cerebrovascular accident * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Seizure * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  2 0/30 (0.00%)  0
Psychiatric disorders               
Mental status change * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Renal and urinary disorders               
Acute kidney injury * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Respiratory, thoracic and mediastinal disorders               
Epistaxis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 1/30 (3.33%)  1
Respiratory failure * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 1/30 (3.33%)  1
Tachypnea * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 1/30 (3.33%)  1
Dyspnea * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 3/50 (6.00%)  5 0/30 (0.00%)  0
Nasal congestion * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Skin and subcutaneous tissue disorders               
Acute febrile neutrophilic dermatosis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 0/30 (0.00%)  0
Vascular disorders               
Peripheral ischemia * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 1/30 (3.33%)  1
Hypertension * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 2/50 (4.00%)  2 0/30 (0.00%)  0
1
Term from vocabulary, MedDRA 20.0
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Phase 1 Dose Escalation Cohort 1 Phase 1 Dose Escalation Cohort 2 Phase 1 Dose Escalation Cohort 3 Phase 1 Dose Escalation Cohort 4 Phase 1 Dose Escalation Cohort 5 Phase 2 Dose Confirmation Phase 2 Fixed-Dose Combination
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/7 (85.71%)      6/6 (100.00%)      6/6 (100.00%)      5/6 (83.33%)      18/19 (94.74%)      48/50 (96.00%)      30/30 (100.00%)    
Blood and lymphatic system disorders               
Thrombocytopenia * 1  4/7 (57.14%)  12 3/6 (50.00%)  4 4/6 (66.67%)  11 3/6 (50.00%)  7 9/19 (47.37%)  24 27/50 (54.00%)  66 14/30 (46.67%)  58
Neutropenia * 1  3/7 (42.86%)  13 2/6 (33.33%)  12 4/6 (66.67%)  4 1/6 (16.67%)  4 4/19 (21.05%)  7 28/50 (56.00%)  119 12/30 (40.00%)  52
Anemia * 1  4/7 (57.14%)  7 1/6 (16.67%)  1 2/6 (33.33%)  2 2/6 (33.33%)  4 4/19 (21.05%)  7 14/50 (28.00%)  40 7/30 (23.33%)  21
Leukopenia * 1  1/7 (14.29%)  6 2/6 (33.33%)  6 1/6 (16.67%)  2 0/6 (0.00%)  0 3/19 (15.79%)  6 11/50 (22.00%)  45 10/30 (33.33%)  42
Lymphadenopathy * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Febrile neutropenia * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 5/50 (10.00%)  7 5/30 (16.67%)  6
Thrombocytosis * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Cardiac disorders               
Sinus tachycardia * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 2/19 (10.53%)  2 0/50 (0.00%)  0 0/30 (0.00%)  0
Bradycardia * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Pericardial effusion * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Sinus bradycardia * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Palpitations * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 3/50 (6.00%)  3 0/30 (0.00%)  0
Ear and labyrinth disorders               
Vertigo * 1  1/7 (14.29%)  1 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Cerumen impaction * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Ear pain * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Eye disorders               
Diplopia * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Dry eye * 1  1/7 (14.29%)  2 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Eye irritation * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Eye pruritus * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Vision blurred * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Vitreous floaters * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Conjunctival hemorrhage * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 2/30 (6.67%)  2
Gastrointestinal disorders               
Constipation * 1  2/7 (28.57%)  2 5/6 (83.33%)  5 1/6 (16.67%)  1 1/6 (16.67%)  1 7/19 (36.84%)  8 17/50 (34.00%)  22 13/30 (43.33%)  15
Nausea * 1  1/7 (14.29%)  2 4/6 (66.67%)  4 3/6 (50.00%)  3 2/6 (33.33%)  3 4/19 (21.05%)  5 13/50 (26.00%)  18 14/30 (46.67%)  18
Diarrhea * 1  2/7 (28.57%)  3 1/6 (16.67%)  2 2/6 (33.33%)  3 1/6 (16.67%)  2 1/19 (5.26%)  1 19/50 (38.00%)  26 9/30 (30.00%)  10
Abdominal pain * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 2/6 (33.33%)  2 2/19 (10.53%)  2 3/50 (6.00%)  3 3/30 (10.00%)  3
Hemorrhoids * 1  1/7 (14.29%)  1 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 3/19 (15.79%)  3 2/50 (4.00%)  2 3/30 (10.00%)  3
Stomatitis * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 2/6 (33.33%)  2 2/19 (10.53%)  3 4/50 (8.00%)  4 4/30 (13.33%)  5
Dry mouth * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 1/6 (16.67%)  1 1/6 (16.67%)  1 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Dyspepsia * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 1/6 (16.67%)  1 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 2/30 (6.67%)  2
Mouth ulceration * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  2 1/6 (16.67%)  2 1/19 (5.26%)  1 9/50 (18.00%)  11 0/30 (0.00%)  0
Vomiting * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  2 1/6 (16.67%)  1 1/19 (5.26%)  1 2/50 (4.00%)  2 8/30 (26.67%)  10
Abdominal distension * 1  1/7 (14.29%)  1 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 2/50 (4.00%)  2 2/30 (6.67%)  2
Gingival bleeding * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 1/19 (5.26%)  2 0/50 (0.00%)  0 0/30 (0.00%)  0
Oral pain * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 1/6 (16.67%)  1 0/19 (0.00%)  0 3/50 (6.00%)  4 1/30 (3.33%)  1
Rectal hemorrhage * 1  2/7 (28.57%)  2 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Abdominal discomfort * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Ascites * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Duodenitis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Dysphagia * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Gastrointestinal pain * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Gastroesophageal reflux disease * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Inguinal hernia * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Lip dry * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Lower gastrointestinal hemorrhage * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Pancreatic cyst * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Periodontal disease * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Proctalgia * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 2/50 (4.00%)  2 2/30 (6.67%)  2
Tongue discoloration * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Tongue ulceration * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Abdominal pain upper * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 6/30 (20.00%)  7
Dental caries * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 1/50 (2.00%)  1 2/30 (6.67%)  2
General disorders               
Fatigue * 1  2/7 (28.57%)  4 5/6 (83.33%)  6 3/6 (50.00%)  4 4/6 (66.67%)  6 5/19 (26.32%)  5 21/50 (42.00%)  35 11/30 (36.67%)  14
Edema peripheral * 1  0/7 (0.00%)  0 2/6 (33.33%)  2 1/6 (16.67%)  1 2/6 (33.33%)  2 4/19 (21.05%)  4 12/50 (24.00%)  15 3/30 (10.00%)  3
Pyrexia * 1  1/7 (14.29%)  1 2/6 (33.33%)  2 1/6 (16.67%)  1 2/6 (33.33%)  3 1/19 (5.26%)  1 6/50 (12.00%)  12 7/30 (23.33%)  9
Edema * 1  1/7 (14.29%)  1 2/6 (33.33%)  2 0/6 (0.00%)  0 1/6 (16.67%)  3 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Asthenia * 1  1/7 (14.29%)  1 1/6 (16.67%)  1 2/6 (33.33%)  2 0/6 (0.00%)  0 0/19 (0.00%)  0 7/50 (14.00%)  8 9/30 (30.00%)  11
Pain * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 1/6 (16.67%)  1 1/19 (5.26%)  1 3/50 (6.00%)  3 0/30 (0.00%)  0
Chills * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 2/6 (33.33%)  2 0/19 (0.00%)  0 3/50 (6.00%)  4 3/30 (10.00%)  4
Catheter site erythema * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Chest discomfort * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Cyst * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Generalized edema * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Implant site erythema * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  2 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Peripheral swelling * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Influenza like illness * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 3/50 (6.00%)  3 0/30 (0.00%)  0
Immune system disorders               
Seasonal allergy * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Infections and infestations               
Pneumonia * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 1/6 (16.67%)  1 1/19 (5.26%)  1 4/50 (8.00%)  4 1/30 (3.33%)  1
Atypical mycobacterial infection * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Bronchitis * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Device related infection * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Diverticulitis * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Eye infection * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Furuncle * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Gastroenteritis * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Heliobacter infection * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Laryngitis * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Oral herpes * 1  1/7 (14.29%)  2 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 3/50 (6.00%)  4 1/30 (3.33%)  1
Otitis externa * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Rash pustular * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Sepsis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Sinusitis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 2/50 (4.00%)  2 3/30 (10.00%)  3
Subcutaneous abscess * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Tooth infection * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 2/30 (6.67%)  2
Urinary tract infection * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 4/50 (8.00%)  5 1/30 (3.33%)  1
Vaginal infection * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Upper respiratory tract infection * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 3/50 (6.00%)  3 3/30 (10.00%)  3
Influenza * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 2/30 (6.67%)  2
Nasopharyngitis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 2/50 (4.00%)  2 2/30 (6.67%)  2
Cellulitis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 9/50 (18.00%)  10 0/30 (0.00%)  0
Oral candidiasis * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 2/50 (4.00%)  2 2/30 (6.67%)  3
Injury, poisoning and procedural complications               
Fall * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 2/19 (10.53%)  2 6/50 (12.00%)  7 5/30 (16.67%)  5
Contusion * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 1/19 (5.26%)  1 7/50 (14.00%)  8 4/30 (13.33%)  5
Laceration * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 4/50 (8.00%)  4 2/30 (6.67%)  2
Arthropod bite * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Iliotibial band syndrome * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Ligament sprain * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Rib fracture * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0 0/30 (0.00%)  0
Skin abrasion * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Subdural hematoma * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 1/30 (3.33%)  1
Transfusion reaction * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  1 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Investigations               
Alanine aminotransferase increased * 1  1/7 (14.29%)  3 1/6 (16.67%)  2 1/6 (16.67%)  1 1/6 (16.67%)  1 5/19 (26.32%)  7 11/50 (22.00%)  20 4/30 (13.33%)  9
Electrocardiogram QT prolonged * 1  1/7 (14.29%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 1/50 (2.00%)  1 4/30 (13.33%)  7
Weight decreased * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 4/19 (21.05%)  5 7/50 (14.00%)  10 6/30 (20.00%)  7
Blood creatinine increased * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 3/19 (15.79%)  4 7/50 (14.00%)  8 4/30 (13.33%)  4
Aspartate aminotransferase increased * 1  1/7 (14.29%)  3 2/6 (33.33%)  3 0/6 (0.00%)  0 2/6 (33.33%)  4 4/19 (21.05%)  6 9/50 (18.00%)  18 3/30 (10.00%)  5
Blood bilirubin increased * 1  2/7 (28.57%)  4 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  5 5/50 (10.00%)  9 4/30 (13.33%)  4
Blood alkaline phosphatase increased * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/6 (16.67%)  2 2/19 (10.53%)  4 4/50 (8.00%)  9 1/30 (3.33%)  1
Activated partial thromboplastin time prolonged * 1  0/7 (0.00%)  0 1/6 (16.67%)  1 0/6 (0.00%)  0 0/6 (0.00%)  0 0/19 (0.00%)  0 0/50 (0.00%)  0 0/30 (0.00%)  0
Alanine aminotransferase decreased * 1  0/7 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 0/6 (0.00%)  0 1/19 (5.26%)  1 0/50 (0.00%)  0