Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral Cytidine Deaminase Inhibitor (CDAi) in Patients With Myelodysplastic Syndromes (MDS)
Sponsor
Astex Pharmaceuticals, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT02103478
Collaborator
(none)
130
17
3
61.2
7.6
0.1
Study Details
Study Description
Brief Summary
This first-in-human, 3-stage, open-label study evaluated the safety and pharmacokinetics of ASTX727, as well as determined the dose for later stages.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
The trial was designed to define daily doses of the individual components (cedazuridine [E7727] or decitabine) so that decitabine exposure after oral administration would be comparable to exposure after IV decitabine at the approved daily dose of 20 mg/m^2. The main objective of Phases 1 and 2 was to establish and confirm the doses of the 2 components to be used in the final fixed-dose combination (FDC) product (ASTX727) using mainly pharmacokinetics and pharmacodynamics as endpoints.
Study Design
Study Type:
Interventional
Actual Enrollment
:
130 participants
Allocation:
Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 With Oral Decitabine in Subjects With Myelodysplastic Syndromes (MDS)
Actual Study Start Date
:
Oct 28, 2014
Actual Primary Completion Date
:
Jun 5, 2018
Actual Study Completion Date
:
Dec 4, 2019
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Phase 1 Dose Escalation Starting cohort was administered 40 mg oral cedazuridine and 20 mg oral decitabine. Participants were enrolled into successive cohorts in which either the cedazuridine or decitabine oral dose was varied in Course 1 Day 2 through Course 1 Day 5 for comparison with a single dose of IV decitabine at 20 mg/m^2 administered on Day 1 by continuous IV infusion over 1 hour (28 days per course). |
Drug: ASTX727 Dose Escalation
Oral investigational product and approved IV decitabine
Other Names:
|
| Experimental: Phase 2 Dose Confirmation Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (E7727) (100 mg) + decitabine (35 mg) capsules Dailyx5 in Course 1 followed by IV decitabine (20 mg/m^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study. |
Drug: ASTX727 Dose Confirmation
Randomization cross over design for courses 1 and 2
Other Names:
|
| Experimental: Phase 2 Fixed-Dose Combination Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine (E7727)/35 mg decitabine) Dailyx5 in Course 1 followed by IV decitabine (20 mg/m^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, all participants received the FDC tablet Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study. |
Drug: ASTX727 Fixed-Dose Combination
Fixed-dose investigational product
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1 [Day 5]
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).
- Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2 [Pre-dose to Day 5]
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.
- Number of Participants With Dose-limiting Toxicity in Phase 1 [Up to Day 28 in Course 1 (28 days per course)]
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.
- Mean Maximum %LINE Demethylation in Phase 2 [Pre-dose to Day 28 in Course 2 (28 days per course)]
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.
- Number of Participants With Overall Response in Phase 2 [Up to approximately 29 months]
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).
Secondary Outcome Measures
- Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer [At specified timepoints from 0 to 24 hours post-dose]
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.
- Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer [At specific timepoints from 0 to 24 hours post-dose]
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 to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer [At specific timepoints from 0 to 24 hours post-dose]
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.
- Maximum Observed Plasma Concentration (Cmax) of Decitabine [At specific timepoints from 0 to 24 hours post-dose]
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 to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2 [At specific timepoints from 0 to 24 hours post-dose]
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.
- Duration of Complete Response in Phase 1 [Up to 32 Months]
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.
- Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate [Up to approximately 29 months]
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.
- Mean Maximum %LINE Demethylation in Phase 1 [Pre-dose to Day 28 in Course 2 (28 days per course)]
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.
- Number of Participants With Overall Response in Phase 1 [Up to 32 months]
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).
- Number of Participants With Adverse Events [Up to 5 years]
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.
- Number of Participants With Hematological Improvement [Up to 32 months]
Hematological improvement was calculated as defined by the IWG 2006 MDS Response Criteria.
- Number of Participants With Transfusion Independence [Up to 32 months]
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.
- Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death [Up to 32 months]
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.
- Number of Participants With Overall Survival [Up to 32 months]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
International Prognostic Scoring System (IPSS) low, intermediate -1, intermediate-2, or high risk MDS (including chronic myelomonocytic leukemia; CMML) in Dose Escalation and Dose Confirmation-Randomization; only intermediate-2, or high risk MDS in Dose Confirmation-Open Label
-
Eastern Cooperative Oncology Group (ECOG) 0 to 2
-
No major surgery within 2 weeks of starting study treatment
-
No cytotoxic chemotherapy within 2 weeks of starting study treatment
-
Able to swallow pills
Exclusion Criteria:
-
Previous treatment with 2 or more courses of decitabine (all stages) or azacitidine (Dose Confirmation stage only)
-
Treatment with investigational therapy within 2 weeks of study treatment
-
Uncontrolled medical disease(s) or active, uncontrolled infection
-
Diagnosed with acute myeloid leukemia (AML)
-
Active uncontrolled gastric or duodenal ulcer
-
Known history of HIV or hepatitis C or B
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Mayo Clinic | Phoenix | Arizona | United States | 85054 |
| 2 | University of Southern California | Los Angeles | California | United States | 90024 |
| 3 | University of Chicago | Chicago | Illinois | United States | 60637 |
| 4 | Horizon Oncology | Lafayette | Indiana | United States | 47905 |
| 5 | Johns Hopkins | Baltimore | Maryland | United States | 21231 |
| 6 | Massachusetts General Hospital | Boston | Massachusetts | United States | 02114 |
| 7 | Dana Farber Cancer Institute | Boston | Massachusetts | United States | 02215 |
| 8 | John Theurer Cancer Center/ Hackensack University Medical Center | Hackensack | New Jersey | United States | 07601 |
| 9 | Roswell Park Cancer Institute | Buffalo | New York | United States | 14263 |
| 10 | Weill Cornell Medical College - New York Presbyterian Hospital | New York | New York | United States | 10021 |
| 11 | Vanderbilt Ingram Cancer Center | Nashville | Tennessee | United States | 37232 |
| 12 | M. D. Anderson | Houston | Texas | United States | 77030 |
| 13 | Medical College of Wisconsin | Milwaukee | Wisconsin | United States | 53226 |
| 14 | University of Alberta Hospital | Edmonton | Alberta | Canada | T6G 2G3 |
| 15 | Sunnybrook Health Sciences Centre, Odette Cancer Centre | Toronto | Ontario | Canada | M4N 3M5 |
| 16 | Princess Margaret Cancer Center | Toronto | Ontario | Canada | M5G 2M9 |
| 17 | Hôpital Maisonneuve-Rosemont | Montréal | Quebec | Canada | H1T 2M4 |
Sponsors and Collaborators
- Astex Pharmaceuticals, Inc.
Investigators
- Study Director: Mohammad Azab, MD, Astex Pharmaceuticals, Inc.
- Study Chair: James Lowder, MD, Astex Pharmaceuticals, Inc.
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Astex Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT02103478
Other Study ID Numbers:
- ASTX727-01
First Posted:
Apr 4, 2014
Last Update Posted:
Dec 23, 2020
Last Verified:
Dec 1, 2020
Individual Participant Data (IPD) Sharing Statement:
Undecided
Plan to Share IPD:
Undecided
Keywords provided by Astex Pharmaceuticals, Inc.
Additional relevant MeSH terms:
Study Results
Participant Flow
| 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 Detail | Response data for Phase 1 per June 2017 data cut and for Phase 2 per June 2018 data cut. Median follow up in Phase 1 was 1915.5 days (range: 1771-2213) and 1563.0 days in Phase 2 (range: 1199-1710). |
| 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 |
|---|---|---|---|---|---|---|---|---|---|
| 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 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 7 | 6 | 6 | 6 | 19 | 25 | 25 | 16 | 14 |
Baseline Characteristics
| 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 |
|---|---|---|---|---|---|---|---|---|
| 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 Participants | 7 | 6 | 6 | 6 | 19 | 50 | 30 | 124 |
| Age (years) [Mean (Standard Deviation) ] | ||||||||
| Mean (Standard Deviation) [years] |
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 (Count of Participants) | ||||||||
| Female |
4
57.1%
|
1
16.7%
|
3
50%
|
2
33.3%
|
4
21.1%
|
9
18%
|
10
33.3%
|
33
26.6%
|
| Male |
3
42.9%
|
5
83.3%
|
3
50%
|
4
66.7%
|
15
78.9%
|
41
82%
|
20
66.7%
|
91
73.4%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||||||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
1
16.7%
|
0
0%
|
2
4%
|
3
10%
|
6
4.8%
|
| Not Hispanic or Latino |
7
100%
|
6
100%
|
5
83.3%
|
5
83.3%
|
18
94.7%
|
46
92%
|
26
86.7%
|
113
91.1%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
1
16.7%
|
0
0%
|
1
5.3%
|
2
4%
|
1
3.3%
|
5
4%
|
| Race (NIH/OMB) (Count of Participants) | ||||||||
| American Indian or Alaska Native |
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%
|
1
2%
|
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%
|
| Black or African American |
1
14.3%
|
0
0%
|
0
0%
|
1
16.7%
|
1
5.3%
|
2
4%
|
0
0%
|
5
4%
|
| White |
6
85.7%
|
6
100%
|
5
83.3%
|
5
83.3%
|
18
94.7%
|
46
92%
|
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%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
1
16.7%
|
0
0%
|
0
0%
|
1
2%
|
2
6.7%
|
4
3.2%
|
| Region of Enrollment (participants) [Number] | ||||||||
| Canada |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
8
16%
|
8
26.7%
|
16
12.9%
|
| United States |
7
100%
|
6
100%
|
6
100%
|
6
100%
|
19
100%
|
42
84%
|
22
73.3%
|
108
87.1%
|
Outcome Measures
| Title | Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|
| 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). |
| Measure Participants | 5 | 6 | 6 | 6 | 19 |
| Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL] |
53.6
(40)
|
68.9
(44)
|
94.8
(46)
|
221
(74)
|
146
(50)
|
| Title | Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 40 | 24 |
| Geometric Least Squares Mean (80% Confidence Interval) [Ratio of Geometric LSM] |
93.52
|
97.59
|
| Title | Number of Participants With Dose-limiting Toxicity in Phase 1 |
|---|---|
| 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) |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|
| 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). |
| Measure Participants | 7 | 6 | 6 | 6 | 19 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
5.3%
|
| Title | Mean Maximum %LINE Demethylation in Phase 2 |
|---|---|
| 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) |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 48 | 30 |
| Course 1 - Treatment |
11.159
|
10.077
|
| Course 1 - IV Decitabine |
11.303
|
12.665
|
| Course 2 - Treatment |
9.833
|
8.134
|
| Course 2 - IV Decitabine |
9.920
|
8.230
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase 1 Dose Escalation Cohort 1 |
|---|---|---|
| Comments | ||
| 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. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -0.144 | |
| Confidence Interval |
(2-Sided) 95% -3.165 to 2.876 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Course 1 | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Phase 1 Dose Escalation Cohort 1 |
|---|---|---|
| Comments | ||
| 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. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -0.087 | |
| Confidence Interval |
(2-Sided) 95% -3.463 to 3.288 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Course 2 | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Phase 1 Dose Escalation Cohort 2 |
|---|---|---|
| Comments | ||
| 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. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -2.588 | |
| Confidence Interval |
(2-Sided) 95% -6.074 to 0.899 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Course 1 | |
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Phase 1 Dose Escalation Cohort 2 |
|---|---|---|
| Comments | ||
| 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. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -0.096 | |
| Confidence Interval |
(2-Sided) 95% -5.080 to 4.888 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Course 2 | |
| Title | Number of Participants With Overall Response in Phase 2 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 50 | 30 |
| Count of Participants [Participants] |
29
414.3%
|
19
316.7%
|
| Title | Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|---|---|
| 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. |
| Measure Participants | 6 | 6 | 6 | 6 | 19 | 37 | 19 |
| Cedazuridine |
1650
(43)
|
1990
(64)
|
3190
(53)
|
4830
(51)
|
3490
(46)
|
2370
(56.8)
|
1510
(49.4)
|
| Cedazuridine-epimer |
503
(20)
|
917
(64)
|
1670
(48)
|
2180
(34)
|
1560
(56)
|
1190
(48.3)
|
710
(38)
|
| Title | Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|---|---|
| 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. |
| Measure Participants | 6 | 6 | 6 | 6 | 19 | 47 | 29 |
| 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)
|
| Title | Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|---|---|
| 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. |
| Measure Participants | 6 | 6 | 6 | 6 | 19 | 47 | 30 |
| Cedazuridine |
3
|
3
|
3
|
3
|
3
|
3
|
3
|
| Cedazuridine-epimer |
3
|
3
|
3
|
3
|
3
|
3
|
3.05
|
| Title | Maximum Observed Plasma Concentration (Cmax) of Decitabine |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|---|---|
| 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. |
| Measure Participants | 6 | 6 | 6 | 6 | 19 | 47 | 29 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
54.0
(36)
|
76.5
(42)
|
80.9
(41)
|
161
(51)
|
138
(55)
|
126
(70.9)
|
126
(76.2)
|
| Title | Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2 |
|---|---|
| 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants with evaluable PK measurements are included. |
| Arm/Group Title | Phase 2 Dose Confirmation | Phase 2 Fixed-Dose Combination |
|---|---|---|
| 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. |
| Measure Participants | 49 | 29 |
| Median (Full Range) [hours] |
1.00
|
0.95
|
| Title | Duration of Complete Response in Phase 1 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|
| 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). |
| Measure Participants | 7 | 6 | 6 | 6 | 19 |
| Median (Full Range) [days] |
546.00
|
364.00
|
470.00
|
29.00
|
399.0
|
| Title | Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|
| 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. |
| Measure Participants | 50 | 30 |
| Median (95% Confidence Interval) [days] |
413.0
|
155.0
|
| Title | Mean Maximum %LINE Demethylation in Phase 1 |
|---|---|
| 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) |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|
| 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). |
| Measure Participants | 6 | 6 | 6 | 6 | 18 |
| 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)
|
| Title | Number of Participants With Overall Response in Phase 1 |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|
| 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). |
| Measure Participants | 7 | 6 | 6 | 6 | 19 |
| Count of Participants [Participants] |
4
57.1%
|
3
50%
|
2
33.3%
|
1
16.7%
|
3
15.8%
|
| Title | Number of Participants With Adverse Events |
|---|---|
| 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 5 years |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|---|---|
| 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. |
| Measure Participants | 7 | 6 | 6 | 6 | 19 | 50 | 30 |
| Any Adverse Event |
6
85.7%
|
6
100%
|
6
100%
|
6
100%
|
19
100%
|
50
100%
|
30
100%
|
| Any Grade ≥3 Adverse Event |
5
71.4%
|
6
100%
|
5
83.3%
|
6
100%
|
18
94.7%
|
48
96%
|
28
93.3%
|
| Title | Number of Participants With Hematological Improvement |
|---|---|
| Description | Hematological improvement was calculated as defined by the IWG 2006 MDS Response Criteria. |
| Time Frame | Up to 32 months |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|---|---|
| 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. |
| Measure Participants | 7 | 6 | 6 | 6 | 19 | 50 | 30 |
| Count of Participants [Participants] |
4
57.1%
|
3
50%
|
2
33.3%
|
0
0%
|
3
15.8%
|
8
16%
|
7
23.3%
|
| Title | Number of Participants With Transfusion Independence |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|---|---|
| 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. |
| Measure Participants | 4 | 2 | 6 | 5 | 12 | 29 | 21 |
| Red Blood Cell |
2
28.6%
|
0
0%
|
3
50%
|
0
0%
|
2
10.5%
|
11
22%
|
8
26.7%
|
| Platelet |
0
0%
|
0
0%
|
1
16.7%
|
0
0%
|
1
5.3%
|
3
6%
|
3
10%
|
| Title | Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|---|---|
| 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. |
| Measure Participants | 7 | 6 | 6 | 6 | 19 | 50 | 30 |
| Censored |
4
57.1%
|
5
83.3%
|
6
100%
|
5
83.3%
|
11
57.9%
|
22
44%
|
11
36.7%
|
| Event |
3
42.9%
|
1
16.7%
|
0
0%
|
1
16.7%
|
8
42.1%
|
28
56%
|
19
63.3%
|
| Title | Number of Participants With Overall Survival |
|---|---|
| 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 |
Outcome Measure Data
| 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 |
|---|---|---|---|---|---|---|---|
| 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. |
| Measure Participants | 7 | 6 | 6 | 6 | 19 | 50 | 30 |
| Censored |
6
85.7%
|
5
83.3%
|
6
100%
|
5
83.3%
|
15
78.9%
|
26
52%
|
14
46.7%
|
| Event |
1
14.3%
|
1
16.7%
|
0
0%
|
1
16.7%
|
4
21.1%
|
24
48%
|
16
53.3%
|
Adverse Events
| Time Frame | Up to 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 | |||||||
| 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 (%) | # 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 (28.6%) | 2/6 (33.3%) | 1/6 (16.7%) | 1/6 (16.7%) | 5/19 (26.3%) | 29/50 (58%) | 21/30 (70%) | |||||||
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 (28.6%) | 4/6 (66.7%) | 2/6 (33.3%) | 6/6 (100%) | 14/19 (73.7%) | 39/50 (78%) | 25/30 (83.3%) | |||||||
| Blood and lymphatic system disorders | ||||||||||||||
| Febrile neutropenia | 1/7 (14.3%) | 5 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 8 | 2/19 (10.5%) | 2 | 17/50 (34%) | 31 | 7/30 (23.3%) | 10 |
| Anemia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/19 (5.3%) | 2 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Cardiac disorders | ||||||||||||||
| Cardiac arrest | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| Cardiogenic shock | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Tachycardia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Myocarditis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Palpitations | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Sinus tachycardia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Gastrointestinal disorders | ||||||||||||||
| Abdominal pain | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Gastrointestinal hemorrhage | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 2/50 (4%) | 3 | 1/30 (3.3%) | 1 |
| Large intestinal obstruction | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Diarrhea | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Malena | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| Nausea | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 2/50 (4%) | 2 | 0/30 (0%) | 0 |
| Pancreatitis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Anal fissure | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| Large intestine perforation | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| General disorders | ||||||||||||||
| Edema peripheral | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| Multiple organ dysfunction syndrome | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| Pyrexia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 3/50 (6%) | 3 | 1/30 (3.3%) | 1 |
| Sudden death | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| Fatigue | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 2/50 (4%) | 3 | 0/30 (0%) | 0 |
| Asthenia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 2/50 (4%) | 3 | 0/30 (0%) | 0 |
| Immune system disorders | ||||||||||||||
| Hypersensitivity | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Infections and infestations | ||||||||||||||
| Pneumonia | 0/7 (0%) | 0 | 1/6 (16.7%) | 2 | 0/6 (0%) | 0 | 2/6 (33.3%) | 2 | 3/19 (15.8%) | 3 | 8/50 (16%) | 8 | 5/30 (16.7%) | 6 |
| Bacteremia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/19 (5.3%) | 1 | 3/50 (6%) | 3 | 0/30 (0%) | 0 |
| Cellulitis | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 4/50 (8%) | 4 | 1/30 (3.3%) | 1 |
| Sepsis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 2 | 2/19 (10.5%) | 2 | 5/50 (10%) | 5 | 8/30 (26.7%) | 8 |
| Tooth infection | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Atypical mycobacterial infection | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Clostridium difficile colitis | 0/7 (0%) | 0 | 1/6 (16.7%) | 2 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Diverticulitis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Influenza | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 1/50 (2%) | 1 | 1/30 (3.3%) | 1 |
| Respiratory syncytial virus infection | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Respiratory tract infection | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Upper respiratory tract infection | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 1/50 (2%) | 1 | 1/30 (3.3%) | 1 |
| Septic shock | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 2/30 (6.7%) | 2 |
| Bacterial infection | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Endocarditis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Escherichia infection | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Pharyngitis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Subcutaneous abscess | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Atypical pneumonia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| Anal abscess | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Pyomyositis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Soft tissue infection | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Oral infection | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Alpha hemolytic streptococcal infection | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Perirectal abscess | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||||||||
| Cervical vertebral fracture | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Facial bones fracture | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Upper limb fracture | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Fall | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Subdural hemorrhage | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| Investigations | ||||||||||||||
| Liver function test increased | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||||||||||
| Failure to thrive | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 1/50 (2%) | 1 | 1/30 (3.3%) | 1 |
| Dehydration | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 1/30 (3.3%) | 1 |
| Gout | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Hyperkalemia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||||||||
| Arthralgia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Back pain | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 2/50 (4%) | 2 | 0/30 (0%) | 0 |
| Bursitis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Joint stiffness | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Musculoskeletal stiffness | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Neck pain | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||
| Squamous cell carcinoma | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Small cell lung cancer | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| Squamous cell carcinoma of the tongue | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Nervous system disorders | ||||||||||||||
| Vertebral artery dissection | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Syncope | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 2/30 (6.7%) | 2 |
| Cerebrovascular accident | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Seizure | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 2 | 0/30 (0%) | 0 |
| Psychiatric disorders | ||||||||||||||
| Mental status change | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Renal and urinary disorders | ||||||||||||||
| Acute kidney injury | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||
| Epistaxis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| Respiratory failure | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 1/30 (3.3%) | 1 |
| Tachypnea | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| Dyspnea | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 3/50 (6%) | 5 | 0/30 (0%) | 0 |
| Nasal congestion | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||||||||||
| Acute febrile neutrophilic dermatosis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 0/30 (0%) | 0 |
| Vascular disorders | ||||||||||||||
| Peripheral ischemia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| Hypertension | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 2/50 (4%) | 2 | 0/30 (0%) | 0 |
Other (Not Including 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 | 6/7 (85.7%) | 6/6 (100%) | 6/6 (100%) | 6/6 (100%) | 18/19 (94.7%) | 48/50 (96%) | 30/30 (100%) | |||||||
| Blood and lymphatic system disorders | ||||||||||||||
| Thrombocytopenia | 4/7 (57.1%) | 16 | 3/6 (50%) | 4 | 4/6 (66.7%) | 11 | 3/6 (50%) | 7 | 10/19 (52.6%) | 34 | 27/50 (54%) | 67 | 15/30 (50%) | 59 |
| Neutropenia | 3/7 (42.9%) | 13 | 2/6 (33.3%) | 12 | 4/6 (66.7%) | 4 | 1/6 (16.7%) | 4 | 6/19 (31.6%) | 24 | 28/50 (56%) | 125 | 12/30 (40%) | 53 |
| Anemia | 4/7 (57.1%) | 8 | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 2 | 3/6 (50%) | 6 | 5/19 (26.3%) | 16 | 16/50 (32%) | 46 | 8/30 (26.7%) | 23 |
| Leukopenia | 1/7 (14.3%) | 6 | 2/6 (33.3%) | 6 | 1/6 (16.7%) | 2 | 0/6 (0%) | 0 | 4/19 (21.1%) | 24 | 12/50 (24%) | 47 | 11/30 (36.7%) | 45 |
| Lymphadenopathy | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Febrile neutropenia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 5/50 (10%) | 7 | 5/30 (16.7%) | 6 |
| Thrombocytosis | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Cardiac disorders | ||||||||||||||
| Sinus tachycardia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 2/19 (10.5%) | 2 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Bradycardia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Pericardial effusion | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Sinus bradycardia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Palpitations | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 3/50 (6%) | 3 | 0/30 (0%) | 0 |
| Ear and labyrinth disorders | ||||||||||||||
| Vertigo | 1/7 (14.3%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Cerumen impaction | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Ear pain | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Eye disorders | ||||||||||||||
| Diplopia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Dry eye | 1/7 (14.3%) | 2 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Eye irritation | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Eye pruritus | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Vision blurred | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Vitreous floaters | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Conjunctival hemorrhage | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 2/30 (6.7%) | 2 |
| Cataract | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 2/30 (6.7%) | 2 |
| Gastrointestinal disorders | ||||||||||||||
| Constipation | 2/7 (28.6%) | 2 | 5/6 (83.3%) | 5 | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 4 | 7/19 (36.8%) | 8 | 17/50 (34%) | 24 | 12/30 (40%) | 15 |
| Nausea | 1/7 (14.3%) | 2 | 4/6 (66.7%) | 4 | 3/6 (50%) | 3 | 3/6 (50%) | 4 | 5/19 (26.3%) | 6 | 13/50 (26%) | 20 | 14/30 (46.7%) | 18 |
| Diarrhea | 2/7 (28.6%) | 3 | 1/6 (16.7%) | 2 | 2/6 (33.3%) | 3 | 1/6 (16.7%) | 2 | 1/19 (5.3%) | 1 | 19/50 (38%) | 28 | 9/30 (30%) | 11 |
| Abdominal pain | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 3/6 (50%) | 4 | 2/19 (10.5%) | 2 | 3/50 (6%) | 3 | 3/30 (10%) | 3 |
| Hemorrhoids | 1/7 (14.3%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 3/19 (15.8%) | 3 | 2/50 (4%) | 2 | 2/30 (6.7%) | 2 |
| Stomatitis | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 2 | 2/19 (10.5%) | 3 | 4/50 (8%) | 5 | 5/30 (16.7%) | 7 |
| Dry mouth | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Dyspepsia | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 2/30 (6.7%) | 2 |
| Mouth ulceration | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 1/6 (16.7%) | 2 | 1/19 (5.3%) | 1 | 6/50 (12%) | 8 | 0/30 (0%) | 0 |
| Vomiting | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 1/6 (16.7%) | 1 | 2/19 (10.5%) | 2 | 3/50 (6%) | 3 | 8/30 (26.7%) | 10 |
| Abdominal distension | 1/7 (14.3%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 2/50 (4%) | 2 | 2/30 (6.7%) | 2 |
| Gingival bleeding | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/19 (5.3%) | 2 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Oral pain | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 6/50 (12%) | 7 | 1/30 (3.3%) | 1 |
| Rectal hemorrhage | 2/7 (28.6%) | 2 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Abdominal discomfort | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Ascites | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Duodenitis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Dysphagia | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Gastroesophageal reflux disease | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Inguinal hernia | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Lip dry | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Lower gastrointestinal hemorrhage | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Pancreatic cyst | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Periodontal disease | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Proctalgia | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 2/50 (4%) | 2 | 2/30 (6.7%) | 2 |
| Tongue ulceration | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Abdominal pain upper | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 6/30 (20%) | 7 |
| Dental caries | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 2/30 (6.7%) | 2 |
| Toothache | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 3/50 (6%) | 4 | 0/30 (0%) | 0 |
| Hematochezia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Esophageal stenosis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Trichoglossia | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| General disorders | ||||||||||||||
| Fatigue | 2/7 (28.6%) | 4 | 5/6 (83.3%) | 7 | 3/6 (50%) | 4 | 5/6 (83.3%) | 7 | 6/19 (31.6%) | 6 | 23/50 (46%) | 37 | 12/30 (40%) | 15 |
| Edema peripheral | 0/7 (0%) | 0 | 3/6 (50%) | 4 | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 2 | 4/19 (21.1%) | 4 | 13/50 (26%) | 16 | 3/30 (10%) | 3 |
| Pyrexia | 1/7 (14.3%) | 1 | 2/6 (33.3%) | 2 | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 3 | 1/19 (5.3%) | 1 | 7/50 (14%) | 13 | 7/30 (23.3%) | 9 |
| Edema | 1/7 (14.3%) | 1 | 2/6 (33.3%) | 2 | 0/6 (0%) | 0 | 1/6 (16.7%) | 3 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Asthenia | 1/7 (14.3%) | 1 | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 2 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 7/50 (14%) | 8 | 9/30 (30%) | 12 |
| Pain | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/19 (5.3%) | 1 | 3/50 (6%) | 3 | 0/30 (0%) | 0 |
| Chills | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 2 | 0/19 (0%) | 0 | 3/50 (6%) | 5 | 3/30 (10%) | 4 |
| Catheter site erythema | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 3 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Chest discomfort | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 2 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Generalized edema | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Peripheral swelling | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Hepatobiliary disorders | ||||||||||||||
| Hyperbilirubinemia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Immune system disorders | ||||||||||||||
| Seasonal allergy | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Drug hypersensitivity | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Infections and infestations | ||||||||||||||
| Pneumonia | 1/7 (14.3%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/19 (5.3%) | 1 | 4/50 (8%) | 4 | 1/30 (3.3%) | 1 |
| Atypical mycobacterial infection | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Bronchitis | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Device related infection | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Diverticulitis | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Eye infection | 0/7 (0%) | 0 | 2/6 (33.3%) | 2 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Furuncle | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Gastroenteritis | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Heliobacter infection | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Laryngitis | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Oral herpes | 1/7 (14.3%) | 2 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 3/50 (6%) | 4 | 1/30 (3.3%) | 1 |
| Otitis externa | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Rash pustular | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Sepsis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Sinusitis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 2/50 (4%) | 2 | 3/30 (10%) | 3 |
| Subcutaneous abscess | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Tooth infection | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 2/30 (6.7%) | 2 |
| Urinary tract infection | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 4/50 (8%) | 5 | 1/30 (3.3%) | 1 |
| Vaginal infection | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Upper respiratory tract infection | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 6/50 (12%) | 6 | 2/30 (6.7%) | 2 |
| Influenza | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 2/30 (6.7%) | 2 |
| Nasopharyngitis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 2/50 (4%) | 2 | 3/30 (10%) | 3 |
| Cellulitis | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 9/50 (18%) | 12 | 1/30 (3.3%) | 1 |
| Oral candidiasis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 2/50 (4%) | 2 | 2/30 (6.7%) | 3 |
| Gasdtroenteritis viral | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Respiratory syncytial virus infection | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||||||||
| Fall | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 2/19 (10.5%) | 2 | 6/50 (12%) | 7 | 5/30 (16.7%) | 6 |
| Contusion | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 1/19 (5.3%) | 1 | 7/50 (14%) | 8 | 4/30 (13.3%) | 5 |
| Laceration | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 4/50 (8%) | 4 | 2/30 (6.7%) | 2 |
| Arthropod bite | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Iliotibial band syndrome | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Ligament sprain | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Rib fracture | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/19 (10.5%) | 2 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Skin abrasion | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Subdural hematoma | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 1/30 (3.3%) | 1 |
| Transfusion reaction | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Limb injury | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Investigations | ||||||||||||||
| Alanine aminotransferase increased | 1/7 (14.3%) | 3 | 1/6 (16.7%) | 2 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 5/19 (26.3%) | 10 | 11/50 (22%) | 22 | 4/30 (13.3%) | 9 |
| Electrocardiogram QT prolonged | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 1/50 (2%) | 1 | 4/30 (13.3%) | 7 |
| Weight decreased | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 4/19 (21.1%) | 5 | 7/50 (14%) | 10 | 6/30 (20%) | 7 |
| Blood creatinine increased | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 3/19 (15.8%) | 4 | 8/50 (16%) | 10 | 4/30 (13.3%) | 4 |
| Aspartate aminotransferase increased | 1/7 (14.3%) | 4 | 2/6 (33.3%) | 3 | 0/6 (0%) | 0 | 2/6 (33.3%) | 4 | 4/19 (21.1%) | 8 | 9/50 (18%) | 18 | 3/30 (10%) | 5 |
| Blood bilirubin increased | 2/7 (28.6%) | 4 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 5 | 5/50 (10%) | 9 | 4/30 (13.3%) | 4 |
| Blood alkaline phosphatase increased | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 2/19 (10.5%) | 4 | 6/50 (12%) | 11 | 1/30 (3.3%) | 1 |
| Activated partial thromboplastin time prolonged | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Alanine aminotransferase decreased | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Blood urea increased | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 3/50 (6%) | 3 | 1/30 (3.3%) | 1 |
| Electrocardiogram repolarization abnormality | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Weight increased | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Blood lactate dehydrogenase increased | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 4/50 (8%) | 5 | 1/30 (3.3%) | 2 |
| Troponin increased | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||||||||||
| Hypomagnesemia | 2/7 (28.6%) | 3 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 5 | 3/6 (50%) | 4 | 2/19 (10.5%) | 3 | 12/50 (24%) | 23 | 5/30 (16.7%) | 13 |
| Hypoalbuminemia | 1/7 (14.3%) | 3 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 5/19 (26.3%) | 9 | 10/50 (20%) | 13 | 6/30 (20%) | 12 |
| Hypokalemia | 2/7 (28.6%) | 3 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 2/6 (33.3%) | 2 | 3/19 (15.8%) | 5 | 5/50 (10%) | 6 | 6/30 (20%) | 9 |
| Hyperkalemia | 1/7 (14.3%) | 2 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 3 | 5/19 (26.3%) | 5 | 7/50 (14%) | 16 | 2/30 (6.7%) | 3 |
| Hyponatremia | 1/7 (14.3%) | 2 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 2/19 (10.5%) | 2 | 6/50 (12%) | 13 | 5/30 (16.7%) | 7 |
| Decreased appetite | 0/7 (0%) | 0 | 2/6 (33.3%) | 2 | 0/6 (0%) | 0 | 2/6 (33.3%) | 4 | 3/19 (15.8%) | 3 | 8/50 (16%) | 12 | 7/30 (23.3%) | 8 |
| Hypernatremia | 1/7 (14.3%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/19 (5.3%) | 3 | 4/50 (8%) | 7 | 1/30 (3.3%) | 1 |
| Hyperphosphatemia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 1/6 (16.7%) | 2 | 2/19 (10.5%) | 2 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Hypocalcemia | 1/7 (14.3%) | 2 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/19 (5.3%) | 1 | 10/50 (20%) | 13 | 3/30 (10%) | 5 |
| Hyperglycemia | 1/7 (14.3%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 6/50 (12%) | 9 | 3/30 (10%) | 5 |
| Hyperuricemia | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/19 (10.5%) | 2 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Dehydration | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 2/50 (4%) | 2 | 3/30 (10%) | 5 |
| Hypophosphatemia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 3/50 (6%) | 3 | 1/30 (3.3%) | 1 |
| Hyperuricemia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 3/50 (6%) | 3 | 1/30 (3.3%) | 1 |
| Hyperlipidemia | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||||||||
| Back pain | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 2/6 (33.3%) | 3 | 3/19 (15.8%) | 5 | 11/50 (22%) | 15 | 4/30 (13.3%) | 4 |
| Muscle spasms | 2/7 (28.6%) | 2 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 2/19 (10.5%) | 2 | 2/50 (4%) | 2 | 2/30 (6.7%) | 3 |
| Pain in extremity | 1/7 (14.3%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/19 (5.3%) | 1 | 4/50 (8%) | 4 | 5/30 (16.7%) | 5 |
| Arthralgia | 1/7 (14.3%) | 2 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 3 | 0/19 (0%) | 0 | 12/50 (24%) | 15 | 10/30 (33.3%) | 13 |
| Bone pain | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 2/30 (6.7%) | 2 |
| Arthritis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Flank pain | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Joint swelling | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Muscle tightness | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Myalgia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 6/50 (12%) | 6 | 4/30 (13.3%) | 6 |
| Musculoskeletal pain | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 2/50 (4%) | 3 | 2/30 (6.7%) | 3 |
| Neck pain | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||
| Basal cell carcinoma | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Squamous cell carcinoma | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Nervous system disorders | ||||||||||||||
| Headache | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 4 | 0/6 (0%) | 0 | 4/19 (21.1%) | 4 | 6/50 (12%) | 12 | 7/30 (23.3%) | 7 |
| Dizziness | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 2 | 1/19 (5.3%) | 1 | 14/50 (28%) | 19 | 13/30 (43.3%) | 14 |
| Dysgeusia | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Hypoasthesia | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 3/50 (6%) | 3 | 0/30 (0%) | 0 |
| Lethargy | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Memory impairment | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Neuralgia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Paresthesia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 3/50 (6%) | 3 | 0/30 (0%) | 0 |
| Sciatica | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Seizure | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Somnolence | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Presyncope | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 2/30 (6.7%) | 2 |
| Dysarthria | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Psychiatric disorders | ||||||||||||||
| Insomnia | 2/7 (28.6%) | 2 | 2/6 (33.3%) | 2 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 3/19 (15.8%) | 3 | 6/50 (12%) | 7 | 4/30 (13.3%) | 4 |
| Confusional state | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 2/30 (6.7%) | 3 |
| Anxiety | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 7/50 (14%) | 7 | 1/30 (3.3%) | 1 |
| Delirium | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 2/30 (6.7%) | 2 |
| Renal and urinary disorders | ||||||||||||||
| Acute kidney injury | 0/7 (0%) | 0 | 3/6 (50%) | 3 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 2/19 (10.5%) | 2 | 2/50 (4%) | 3 | 3/30 (10%) | 3 |
| Pollakiuria | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/19 (10.5%) | 2 | 3/50 (6%) | 4 | 1/30 (3.3%) | 1 |
| Hematuria | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 2/50 (4%) | 2 | 2/30 (6.7%) | 2 |
| Hydronephrosis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Nocturia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Urinary hesitation | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Reproductive system and breast disorders | ||||||||||||||
| Penile pain | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Vaginal hemorrhage | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||
| Cough | 1/7 (14.3%) | 1 | 2/6 (33.3%) | 2 | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 2 | 2/19 (10.5%) | 2 | 12/50 (24%) | 14 | 7/30 (23.3%) | 8 |
| Dyspnea | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 4/19 (21.1%) | 4 | 12/50 (24%) | 15 | 7/30 (23.3%) | 7 |
| Epistaxis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 2/19 (10.5%) | 3 | 6/50 (12%) | 7 | 6/30 (20%) | 10 |
| Oropharyngeal pain | 3/7 (42.9%) | 4 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/19 (10.5%) | 2 | 6/50 (12%) | 15 | 5/30 (16.7%) | 6 |
| Nasal congestion | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 3/50 (6%) | 4 | 1/30 (3.3%) | 1 |
| Dysphonia | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Dyspnea exertional | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 5/50 (10%) | 5 | 2/30 (6.7%) | 2 |
| Hemoptysis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 3/30 (10%) | 3 |
| Hypoxia | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Pleural effusion | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Productive cough | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/19 (10.5%) | 2 | 1/50 (2%) | 1 | 2/30 (6.7%) | 2 |
| Respiratory failure | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Rhinitis allergic | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Vocal cord disorder | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Wheezing | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Pulmonary edema | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 2/50 (4%) | 2 | 3/30 (10%) | 3 |
| Upper airway cough syndrome | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 4/50 (8%) | 4 | 0/30 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||||||||||
| Rash maculo-papular | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 3/19 (15.8%) | 4 | 4/50 (8%) | 5 | 2/30 (6.7%) | 2 |
| Petechiae | 1/7 (14.3%) | 2 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/19 (5.3%) | 1 | 3/50 (6%) | 3 | 2/30 (6.7%) | 2 |
| Night sweats | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 2 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Pruritus | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 1/50 (2%) | 1 | 4/30 (13.3%) | 4 |
| Rash | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Actinic keratosis | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Decubitus ulcer | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 1/50 (2%) | 1 | 2/30 (6.7%) | 3 |
| Dermal cyst | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/19 (10.5%) | 4 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Ecchymosis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Erythema | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 2/50 (4%) | 2 | 3/30 (10%) | 3 |
| Purpura | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Seborrheic dermatitis | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Skin exfoliation | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Skin irritation | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Blood blister | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 1/50 (2%) | 1 | 2/30 (6.7%) | 2 |
| Dry skin | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 3/50 (6%) | 3 | 1/30 (3.3%) | 1 |
| Hyperhidrosis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 3/50 (6%) | 4 | 1/30 (3.3%) | 1 |
| Dermatitis contact | 1/7 (14.3%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Nail discoloration | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Vascular disorders | ||||||||||||||
| Hypotension | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 3/19 (15.8%) | 3 | 2/50 (4%) | 2 | 5/30 (16.7%) | 5 |
| Hematoma | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 2/50 (4%) | 3 | 2/30 (6.7%) | 2 |
| Deep vein thrombosis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 3/50 (6%) | 3 | 1/30 (3.3%) | 1 |
| Hypertension | 1/7 (14.3%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 5/50 (10%) | 6 | 0/30 (0%) | 0 |
| Arteriosclerosis | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/19 (5.3%) | 1 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Phlebitis | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
| Thrombophlebitis superficial | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/19 (0%) | 0 | 0/50 (0%) | 0 | 0/30 (0%) | 0 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Medical Monitor |
|---|---|
| Organization | Astex Pharmaceuticals, Inc. |
| Phone | 925-560-0100 |
| Harold.Keer@astx.com |
Responsible Party:
Astex Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:
NCT02103478
Other Study ID Numbers:
- ASTX727-01
First Posted:
Apr 4, 2014
Last Update Posted:
Dec 23, 2020
Last Verified:
Dec 1, 2020