Safety, Tolerability and Pharmacokinetics of Milademetan Alone and With 5-Azacitidine (AZA) in Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)
Sponsor
Daiichi Sankyo, Inc. (Industry)
Overall Status
Terminated
CT.gov ID
NCT02319369
Collaborator
(none)
74
5
5
68.9
14.8
0.2
Study Details
Study Description
Brief Summary
This study will take place in parts:
-
Dose Escalation (Part 1): Participants receive milademetan alone with different dose schedules
-
Dose Escalation (Part 1A): Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules
The recommended dose for Part 2 will be selected.
- Dose Expansion (Part 2): After Part 1A, participants will receive the recommended Part 2 dose schedule. There will be three groups - those with:
-
refractory or relapsed acute myelogenous leukemia (AML)
-
newly diagnosed AML unfit for intensive chemotherapy
-
high-risk myelodysplastic syndrome (MDS)
- End-of-Study Follow-Up: Safety information will be collected until 30 days after the last treatment. This is the end of the study.
The recommended dose for the next study will be selected.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
The primary analysis will occur after all participants have either discontinued the study or completed at least 6 months of treatment. After the primary analysis, the main study will be closed. Participants who are still on study at least 6 months after enrollment of the last participant in the study may be eligible to continue receiving study drug in a separate extension phase of the protocol
Study Design
Study Type:
Interventional
Actual Enrollment
:
74 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Intervention Model Description:
Parts 1 and 1A are sequential, then Part 2 is parallelParts 1 and 1A are sequential, then Part 2 is parallel
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1 Study of Milademetan (DS 3032b), an Oral MDM2 Inhibitor, In Dose Escalation as a Single Agent and In Dose Escalation/Expansion In Combination With 5 Azacitidine In Subjects With Acute Myelogenous Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)
Actual Study Start Date
:
Nov 25, 2014
Actual Primary Completion Date
:
Aug 21, 2020
Actual Study Completion Date
:
Aug 21, 2020
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part 1, Milademetan Alone Participants receive milademetan alone with different dose schedules |
Drug: Milademetan
Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5 mg, 20 mg, 80 mg, and/or 200 mg
Other Names:
|
| Experimental: Part 1A, Milademetan with 5-azacytidine (AZA) Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules |
Drug: Milademetan
Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5 mg, 20 mg, 80 mg, and/or 200 mg
Other Names:
Drug: AZA
AZA will be administered at 75 mg/m^2 subcutaneously or intravenously
Other Names:
|
| Experimental: Part 2, Cohort 1 Participants with refractory or relapsed acute myelogenous leukemia (AML) receive the recommended dose for Part 2 of milademetan or milademetan with5-azacytidine (AZA) |
Drug: AZA
AZA will be administered at 75 mg/m^2 subcutaneously or intravenously
Other Names:
Drug: Milademetan
Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5, 20, 80, and/or 200 mg. An alternate combination of 30 mg, 80 mg, and/or 100 mg milademetan may be utilized.
Other Names:
|
| Experimental: Part 2, Cohort 2 Participants with newly diagnosed acute myelogenous leukemia (AML) unfit for intensive chemotherapy receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA) |
Drug: AZA
AZA will be administered at 75 mg/m^2 subcutaneously or intravenously
Other Names:
Drug: Milademetan
Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5, 20, 80, and/or 200 mg. An alternate combination of 30 mg, 80 mg, and/or 100 mg milademetan may be utilized.
Other Names:
|
| Experimental: Part 2, Cohort 3 Participants with high-risk myelodysplastic syndrome (MDS) receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA) |
Drug: AZA
AZA will be administered at 75 mg/m^2 subcutaneously or intravenously
Other Names:
Drug: Milademetan
Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5, 20, 80, and/or 200 mg. An alternate combination of 30 mg, 80 mg, and/or 100 mg milademetan may be utilized.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA) [From the date the participant signed the informed consent form up to 5 years of first participant enrolled]
A DLT was defined as any treatment-emergent adverse event not attributable to disease or disease-related processes occurring during the observation period (Cycle 1) in each dose-level cohort and is Grade (Gr) 3 or higher according to NCI CTCAE Version 5.0 (Version 4.03 before 01 Apr 2018), with these exceptions: for elevations in hepatic function enzymes, a DLT is defined as: Gr ≥3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels lasting >3 days; AST/ALT >5 × ULN if accompanied by ≥Gr 2 elevation in bilirubin. Potential DLTs include: Participants who are unable to complete at least 75% of milademetan or AZA in Cycle 1 as a result of non-disease-related Gr ≥2 events; Persistent bone marrow aplasia in the absence of malignant cell infiltration, and failure to recover a peripheral absolute neutrophil count ≥0.5 × 10^9/L and platelets ≥20 × 10^9/L while withholding study drug, resulting in >2-week delay in initiating Cycle 2.
- Number of Participants (≥10%) With Treatment-emergent Adverse Events (TEAEs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA) [From the date the participant signed the informed consent form up to 30 days after the last dose in the last participant, up to approximately 6 years of first participant enrolled]
A treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during the treatment period (up to 30 days after last dose), having been absent at pre-treatment; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-treatment state, when the adverse event is continuous.
Secondary Outcome Measures
- Maximum Plasma Concentration (Cmax) Following Administration of Milademetan Alone [Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)]
Pharmacokinetic parameter maximum plasma concentration (Cmax) of milademetan was assessed at select time points and the geometric means (coefficient of variation %) are presented.
- Maximum Plasma Concentration (Cmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA) [Predose, 0.5 hour (hr), 1 hr, 2 hr, 3 hr, 6 hr of Cycle 1, Day 1 (AZA); Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Day 5, Day 7 (predose) (Cohorts 10e and 12e), Day 8 (Cohorts 11f and 13f), and Day 14 (Cohorts 10e-13f) (each cycle is 28 days)]
Pharmacokinetic parameter maximum plasma concentration (Cmax) was assessed at select time points and the geometric means (coefficient of variation %) are presented.
- Time to Maximum Concentration (Tmax) Following Administration of Milademetan Alone [Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)]
Pharmacokinetic parameter time to maximum concentration (Tmax) of milademetan was assessed at select time points.
- Time to Maximum Concentration (Tmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA) [Predose, 0.5 hour (hr), 1 hr, 2 hr, 3 hr, 6 hr of Cycle 1, Day 1 (AZA); Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Day 5, Day 7 (predose) (Cohorts 10e and 12e), Day 8 (Cohorts 11f and 13f), and Day 14 (Cohorts 10e-13f) (each cycle is 28 days)]
Pharmacokinetic parameter time to maximum concentration (Tmax) was assessed at select time points.
- Trough Plasma Concentration (Ctrough) Following Administration of Milademetan Alone [Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)]
Pharmacokinetic parameter plasma concentration before next dose (Ctrough) of milademetan was assessed at Cycle 1, Day 15 and the geometric means (coefficient of variation %) are presented.
- Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan Alone [Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)]
Pharmacokinetic parameter area under the plasma concentration curve up to 24 hours (AUC0-24) of milademetan was assessed at select time points and the geometric means (coefficient of variation %) are presented.
- Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA) [Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Cycle 1, Day 5 (Cohorts 10e and 12e) and Predose of Cycle 1, Day 14 (Cohorts 10e, 11f, and 12e) (each cycle is 28 days)]
Pharmacokinetic parameter area under the plasma concentration curve up to 24 hours (AUC0-24) was assessed at select time points and the geometric means (coefficient of variation %) are presented.
- Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan Alone [Day 1 (6 hours postdose) up to Day 21-22 (predose), up to approximately 6 years of first participant enrolled]
Pharmacodynamic biomarker serum macrophage inhibitory cytokine-1 (MIC-1) concentrations of milademetan were assessed for Cohorts 1 though 9d. Fold change is the ratio of post-baseline MIC-1 values with respect to the baseline values and is the measure of change of MIC-1 from baseline.
- Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan In Combination With 5-Azacitidine (AZA) [Day 5 (predose) up to Day 22 (predose), up to approximately 6 years of first participant enrolled]
Pharmacodynamic biomarker serum macrophage inhibitory cytokine-1 (MIC-1) concentrations were assessed for Cohorts 10e though 13f. Fold change is the ratio of post-baseline MIC-1 values with respect to the baseline values and is the measure of change of MIC-1 from baseline.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria
- Has a diagnosis of refractory or relapsed (R/R) AML or high-risk MDS:
-
Part 1 and 1A (Dose Escalation)
-
Participants with R/R AML, OR
-
Participants with untreated, high-risk MDS or participants who have received prior MDS treatment regimens.
-
Participants ≥18 years old.
-
Part 2 (Dose Expansion)
-
Cohort 1: R/R AML
-
Participants who have treatment failure to prior AML therapy or have relapsed after prior AML therapy.
-
Participants ≥18 years old.
-
Cohort 2: Newly diagnosed AML
-
Participants with newly diagnosed AML who are ineligible for intensive induction chemotherapy. Participants must have had no prior AML treatment, with the exceptions of therapy for antecedent hematologic malignancies or hydroxyurea.
-
Participants ≥75 years old, OR Participants between 18 and 74 years old (inclusive) with at least one of the specific protocol-defined comorbidities.
-
Cohort 3: High-risk MDS
-
Participants with untreated, high-risk MDS or who received up to 2 prior MDS treatment regimens.
- Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
- As an exception, participants with newly diagnosed AML between 18 and 74 years old (inclusive) in Part 2 Cohort 2 with ECOG Performance Status of 3 will be eligible.
-
Has protocol-defined adequate renal, hepatic and blood clotting functions.
-
Is able to provide written informed consent (or authorized representative), comply with protocol visits and procedures, and take oral medication, and does not have any active infection or comorbidity that would interfere with therapy.
-
If female, is either postmenopausal (no menstrual period for a minimum of 12 months), surgically sterile, or, if of childbearing potential, has a negative serum pregnancy test upon entry into this study and is willing to use maximally effective birth control during the period of therapy and for 6 months following the last investigational drug dose.
- If male, is surgically sterile or willing to use a maximally effective double-barrier contraception method upon enrollment, during the course of the study, and for 6 months following the last investigational drug dose.
-
Is fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects).
-
Signs and dates an Institutional Review Board-approved informed consent form (including Health Insurance Portability and Accountability Act authorization, if applicable) before performance of any study-specific procedures or tests.
-
Is able and willing to provide bone marrow biopsies/aspirates as requested by the protocol.
-
Is willing to undergo malignancy genotyping for TP53 mutation, insertion, or deletion at screening.
Exclusion Criteria
-
Has a diagnosis of acute promyelocytic leukemia.
-
Has a malignancy that is known to contain a non-synonymous mutation, insertion, or deletion in the TP53 gene determined previously or at screening.
-
Has presence of central nervous system (CNS) involvement of leukemia or a history of primary CNS leukemia.
-
Has a second concurrent primary malignancy that required active treatment within the previous 2 years, except for localized cancers that have apparently been cured, such as non-melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast.
-
Has any condition that would preclude adequate absorption of DS-3032b, including refractory nausea and vomiting, malabsorption, biliary shunt, significant bowel resection, and/or graft-versus-host disease (GVHD) affecting the gut.
-
Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known human immunodeficiency virus infection, or active hepatitis B or C infection.
-
Has a concomitant medical condition that would increase the risk of toxicity.
-
Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE Grade ≤ 1, or baseline. Subjects with chronic Grade 2 toxicities may be eligible at the discretion of the Investigator and Sponsor (eg, Grade 2 chemotherapy-induced neuropathy).
-
Has received Hematopoietic Stem Cell Transplantation (HSCT) within 60 days of the first dose of study drugs or has clinically significant GVHD or GVHD requiring initiation of systemic treatment or systemic treatment escalation within 21 days prior to Screening and/or >Grade 1 persistent or clinically significant GVHD or other non-hematologic toxicity related to HCT.
-
Is receiving concomitant treatment with a strong inhibitor or inducer of cytochrome P450 3A4/5.
-
Has received any therapies intended to treat malignancy within 7 days (small molecules) or 21 days (anti-body/immune based biologics) of first receipt of study drugs [except for hydroxyurea, which must be discontinued at least 48 hours (Day -2) prior to study treatment].
-
Had major surgery within 4 weeks prior to study drug treatment.
-
Participated in a therapeutic clinical study within a washout time of 2 weeks or 5 half-lives of the drug/biologic (whichever is longer) before starting study drug treatment under this protocol, or current participation in other therapeutic investigational procedures.
-
Has prolongation of corrected QT interval using Fridericia's method (QTcF) at rest, where the mean QTcF interval is > 480 ms based on triplicate electrocardiograms (ECGs).
-
Is pregnant or breastfeeding.
-
Has substance abuse or medical, psychological, or social conditions that, in the opinion of the Investigator, may interfere with the subject's participation in the clinical study or evaluation of the clinical study results.
-
Prior treatment with an MDM2 inhibitor.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope National Medical Center | Duarte | California | United States | 91010 |
| 2 | University of California San Francisco Medical Center | San Francisco | California | United States | 94143 |
| 3 | University of Kansas Cancer Center | Fairway | Kansas | United States | 66205 |
| 4 | Roswell Park Comprehensive Cancer Center | Buffalo | New York | United States | 14263 |
| 5 | M D Anderson Cancer Center | Houston | Texas | United States | 77031 |
Sponsors and Collaborators
- Daiichi Sankyo, Inc.
Investigators
- Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier:
NCT02319369
Other Study ID Numbers:
- DS3032-A-U102
First Posted:
Dec 18, 2014
Last Update Posted:
Oct 11, 2021
Last Verified:
Sep 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Daiichi Sankyo, Inc.
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | A total of 74 participants who met all inclusion criteria and no exclusion criteria were enrolled and treated at 5 clinic sites in the United States. |
|---|---|
| Pre-assignment Detail | Dose escalation of milademetan was used to determine the maximum tolerated dose. A starting dose of 60 mg milademetan was based on safety and tolerability data obtained in the solid tumor or lymphoma first-in-human study of milademetan (Study DS3032-A-U101; NCT01877382). |
| Arm/Group Title | Cohort 1: Milademetan 60 mg | Cohort 2: Milademetan 90 mg | Cohort 3: Milademetan 120 mg | Cohort 4: Milademetan 160 mg | Cohort 5: Milademetan 210 mg | Cohort 6b: Milademetan 160 mg | Cohort 7c: Milademetan 160 mg | Cohort 8d: Milademetan 160 mg | Cohort 9d: Milademetan 220 mg | Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 | Cohort 13f: Milademetan 200 mg + Azacitidine 75 mg/m^2 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants were administered 60 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 90 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 120 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 210 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 7 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules for 3 of 14 days repeated twice in a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. | Participants were administered 220 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 160 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. |
| Period Title: Overall Study | |||||||||||||
| STARTED | 7 | 6 | 11 | 8 | 5 | 7 | 3 | 6 | 4 | 9 | 3 | 4 | 1 |
| COMPLETED | 7 | 6 | 11 | 8 | 5 | 7 | 3 | 6 | 4 | 9 | 3 | 4 | 1 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Cohort 1: Milademetan 60 mg | Cohort 2: Milademetan 90 mg | Cohort 3: Milademetan 120 mg | Cohort 4: Milademetan 160 mg | Cohort 5: Milademetan 210 mg | Cohort 6b: Milademetan 160 mg | Cohort 7c: Milademetan 160 mg | Cohort 8d: Milademetan 160 mg | Cohort 9d: Milademetan 220 mg | Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 | Cohort 13f: Milademetan 200 mg + Azacitidine 75 mg/m^2 | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants were administered 60 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 90 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 120 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 210 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 7 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules for 3 of 14 days repeated twice in a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. | Participants were administered 220 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 160 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Total of all reporting groups |
| Overall Participants | 7 | 6 | 11 | 8 | 5 | 7 | 3 | 6 | 4 | 9 | 3 | 4 | 1 | 74 |
| Age (years) [Mean (Standard Deviation) ] | ||||||||||||||
| Mean (Standard Deviation) [years] |
67.0
(14.7)
|
63.8
(10.6)
|
61.8
(15.6)
|
70.4
(6.1)
|
69.2
(7.2)
|
71.3
(6.4)
|
66.7
(7.6)
|
61.8
(20.1)
|
72.0
(8.2)
|
60.3
(19.8)
|
49.3
(25.4)
|
70.8
(7.1)
|
60.0
(NA)
|
66.6
(12.1)
|
| Age, Customized (Count of Participants) | ||||||||||||||
| ≤65 years |
4
57.1%
|
4
66.7%
|
5
45.5%
|
2
25%
|
1
20%
|
1
14.3%
|
1
33.3%
|
3
50%
|
1
25%
|
5
55.6%
|
2
66.7%
|
1
25%
|
1
100%
|
31
41.9%
|
| >65 years |
3
42.9%
|
2
33.3%
|
6
54.5%
|
6
75%
|
4
80%
|
6
85.7%
|
2
66.7%
|
3
50%
|
3
75%
|
4
44.4%
|
1
33.3%
|
3
75%
|
0
0%
|
43
58.1%
|
| Sex: Female, Male (Count of Participants) | ||||||||||||||
| Female |
4
57.1%
|
2
33.3%
|
3
27.3%
|
3
37.5%
|
1
20%
|
2
28.6%
|
1
33.3%
|
1
16.7%
|
3
75%
|
6
66.7%
|
1
33.3%
|
1
25%
|
1
100%
|
29
39.2%
|
| Male |
3
42.9%
|
4
66.7%
|
8
72.7%
|
5
62.5%
|
4
80%
|
5
71.4%
|
2
66.7%
|
5
83.3%
|
1
25%
|
3
33.3%
|
2
66.7%
|
3
75%
|
0
0%
|
45
60.8%
|
| 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%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
1
14.3%
|
0
0%
|
1
9.1%
|
0
0%
|
0
0%
|
0
0%
|
1
33.3%
|
1
16.7%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
4
5.4%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
20%
|
1
14.3%
|
1
33.3%
|
0
0%
|
0
0%
|
0
0%
|
2
66.7%
|
0
0%
|
0
0%
|
5
6.8%
|
| White |
6
85.7%
|
6
100%
|
9
81.8%
|
6
75%
|
4
80%
|
6
85.7%
|
1
33.3%
|
4
66.7%
|
4
100%
|
8
88.9%
|
1
33.3%
|
4
100%
|
1
100%
|
60
81.1%
|
| More than one race |
0
0%
|
0
0%
|
1
9.1%
|
2
25%
|
0
0%
|
0
0%
|
0
0%
|
1
16.7%
|
0
0%
|
1
11.1%
|
0
0%
|
0
0%
|
0
0%
|
5
6.8%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | ||||||||||||||
| United States |
7
100%
|
6
100%
|
11
100%
|
8
100%
|
5
100%
|
7
100%
|
3
100%
|
6
100%
|
4
100%
|
9
100%
|
3
100%
|
4
100%
|
1
100%
|
74
100%
|
Outcome Measures
| Title | Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA) |
|---|---|
| Description | A DLT was defined as any treatment-emergent adverse event not attributable to disease or disease-related processes occurring during the observation period (Cycle 1) in each dose-level cohort and is Grade (Gr) 3 or higher according to NCI CTCAE Version 5.0 (Version 4.03 before 01 Apr 2018), with these exceptions: for elevations in hepatic function enzymes, a DLT is defined as: Gr ≥3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels lasting >3 days; AST/ALT >5 × ULN if accompanied by ≥Gr 2 elevation in bilirubin. Potential DLTs include: Participants who are unable to complete at least 75% of milademetan or AZA in Cycle 1 as a result of non-disease-related Gr ≥2 events; Persistent bone marrow aplasia in the absence of malignant cell infiltration, and failure to recover a peripheral absolute neutrophil count ≥0.5 × 10^9/L and platelets ≥20 × 10^9/L while withholding study drug, resulting in >2-week delay in initiating Cycle 2. |
| Time Frame | From the date the participant signed the informed consent form up to 5 years of first participant enrolled |
Outcome Measure Data
| Analysis Population Description |
|---|
| Dose-limiting toxicities were reported in the DLT evaluable set for Cohorts 1, 4, 5, and 9d of Part 1 and Cohort 12e of Part 1a. |
| Arm/Group Title | Cohort 1: Milademetan 60 mg | Cohort 4: Milademetan 160 mg | Cohort 5: Milademetan 210 mg | Cohort 9d: Milademetan 220 mg | Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 |
|---|---|---|---|---|---|
| Arm/Group Description | Participants were administered 60 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 210 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle | Participants were administered 220 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. | Participants were administered 200 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. |
| Measure Participants | 5 | 8 | 5 | 3 | 4 |
| Participants with TEAEs classified as DLTs |
1
14.3%
|
2
33.3%
|
3
27.3%
|
2
25%
|
2
40%
|
| Nausea |
0
0%
|
0
0%
|
1
9.1%
|
2
25%
|
0
0%
|
| Fatigue |
0
0%
|
0
0%
|
1
9.1%
|
0
0%
|
2
40%
|
| Cellulitis |
0
0%
|
0
0%
|
1
9.1%
|
0
0%
|
0
0%
|
| Diarrhoea |
0
0%
|
1
16.7%
|
0
0%
|
0
0%
|
0
0%
|
| Hypokalaemia |
0
0%
|
1
16.7%
|
0
0%
|
0
0%
|
0
0%
|
| Renal failure |
0
0%
|
0
0%
|
1
9.1%
|
0
0%
|
0
0%
|
| Vomiting |
1
14.3%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Syncope |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
20%
|
| Title | Number of Participants (≥10%) With Treatment-emergent Adverse Events (TEAEs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA) |
|---|---|
| Description | A treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during the treatment period (up to 30 days after last dose), having been absent at pre-treatment; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-treatment state, when the adverse event is continuous. |
| Time Frame | From the date the participant signed the informed consent form up to 30 days after the last dose in the last participant, up to approximately 6 years of first participant enrolled |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety events were assessed in the Safety Analysis Set. |
| Arm/Group Title | Cohort 1: Milademetan 60 mg | Cohort 2: Milademetan 90 mg | Cohort 3: Milademetan 120 mg | Cohort 4: Milademetan 160 mg | Cohort 5: Milademetan 210 mg | Cohort 6b: Milademetan 160 mg | Cohort 7c: Milademetan 160 mg | Cohort 8d: Milademetan 160 mg | Cohort 9d: Milademetan 220 mg | Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 | Cohort 13f: Milademetan 200 mg + Azacitidine 75 mg/m^2 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants were administered 60 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 90 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 120 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 210 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 7 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules for 3 of 14 days repeated twice in a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. | Participants were administered 220 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 160 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. |
| Measure Participants | 7 | 6 | 11 | 8 | 5 | 7 | 3 | 6 | 4 | 9 | 3 | 4 | 1 |
| Any TEAEs |
7
100%
|
6
100%
|
11
100%
|
8
100%
|
5
100%
|
7
100%
|
3
100%
|
6
100%
|
4
100%
|
9
100%
|
3
100%
|
4
100%
|
1
100%
|
| Nausea |
5
71.4%
|
4
66.7%
|
8
72.7%
|
6
75%
|
4
80%
|
3
42.9%
|
2
66.7%
|
4
66.7%
|
3
75%
|
5
55.6%
|
2
66.7%
|
2
50%
|
1
100%
|
| Diarrhoea |
2
28.6%
|
2
33.3%
|
8
72.7%
|
5
62.5%
|
3
60%
|
4
57.1%
|
2
66.7%
|
3
50%
|
3
75%
|
1
11.1%
|
2
66.7%
|
1
25%
|
0
0%
|
| Vomiting |
2
28.6%
|
1
16.7%
|
4
36.4%
|
4
50%
|
3
60%
|
2
28.6%
|
2
66.7%
|
3
50%
|
3
75%
|
3
33.3%
|
2
66.7%
|
0
0%
|
0
0%
|
| Fatigue |
2
28.6%
|
1
16.7%
|
5
45.5%
|
5
62.5%
|
3
60%
|
2
28.6%
|
0
0%
|
1
16.7%
|
1
25%
|
3
33.3%
|
2
66.7%
|
2
50%
|
0
0%
|
| Thrombocytopenia |
2
28.6%
|
1
16.7%
|
4
36.4%
|
5
62.5%
|
1
20%
|
1
14.3%
|
0
0%
|
0
0%
|
1
25%
|
0
0%
|
0
0%
|
3
75%
|
0
0%
|
| Oedema peripheral |
1
14.3%
|
0
0%
|
4
36.4%
|
2
25%
|
1
20%
|
3
42.9%
|
1
33.3%
|
1
16.7%
|
1
25%
|
1
11.1%
|
1
33.3%
|
1
25%
|
0
0%
|
| Anaemia |
2
28.6%
|
3
50%
|
3
27.3%
|
3
37.5%
|
1
20%
|
1
14.3%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Decreased appetite |
2
28.6%
|
0
0%
|
2
18.2%
|
3
37.5%
|
3
60%
|
2
28.6%
|
0
0%
|
1
16.7%
|
0
0%
|
3
33.3%
|
2
66.7%
|
0
0%
|
0
0%
|
| Hypokalaemia |
0
0%
|
1
16.7%
|
1
9.1%
|
4
50%
|
3
60%
|
2
28.6%
|
0
0%
|
0
0%
|
1
25%
|
1
11.1%
|
0
0%
|
1
25%
|
0
0%
|
| Lung infection |
0
0%
|
1
16.7%
|
2
18.2%
|
2
25%
|
0
0%
|
2
28.6%
|
1
33.3%
|
1
16.7%
|
2
50%
|
3
33.3%
|
3
100%
|
0
0%
|
0
0%
|
| Neutropenia |
1
14.3%
|
2
33.3%
|
2
18.2%
|
3
37.5%
|
1
20%
|
0
0%
|
0
0%
|
0
0%
|
1
25%
|
1
11.1%
|
0
0%
|
1
25%
|
0
0%
|
| Hypomagnesaemia |
0
0%
|
1
16.7%
|
3
27.3%
|
1
12.5%
|
2
40%
|
2
28.6%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Hypotension |
2
28.6%
|
2
33.3%
|
2
18.2%
|
1
12.5%
|
1
20%
|
0
0%
|
0
0%
|
0
0%
|
1
25%
|
3
33.3%
|
1
33.3%
|
1
25%
|
0
0%
|
| Pneumonia |
3
42.9%
|
1
16.7%
|
1
9.1%
|
3
37.5%
|
0
0%
|
0
0%
|
0
0%
|
1
16.7%
|
0
0%
|
3
33.3%
|
1
33.3%
|
1
25%
|
0
0%
|
| Dyspnoea |
0
0%
|
1
16.7%
|
2
18.2%
|
1
12.5%
|
3
60%
|
1
14.3%
|
0
0%
|
0
0%
|
0
0%
|
3
33.3%
|
3
100%
|
0
0%
|
0
0%
|
| Sepsis |
2
28.6%
|
0
0%
|
1
9.1%
|
1
12.5%
|
0
0%
|
1
14.3%
|
1
33.3%
|
1
16.7%
|
1
25%
|
2
22.2%
|
0
0%
|
0
0%
|
0
0%
|
| Abdominal pain |
2
28.6%
|
1
16.7%
|
0
0%
|
0
0%
|
0
0%
|
2
28.6%
|
0
0%
|
2
33.3%
|
0
0%
|
3
33.3%
|
1
33.3%
|
1
25%
|
0
0%
|
| Asthenia |
1
14.3%
|
0
0%
|
1
9.1%
|
1
12.5%
|
2
40%
|
1
14.3%
|
0
0%
|
0
0%
|
1
25%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Dehydration |
1
14.3%
|
0
0%
|
1
9.1%
|
1
12.5%
|
1
20%
|
1
14.3%
|
0
0%
|
0
0%
|
1
25%
|
2
22.2%
|
0
0%
|
0
0%
|
0
0%
|
| Dizziness |
1
14.3%
|
1
16.7%
|
0
0%
|
2
25%
|
2
40%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
22.2%
|
1
33.3%
|
1
25%
|
0
0%
|
| Febrile neutropenia |
1
14.3%
|
0
0%
|
3
27.3%
|
1
12.5%
|
1
20%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Hyperuricaemia |
2
28.6%
|
1
16.7%
|
0
0%
|
1
12.5%
|
2
40%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Malaise |
1
14.3%
|
0
0%
|
1
9.1%
|
0
0%
|
1
20%
|
1
14.3%
|
1
33.3%
|
1
16.7%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Cough |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
4
44.4%
|
3
100%
|
0
0%
|
0
0%
|
| Constipation |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
22.2%
|
2
66.7%
|
1
25%
|
1
100%
|
| Contusion |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
22.2%
|
2
66.7%
|
0
0%
|
0
0%
|
| Myalgia |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
3
33.3%
|
1
33.3%
|
0
0%
|
0
0%
|
| Epistaxis |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
22.2%
|
0
0%
|
1
25%
|
0
0%
|
| Headache |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
22.2%
|
1
33.3%
|
0
0%
|
0
0%
|
| Hypophosphataemia |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
22.2%
|
1
33.3%
|
0
0%
|
0
0%
|
| Muscular weakness |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
22.2%
|
1
33.3%
|
0
0%
|
0
0%
|
| Rash maculo-papular |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
3
75%
|
0
0%
|
| Rhinorrhoea |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
11.1%
|
2
66.7%
|
0
0%
|
0
0%
|
| Alanine aminotransferase increased |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
11.1%
|
1
33.3%
|
0
0%
|
0
0%
|
| Athralgia |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
11.1%
|
1
33.3%
|
0
0%
|
0
0%
|
| Death |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
66.7%
|
0
0%
|
0
0%
|
| Depression |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
11.1%
|
0
0%
|
1
25%
|
0
0%
|
| Device-related infection |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
22.2%
|
0
0%
|
0
0%
|
0
0%
|
| Escherichia infection |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
22.2%
|
0
0%
|
0
0%
|
0
0%
|
| Fluid overload |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
11.1%
|
1
33.3%
|
0
0%
|
0
0%
|
| Hemorrhoids |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
22.2%
|
0
0%
|
0
0%
|
0
0%
|
| Hyponatraemia |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
33.3%
|
1
25%
|
0
0%
|
| Insomnia |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
11.1%
|
1
33.3%
|
0
0%
|
0
0%
|
| Oropharyngeal pain |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
22.2%
|
0
0%
|
0
0%
|
0
0%
|
| Pancytopenia |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
22.2%
|
0
0%
|
0
0%
|
0
0%
|
| Pneumonia fungal |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
33.3%
|
1
25%
|
0
0%
|
| Pyrexia |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
11.1%
|
1
33.3%
|
0
0%
|
0
0%
|
| Title | Maximum Plasma Concentration (Cmax) Following Administration of Milademetan Alone |
|---|---|
| Description | Pharmacokinetic parameter maximum plasma concentration (Cmax) of milademetan was assessed at select time points and the geometric means (coefficient of variation %) are presented. |
| Time Frame | Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetics were assessed in the Pharmacokinetic Analysis Set. |
| Arm/Group Title | Cohort 1: Milademetan 60 mg | Cohort 2: Milademetan 90 mg | Cohort 3: Milademetan 120 mg | Cohort 4: Milademetan 160 mg | Cohort 5: Milademetan 210 mg | Cohort 6b: Milademetan 160 mg | Cohort 7c: Milademetan 160 mg | Cohort 8d: Milademetan 160 mg | Cohort 9d: Milademetan 220 mg |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants were administered 60 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 90 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 120 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 210 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 7 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules for 3 of 14 days repeated twice in a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. | Participants were administered 220 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. |
| Measure Participants | 7 | 6 | 11 | 8 | 5 | 7 | 3 | 6 | 4 |
| Cycle 1, Day 1 |
386.0
(42.2)
|
342.5
(23.4)
|
505.9
(56.8)
|
622.3
(94.5)
|
747.9
(48.1)
|
440.0
(74.7)
|
758.1
(44.8)
|
657.0
(27.2)
|
1607.4
(34.4)
|
| Cycle 1, Day 15 |
498.5
(40.3)
|
562.6
(58.6)
|
614.3
(55.3)
|
753.8
(79.8)
|
1329.2
(21.9)
|
NA
(NA)
|
669.2
(46.0)
|
NA
(NA)
|
NA
(NA)
|
| Title | Maximum Plasma Concentration (Cmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA) |
|---|---|
| Description | Pharmacokinetic parameter maximum plasma concentration (Cmax) was assessed at select time points and the geometric means (coefficient of variation %) are presented. |
| Time Frame | Predose, 0.5 hour (hr), 1 hr, 2 hr, 3 hr, 6 hr of Cycle 1, Day 1 (AZA); Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Day 5, Day 7 (predose) (Cohorts 10e and 12e), Day 8 (Cohorts 11f and 13f), and Day 14 (Cohorts 10e-13f) (each cycle is 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetics were assessed in the Pharmacokinetic Analysis Set. |
| Arm/Group Title | Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 | Cohort 13f: Milademetan 200 mg + Azacitidine 75 mg/m^2 |
|---|---|---|---|---|
| Arm/Group Description | Participants were administered 160 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 160 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. |
| Measure Participants | 9 | 3 | 4 | 1 |
| Cycle 1, Day 1 |
527.0
(61.9)
|
NA
(NA)
|
707.0
(37.7)
|
NA
(NA)
|
| Cycle 1, Day 5 |
704.8
(57.6)
|
NA
(NA)
|
1019.6
(72.2)
|
NA
(NA)
|
| Cycle 1, Day 7 |
702.5
(46.4)
|
NA
(NA)
|
769.8
(46.7)
|
NA
(NA)
|
| Cycle 1, Day 8 |
NA
(NA)
|
327.5
(51.2)
|
NA
(NA)
|
266.0
(NA)
|
| Cycle 1, Day 14 |
1488.6
(55.2)
|
1057.9
(20.4)
|
1448.2
(57.2)
|
1190.0
(NA)
|
| Title | Time to Maximum Concentration (Tmax) Following Administration of Milademetan Alone |
|---|---|
| Description | Pharmacokinetic parameter time to maximum concentration (Tmax) of milademetan was assessed at select time points. |
| Time Frame | Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set. |
| Arm/Group Title | Cohort 1: Milademetan 60 mg | Cohort 2: Milademetan 90 mg | Cohort 3: Milademetan 120 mg | Cohort 4: Milademetan 160 mg | Cohort 5: Milademetan 210 mg | Cohort 6b: Milademetan 160 mg | Cohort 7c: Milademetan 160 mg | Cohort 8d: Milademetan 160 mg | Cohort 9d: Milademetan 220 mg |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants were administered 60 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 90 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 120 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 210 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 7 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules for 3 of 14 days repeated twice in a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. | Participants were administered 220 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. |
| Measure Participants | 7 | 6 | 11 | 8 | 5 | 7 | 3 | 6 | 4 |
| Cycle 1, Day 1 |
3.00
|
4.39
|
3.00
|
4.50
|
3.00
|
3.00
|
3.08
|
4.50
|
4.56
|
| Cycle 1, Day 15 |
3.00
|
2.99
|
3.00
|
2.96
|
4.50
|
NA
|
3.04
|
NA
|
NA
|
| Title | Time to Maximum Concentration (Tmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA) |
|---|---|
| Description | Pharmacokinetic parameter time to maximum concentration (Tmax) was assessed at select time points. |
| Time Frame | Predose, 0.5 hour (hr), 1 hr, 2 hr, 3 hr, 6 hr of Cycle 1, Day 1 (AZA); Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Day 5, Day 7 (predose) (Cohorts 10e and 12e), Day 8 (Cohorts 11f and 13f), and Day 14 (Cohorts 10e-13f) (each cycle is 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set. |
| Arm/Group Title | Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 | Cohort 13f: Milademetan 200 mg + Azacitidine 75 mg/m^2 |
|---|---|---|---|---|
| Arm/Group Description | Participants were administered 160 mg milademetan daily as a single oral capsule on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 160 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. |
| Measure Participants | 9 | 3 | 4 | 1 |
| Cycle 1, Day 1 |
0.77
|
NA
|
0.51
|
NA
|
| Cycle 1, Day 5 |
3.02
|
NA
|
4.41
|
NA
|
| Cycle 1, Day 7 |
0.56
|
NA
|
0.58
|
NA
|
| Cycle 1, Day 8 |
NA
|
6.33
|
NA
|
3.08
|
| Cycle 1, Day 14 |
3.00
|
6.05
|
5.54
|
6.15
|
| Title | Trough Plasma Concentration (Ctrough) Following Administration of Milademetan Alone |
|---|---|
| Description | Pharmacokinetic parameter plasma concentration before next dose (Ctrough) of milademetan was assessed at Cycle 1, Day 15 and the geometric means (coefficient of variation %) are presented. |
| Time Frame | Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set. |
| Arm/Group Title | Cohort 1: Milademetan 60 mg | Cohort 2: Milademetan 90 mg | Cohort 3: Milademetan 120 mg | Cohort 4: Milademetan 160 mg | Cohort 5: Milademetan 210 mg | Cohort 7c: Milademetan 160 mg |
|---|---|---|---|---|---|---|
| Arm/Group Description | Participants were administered 60 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 90 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 120 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 210 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle | Participants were administered 160 mg milademetan daily as oral capsules for 3 of 14 days repeated twice in a 28-day cycle. |
| Measure Participants | 7 | 6 | 11 | 8 | 5 | 3 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
197.13
(23.2)
|
229.28
(82.0)
|
292.60
(59.7)
|
184.60
(279.1)
|
507.07
(24.0)
|
NA
(NA)
|
| Title | Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan Alone |
|---|---|
| Description | Pharmacokinetic parameter area under the plasma concentration curve up to 24 hours (AUC0-24) of milademetan was assessed at select time points and the geometric means (coefficient of variation %) are presented. |
| Time Frame | Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set. |
| Arm/Group Title | Cohort 1: Milademetan 60 mg | Cohort 2: Milademetan 90 mg | Cohort 3: Milademetan 120 mg | Cohort 4: Milademetan 160 mg | Cohort 5: Milademetan 210 mg | Cohort 6b: Milademetan 160 mg | Cohort 7c: Milademetan 160 mg | Cohort 8d: Milademetan 160 mg | Cohort 9d: Milademetan 220 mg |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants were administered 60 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 90 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 120 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 210 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 7 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules for 3 of 14 days repeated twice in a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. | Participants were administered 220 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. |
| Measure Participants | 7 | 6 | 11 | 8 | 5 | 7 | 3 | 6 | 4 |
| Cycle 1, Day 1 |
4646.7
(47.7)
|
4478.1
(31.2)
|
6585.4
(54.8)
|
8315.1
(101.2)
|
9794.0
(39.4)
|
7222.5
(43.1)
|
10165.6
(64.6)
|
8973.9
(28.1)
|
20893.9
(23.2)
|
| Cycle 1, Day 15 |
7244.6
(28.9)
|
8392.9
(56.5)
|
9854.9
(54.6)
|
10710.8
(54.2)
|
20330.2
(15.9)
|
NA
(NA)
|
7714.3
(30.5)
|
NA
(NA)
|
NA
(NA)
|
| Title | Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA) |
|---|---|
| Description | Pharmacokinetic parameter area under the plasma concentration curve up to 24 hours (AUC0-24) was assessed at select time points and the geometric means (coefficient of variation %) are presented. |
| Time Frame | Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Cycle 1, Day 5 (Cohorts 10e and 12e) and Predose of Cycle 1, Day 14 (Cohorts 10e, 11f, and 12e) (each cycle is 28 days) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic parameters were assessed in the Pharmacokinetic Analysis Set. |
| Arm/Group Title | Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 |
|---|---|---|---|
| Arm/Group Description | Participants were administered 160 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 160 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. |
| Measure Participants | 9 | 3 | 4 |
| Cycle 1, Day 5 |
8238.7
(43.0)
|
NA
(NA)
|
21299.3
(16.3)
|
| Cycle 1, Day 14 |
22563.8
(52.9)
|
15755.5
(29.4)
|
19967.5
(18.5)
|
| Title | Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan Alone |
|---|---|
| Description | Pharmacodynamic biomarker serum macrophage inhibitory cytokine-1 (MIC-1) concentrations of milademetan were assessed for Cohorts 1 though 9d. Fold change is the ratio of post-baseline MIC-1 values with respect to the baseline values and is the measure of change of MIC-1 from baseline. |
| Time Frame | Day 1 (6 hours postdose) up to Day 21-22 (predose), up to approximately 6 years of first participant enrolled |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacodynamic biomarker, MIC-1, was assessed in the Safety Analysis Set. |
| Arm/Group Title | Cohort 1: Milademetan 60 mg | Cohort 2: Milademetan 90 mg | Cohort 3: Milademetan 120 mg | Cohort 4: Milademetan 160 mg | Cohort 5: Milademetan 210 mg | Cohort 6b: Milademetan 160 mg | Cohort 7c: Milademetan 160 mg | Cohort 8d: Milademetan 160 mg | Cohort 9d: Milademetan 220 mg |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Participants were administered 60 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 90 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 120 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 210 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 7 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules for 3 of 14 days repeated twice in a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. | Participants were administered 220 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. |
| Measure Participants | 7 | 6 | 11 | 8 | 5 | 7 | 3 | 6 | 4 |
| Day 1 (6 hours postdose) |
3.14
(1.23)
|
2.78
(0.95)
|
3.36
(1.38)
|
3.00
(0.88)
|
4.25
(1.41)
|
2.64
(0.91)
|
3.36
(1.49)
|
2.64
(0.87)
|
4.94
(2.22)
|
| Day 2 (predose) |
2.53
(0.83)
|
3.31
(1.25)
|
3.97
(2.71)
|
3.44
(1.63)
|
5.06
(2.62)
|
2.57
(0.81)
|
3.84
(1.74)
|
3.68
(2.13)
|
8.09
(3.27)
|
| Day 8 (predose) |
4.13
(2.46)
|
6.35
(4.61)
|
7.41
(7.17)
|
5.13
(2.64)
|
9.70
(7.96)
|
4.93
(3.32)
|
1.44
(0.36)
|
5.63
(3.99)
|
13.68
(10.72)
|
| Day 15 (predose) |
2.88
(0.64)
|
5.64
(4.94)
|
6.04
(3.49)
|
5.54
(3.49)
|
9.28
(7.26)
|
1.33
(0.98)
|
1.13
(0.41)
|
5.02
(2.20)
|
6.61
(4.64)
|
| Day 21-22 (predose) |
3.49
(1.88)
|
4.61
(2.66)
|
4.57
(3.53)
|
6.57
(4.22)
|
5.88
(2.75)
|
0.48
(NA)
|
1.24
(NA)
|
0.83
(0.45)
|
1.18
(0.60)
|
| Title | Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan In Combination With 5-Azacitidine (AZA) |
|---|---|
| Description | Pharmacodynamic biomarker serum macrophage inhibitory cytokine-1 (MIC-1) concentrations were assessed for Cohorts 10e though 13f. Fold change is the ratio of post-baseline MIC-1 values with respect to the baseline values and is the measure of change of MIC-1 from baseline. |
| Time Frame | Day 5 (predose) up to Day 22 (predose), up to approximately 6 years of first participant enrolled |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacodynamic biomarker, MIC-1, was assessed in the Safety Analysis Set. |
| Arm/Group Title | Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 | Cohort 13f: Milademetan 200 mg + Azacitidine 75 mg/m^2 |
|---|---|---|---|---|
| Arm/Group Description | Participants were administered 160 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 160 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. |
| Measure Participants | 9 | 3 | 4 | 1 |
| Day 5 (predose) |
1.65
(0.72)
|
1.39
(0.36)
|
||
| Day 5 (6 hours postdose) |
3.12
(2.38)
|
6.07
(2.99)
|
||
| Day 14 (predose) |
10.82
(8.26)
|
4.06
(0.54)
|
8.34
(6.14)
|
|
| Day 22 (predose) |
2.05
(2.34)
|
1.38
(0.29)
|
1.81
(1.20)
|
1.83
(NA)
|
Adverse Events
| Time Frame | Treatment-emergent adverse events (TEAEs) were collected from the date the participant signed the informed consent form up to 30 days after the last dose of study drug, up to approximately 6 years of first participant enrolled. | |||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | A TEAE was defined as an adverse event that emerges during the treatment period (from first dose date till 30 days after last dose date), having been absent at pre-treatment; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-treatment state, when the adverse event is continuous. | |||||||||||||||||||||||||
| Arm/Group Title | Cohort 1: Milademetan 60 mg | Cohort 2: Milademetan 90 mg | Cohort 3: Milademetan 120 mg | Cohort 4: Milademetan 160 mg | Cohort 5: Milademetan 210 mg | Cohort 6b: Milademetan 160 mg | Cohort 7c: Milademetan 160 mg | Cohort 8d: Milademetan 160 mg | Cohort 9d: Milademetan 220 mg | Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 | Cohort 13f: Milademetan 200 mg + Azacitidine 75 mg/m^2 | |||||||||||||
| Arm/Group Description | Participants were administered 60 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 90 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 120 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle. | Participants were administered 210 mg milademetan daily as oral capsules on Days 1 to 21 of a 28-day cycle | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 7 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules for 3 of 14 days repeated twice in a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. | Participants were administered 220 mg milademetan daily as oral capsules on Days 1 to 14 of a 28-day cycle. | Participants were administered 160 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 160 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 5 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | Participants were administered 200 mg milademetan daily as oral capsules on Days 8 to 14 of a 28-day cycle and azacitidine was administered on Days 1 to 7. | |||||||||||||
All Cause Mortality |
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| Cohort 1: Milademetan 60 mg | Cohort 2: Milademetan 90 mg | Cohort 3: Milademetan 120 mg | Cohort 4: Milademetan 160 mg | Cohort 5: Milademetan 210 mg | Cohort 6b: Milademetan 160 mg | Cohort 7c: Milademetan 160 mg | Cohort 8d: Milademetan 160 mg | Cohort 9d: Milademetan 220 mg | Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 | Cohort 13f: Milademetan 200 mg + Azacitidine 75 mg/m^2 | ||||||||||||||
| 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 | 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 | 1/7 (14.3%) | 0/6 (0%) | 1/11 (9.1%) | 1/8 (12.5%) | 1/5 (20%) | 1/7 (14.3%) | 1/3 (33.3%) | 1/6 (16.7%) | 2/4 (50%) | 2/9 (22.2%) | 2/3 (66.7%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
Serious Adverse Events |
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| Cohort 1: Milademetan 60 mg | Cohort 2: Milademetan 90 mg | Cohort 3: Milademetan 120 mg | Cohort 4: Milademetan 160 mg | Cohort 5: Milademetan 210 mg | Cohort 6b: Milademetan 160 mg | Cohort 7c: Milademetan 160 mg | Cohort 8d: Milademetan 160 mg | Cohort 9d: Milademetan 220 mg | Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 | Cohort 13f: Milademetan 200 mg + Azacitidine 75 mg/m^2 | ||||||||||||||
| 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 | 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 | 4/7 (57.1%) | 5/6 (83.3%) | 9/11 (81.8%) | 5/8 (62.5%) | 5/5 (100%) | 4/7 (57.1%) | 2/3 (66.7%) | 3/6 (50%) | 2/4 (50%) | 9/9 (100%) | 3/3 (100%) | 4/4 (100%) | 0/1 (0%) | |||||||||||||
| Blood and lymphatic system disorders | ||||||||||||||||||||||||||
| Febrile neutropenia | 1/7 (14.3%) | 0/6 (0%) | 2/11 (18.2%) | 1/8 (12.5%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Anaemia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Bone marrow failure | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Cardiac disorders | ||||||||||||||||||||||||||
| Atrial fibrillation | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Cardiac failure | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Pericardial effusion | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Gastrointestinal disorders | ||||||||||||||||||||||||||
| Diarrhoea | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Nausea | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Vomiting | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Abdominal pain | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Ileus | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| General disorders | ||||||||||||||||||||||||||
| Pyrexia | 1/7 (14.3%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Asthenia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Fatigue | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Mucosal inflammation | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Multi-organ failure | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Death | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 2/3 (66.7%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Infections and infestations | ||||||||||||||||||||||||||
| Lung infection | 0/7 (0%) | 0/6 (0%) | 2/11 (18.2%) | 1/8 (12.5%) | 0/5 (0%) | 2/7 (28.6%) | 1/3 (33.3%) | 1/6 (16.7%) | 2/4 (50%) | 3/9 (33.3%) | 3/3 (100%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pneumonia | 2/7 (28.6%) | 1/6 (16.7%) | 0/11 (0%) | 3/8 (37.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 2/9 (22.2%) | 1/3 (33.3%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Sepsis | 2/7 (28.6%) | 0/6 (0%) | 1/11 (9.1%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 1/6 (16.7%) | 1/4 (25%) | 2/9 (22.2%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Bacteraemia | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Cellulitis | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 1/8 (12.5%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pneumonia fungal | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Arthritis bacterial | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Arthritis infective | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Clostridium difficile colitis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Device related sepsis | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Zygomycosis | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Splenic infarction | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Bacterial infection | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Device-related infection | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Escherichia infection | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Liver abscess | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Parainfluenzae virus infection | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Periorbital cellulitis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pneumonia bacterial | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Staphylococcal sepsis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Upper respiratory tract infection | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Injury, poisoning and procedural complications | ||||||||||||||||||||||||||
| Upper limb fracture | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Investigations | ||||||||||||||||||||||||||
| Human rhinovirus test positive | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Metabolism and nutrition disorders | ||||||||||||||||||||||||||
| Dehydration | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Failure to thrive | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Fluid overload | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Nervous system disorders | ||||||||||||||||||||||||||
| Hemorrhage intracranial | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Syncope | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Psychiatric disorders | ||||||||||||||||||||||||||
| Confusional state | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Psychogenic seizure | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Renal and urinary disorders | ||||||||||||||||||||||||||
| Renal failure | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Urinary incontinence | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||||||||||||
| Respiratory failure | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Skin and subcutaneous tissue disorders | ||||||||||||||||||||||||||
| Stasis dermatitis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Swelling face | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Vascular disorders | ||||||||||||||||||||||||||
| Hypotension | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
Other (Not Including Serious) Adverse Events |
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| Cohort 1: Milademetan 60 mg | Cohort 2: Milademetan 90 mg | Cohort 3: Milademetan 120 mg | Cohort 4: Milademetan 160 mg | Cohort 5: Milademetan 210 mg | Cohort 6b: Milademetan 160 mg | Cohort 7c: Milademetan 160 mg | Cohort 8d: Milademetan 160 mg | Cohort 9d: Milademetan 220 mg | Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2 | Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 | Cohort 13f: Milademetan 200 mg + Azacitidine 75 mg/m^2 | ||||||||||||||
| 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 | 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 | 7/7 (100%) | 6/6 (100%) | 11/11 (100%) | 8/8 (100%) | 5/5 (100%) | 7/7 (100%) | 3/3 (100%) | 6/6 (100%) | 4/4 (100%) | 9/9 (100%) | 3/3 (100%) | 4/4 (100%) | 1/1 (100%) | |||||||||||||
| Blood and lymphatic system disorders | ||||||||||||||||||||||||||
| Thrombocytopenia | 2/7 (28.6%) | 1/6 (16.7%) | 4/11 (36.4%) | 5/8 (62.5%) | 1/5 (20%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 3/4 (75%) | 0/1 (0%) | |||||||||||||
| Anaemia | 2/7 (28.6%) | 3/6 (50%) | 3/11 (27.3%) | 3/8 (37.5%) | 1/5 (20%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Neutropenia | 1/7 (14.3%) | 2/6 (33.3%) | 2/11 (18.2%) | 3/8 (37.5%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 1/9 (11.1%) | 0/3 (0%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Febrile neutropenia | 1/7 (14.3%) | 0/6 (0%) | 3/11 (27.3%) | 1/8 (12.5%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Leukopenia | 0/7 (0%) | 1/6 (16.7%) | 2/11 (18.2%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Bone marrow failure | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Coagulopathy | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Increased tendency to bruise | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Leukocytosis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Lymphadenitis | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Splenic infarction | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pancytopenia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 2/9 (22.2%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Cardiac disorders | ||||||||||||||||||||||||||
| Pericardial effusion | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Supraventricular tachycardia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Tachycardia | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Angina pectoris | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Atrial fibrillation | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Cardiac failure | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Cardiac tamponade | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Coronary artery disease | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Palpitations | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Bradycardia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Sinus tachycardia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Ear and labyrinth disorders | ||||||||||||||||||||||||||
| Cerumen impaction | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Ear pain | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hearing impaired | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Eye disorders | ||||||||||||||||||||||||||
| Eye pain | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Retinal haemorrhage | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Vision blurred | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Gastrointestinal disorders | ||||||||||||||||||||||||||
| Nausea | 5/7 (71.4%) | 4/6 (66.7%) | 8/11 (72.7%) | 6/8 (75%) | 4/5 (80%) | 3/7 (42.9%) | 2/3 (66.7%) | 4/6 (66.7%) | 3/4 (75%) | 5/9 (55.6%) | 2/3 (66.7%) | 2/4 (50%) | 1/1 (100%) | |||||||||||||
| Diarrhoea | 2/7 (28.6%) | 2/6 (33.3%) | 8/11 (72.7%) | 5/8 (62.5%) | 3/5 (60%) | 4/7 (57.1%) | 2/3 (66.7%) | 3/6 (50%) | 3/4 (75%) | 1/9 (11.1%) | 2/3 (66.7%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Vomiting | 2/7 (28.6%) | 1/6 (16.7%) | 4/11 (36.4%) | 4/8 (50%) | 3/5 (60%) | 2/7 (28.6%) | 2/3 (66.7%) | 3/6 (50%) | 3/4 (75%) | 3/9 (33.3%) | 2/3 (66.7%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Abdominal pain | 2/7 (28.6%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 2/7 (28.6%) | 0/3 (0%) | 2/6 (33.3%) | 0/4 (0%) | 3/9 (33.3%) | 1/3 (33.3%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Dry mouth | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 1/5 (20%) | 2/7 (28.6%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Constipation | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 1/8 (12.5%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 2/9 (22.2%) | 2/3 (66.7%) | 1/4 (25%) | 1/1 (100%) | |||||||||||||
| Gastrooesophageal reflux disease | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 1/4 (25%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Haemorrhoids | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 1/3 (33.3%) | 0/6 (0%) | 1/4 (25%) | 2/9 (22.2%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hemorrhoidal hemorrhage | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Oral disorder | 2/7 (28.6%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Stomatitis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Toothache | 2/7 (28.6%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Abdominal discomfort | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Abdominal distension | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Duodenitis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Dysphagia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Flatulence | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Gastrointestinal pain | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hiatus hernia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Oesophagitis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Proctalgia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Rectal hemorrhage | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Tongue ulceration | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Faeces discoloured | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Ileus | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Mouth haemorrhage | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| General disorders | ||||||||||||||||||||||||||
| Fatigue | 2/7 (28.6%) | 1/6 (16.7%) | 5/11 (45.5%) | 5/8 (62.5%) | 3/5 (60%) | 2/7 (28.6%) | 0/3 (0%) | 1/6 (16.7%) | 1/4 (25%) | 3/9 (33.3%) | 2/3 (66.7%) | 2/4 (50%) | 0/1 (0%) | |||||||||||||
| Oedema peripheral | 1/7 (14.3%) | 0/6 (0%) | 4/11 (36.4%) | 2/8 (25%) | 1/5 (20%) | 3/7 (42.9%) | 1/3 (33.3%) | 1/6 (16.7%) | 1/4 (25%) | 1/9 (11.1%) | 1/3 (33.3%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Asthenia | 1/7 (14.3%) | 0/6 (0%) | 1/11 (9.1%) | 1/8 (12.5%) | 2/5 (40%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Malaise | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 1/5 (20%) | 1/7 (14.3%) | 0/3 (0%) | 1/6 (16.7%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Gait disturbance | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 1/5 (20%) | 1/7 (14.3%) | 0/3 (0%) | 1/6 (16.7%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pyrexia | 1/7 (14.3%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 1/5 (20%) | 1/7 (14.3%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 1/9 (11.1%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Chills | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Mucosal inflammation | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Non-cardiac chest pain | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Localised oedema | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Multi-organ failure | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pain | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Thirst | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Death | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 2/3 (66.7%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Chest pain | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Oedema | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Tenderness | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hepatobiliary disorders | ||||||||||||||||||||||||||
| Hyperbilirubinaemia | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hepatosplenomegaly | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Immune system disorders | ||||||||||||||||||||||||||
| Drug hypersensitivity | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Graft versus host disease in skin | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Infections and infestations | ||||||||||||||||||||||||||
| Lung infection | 0/7 (0%) | 1/6 (16.7%) | 2/11 (18.2%) | 2/8 (25%) | 0/5 (0%) | 2/7 (28.6%) | 1/3 (33.3%) | 1/6 (16.7%) | 2/4 (50%) | 3/9 (33.3%) | 3/3 (100%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pneumonia | 3/7 (42.9%) | 1/6 (16.7%) | 1/11 (9.1%) | 3/8 (37.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 3/9 (33.3%) | 1/3 (33.3%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Sepsis | 2/7 (28.6%) | 0/6 (0%) | 1/11 (9.1%) | 1/8 (12.5%) | 0/5 (0%) | 1/7 (14.3%) | 1/3 (33.3%) | 1/6 (16.7%) | 1/4 (25%) | 2/9 (22.2%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Bacteraemia | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 2/5 (40%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Urinary tract infection | 2/7 (28.6%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Cellulitis | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 1/8 (12.5%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Oral candidiasis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 2/4 (50%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pneumonia fungal | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Arthritis bacterial | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Arthritis infective | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Candida infection | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Clostridium difficile colitis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Clostridium difficile infection | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Device-related sepsis | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Influenzae | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Periorbital cellulitis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Rash pustular | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Sialoadenitis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Sinusitis | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Upper respiratory tract infection | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Vulvitis | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Zygomycosis | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Device-related infection | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 2/9 (22.2%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Escherichia infection | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 2/9 (22.2%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Bacterial infection | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Enterocolitis infectious | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Liver abscess | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Parainfluenzae virus infection | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Peritonitis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pharyngitis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pneumonia bacterial | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Skin infection | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Staphylococcal sepsis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Injury, poisoning and procedural complications | ||||||||||||||||||||||||||
| Fall | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 1/8 (12.5%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 1/1 (100%) | |||||||||||||
| Contusion | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 2/9 (22.2%) | 2/3 (66.7%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Upper limb fracture | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Tooth fracture | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Investigations | ||||||||||||||||||||||||||
| Weight decreased | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 2/5 (40%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 2/4 (50%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Aspartate aminotransferase increased | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Blood alkaline phosphatase increased | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Cardiac murmur | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Electrocardiogram QT prolonged | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Activated partial thromboplastin time prolonged | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Alanine aminotransferase increased | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Bacterial test positive | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Blood bilirubin increased | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Blood creatinine increased | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Blood potassium increased | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Brain natriuretic peptide increased | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Human rhinovirus test positive | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Protein total increased | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Vitamin D decreased | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Metabolism and nutrition disorders | ||||||||||||||||||||||||||
| Decreased appetite | 2/7 (28.6%) | 0/6 (0%) | 2/11 (18.2%) | 3/8 (37.5%) | 3/5 (60%) | 2/7 (28.6%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 3/9 (33.3%) | 2/3 (66.7%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hypokalaemia | 0/7 (0%) | 1/6 (16.7%) | 1/11 (9.1%) | 4/8 (50%) | 3/5 (60%) | 2/7 (28.6%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 1/9 (11.1%) | 0/3 (0%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Hypomagnesaemia | 0/7 (0%) | 1/6 (16.7%) | 3/11 (27.3%) | 1/8 (12.5%) | 2/5 (40%) | 2/7 (28.6%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Dehydration | 1/7 (14.3%) | 0/6 (0%) | 1/11 (9.1%) | 1/8 (12.5%) | 1/5 (20%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 2/9 (22.2%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hyperuricaemia | 2/7 (28.6%) | 1/6 (16.7%) | 0/11 (0%) | 1/8 (12.5%) | 2/5 (40%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hyperphosphataemia | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 2/8 (25%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Fluid overload | 0/7 (0%) | 0/6 (0%) | 2/11 (18.2%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hyponatraemia | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Hypouricaemia | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Tumour lysis syndrome | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Diabetes mellitus | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Failure to thrive | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hyperglycaemia | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hypocalcaemia | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hypophosphataemia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 2/9 (22.2%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Acidosis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||||||||||||||||
| Back pain | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 1/5 (20%) | 1/7 (14.3%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Arthralgia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 1/4 (25%) | 1/9 (11.1%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pain in extremity | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Muscular weakness | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 2/9 (22.2%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Neck pain | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Bone pain | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Flank pain | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Joint effusion | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Myalgia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 3/9 (33.3%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Synovial cyst | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||||||||||||||
| Squamous cell carcinoma | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Nervous system disorders | ||||||||||||||||||||||||||
| Dizziness | 1/7 (14.3%) | 1/6 (16.7%) | 0/11 (0%) | 2/8 (25%) | 2/5 (40%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 2/9 (22.2%) | 1/3 (33.3%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Dysgeusia | 0/7 (0%) | 0/6 (0%) | 2/11 (18.2%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 2/4 (50%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Haemorrhage intracranial | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Headache | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 2/9 (22.2%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Presyncope | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Disturbance in attention | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Dysarthria | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Encephalopathy | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Memory impairment | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Paraesthesia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Syncope | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Psychiatric disorders | ||||||||||||||||||||||||||
| Agitation | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Anxiety | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 1/6 (16.7%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Insomnia | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 2/8 (25%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 1/9 (11.1%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Confusional state | 0/7 (0%) | 1/6 (16.7%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Depression | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Dysphoria | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Psychogenic seizure | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Sleep disorder | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Renal and urinary disorders | ||||||||||||||||||||||||||
| Pollakiuria | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 3/7 (42.9%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Renal failure | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Haematuria | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Haemoglobinuria | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Nocturia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Proteinuria | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Renal failure acute | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Urinary incontinence | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Urinary retention | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Dysuria | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Reproductive system and breast disorders | ||||||||||||||||||||||||||
| Vaginal haemorrhage | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Menorrhagia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||||||||||||
| Dyspnoea | 0/7 (0%) | 1/6 (16.7%) | 2/11 (18.2%) | 1/8 (12.5%) | 3/5 (60%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 3/9 (33.3%) | 3/3 (100%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Cough | 1/7 (14.3%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 4/9 (44.4%) | 3/3 (100%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Oropharyngeal pain | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 2/9 (22.2%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Acute respiratory distress syndrome | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Acute respiratory failure | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Choking | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Dysphonia | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Dyspnoea exertional | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Epistaxis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 2/9 (22.2%) | 0/3 (0%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Haemoptysis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Nasal congestion | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pleural effusion | 1/7 (14.3%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Productive cough | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pulmonary congestion | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Respiratory failure | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Rhinorrhoea | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 1/9 (11.1%) | 2/3 (66.7%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Sinus disorder | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Wheezing | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hypoxia | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pleuritic pain | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Skin and subcutaneous tissue disorders | ||||||||||||||||||||||||||
| Rash maculo-papular | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 1/7 (14.3%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 3/4 (75%) | 0/1 (0%) | |||||||||||||
| Acute febrile neutrophilic dermatosis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Dermatitis acneiform | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Night sweats | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pruritus | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 1/8 (12.5%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Purpura | 0/7 (0%) | 1/6 (16.7%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Skin hyperpigmentation | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Skin lesion | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Skin ulcer | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Ecchymosis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Erythema multiforme | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Hidradenitis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Stasis dermatitis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 1/9 (11.1%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Swelling face | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 1/3 (33.3%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Vascular disorders | ||||||||||||||||||||||||||
| Hypotension | 2/7 (28.6%) | 2/6 (33.3%) | 2/11 (18.2%) | 1/8 (12.5%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 1/4 (25%) | 3/9 (33.3%) | 1/3 (33.3%) | 1/4 (25%) | 0/1 (0%) | |||||||||||||
| Hypertension | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 2/7 (28.6%) | 1/3 (33.3%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Deep vein thrombosis | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 1/5 (20%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Embolism | 0/7 (0%) | 0/6 (0%) | 1/11 (9.1%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Pallor | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 1/6 (16.7%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 0/4 (0%) | 0/1 (0%) | |||||||||||||
| Orthostatic hypotension | 0/7 (0%) | 0/6 (0%) | 0/11 (0%) | 0/8 (0%) | 0/5 (0%) | 0/7 (0%) | 0/3 (0%) | 0/6 (0%) | 0/4 (0%) | 0/9 (0%) | 0/3 (0%) | 1/4 (25%) | 0/1 (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 | Contact for Clinical Trial Information |
|---|---|
| Organization | Daiichi Sankyo |
| Phone | 908-992-6400 |
| CTRinfo@dsi.com |
Responsible Party:
Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier:
NCT02319369
Other Study ID Numbers:
- DS3032-A-U102
First Posted:
Dec 18, 2014
Last Update Posted:
Oct 11, 2021
Last Verified:
Sep 1, 2021