Phase 1 Study of SGI-110 in Patients With Acute Myeloid Leukemia
Sponsor
Otsuka Pharmaceutical Co., Ltd. (Industry)
Overall Status
Completed
CT.gov ID
NCT02293993
Collaborator
(none)
21
3
4
52.7
7
0.1
Study Details
Study Description
Brief Summary
To evaluate the tolerability and pharmacokinetics of SGI-110 when administered subcutaneously to Japanese patients with acute myeloid leukemia (AML).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
21 participants
Allocation:
Non-Randomized
Intervention Model:
Factorial Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase 1 Study of SGI-110 in Patients With Acute Myeloid Leukemia
Actual Study Start Date
:
Jan 7, 2015
Actual Primary Completion Date
:
Jun 14, 2017
Actual Study Completion Date
:
May 31, 2019
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort1 SGI-110 36mg/m2 will be administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). |
Drug: SGI-110
|
| Experimental: Cohort2 SGI-110 60mg/m2 will be administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). |
Drug: SGI-110
|
| Experimental: Cohort3 SGI-110 90mg/m2 will be administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). |
Drug: SGI-110
|
| Experimental: Cohort4 SGI-110 60mg/m2 will be administered subcutaneously once daily for 10 days (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28). |
Drug: SGI-110
|
Outcome Measures
Primary Outcome Measures
- Dose Limiting Toxicity (DLT) [28 days (Day 1 to Day 29)]
DLT was defined as any of the following adverse events (AEs) occurring during Course 1 for which there was a reasonable probability or possibility of a causal relationship with the IMP. The severity of AEs was graded in accordance with Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Nonhematologic toxicity of Grade ≥3, except for (i) nausea, vomiting, or diarrhea of Grade 3 that is controllable by optimal therapy, and (ii) Grade 3 laboratory findings other than serum creatinine, bilirubin, aspartate aminotransferase, or alanine aminotransferase. Grade 4 thrombocytopenia that was not present at trial entry and that is not resolved within 7 days Grade 4 neutropenia that was not present at trial entry and that is not resolved within 7 days Febrile neutropenia (defined as a neutrophil count of <500/μL accompanied by a fever of ≥38°C) Any AE that results in a delay of >4 weeks in starting the next treatment course
Secondary Outcome Measures
- Maximum Plasma Concentration (Cmax) of SGI-110 and Its Active Metabolite Decitabine Following Single and Multiple Administration of SGI-110 [Pre-dose, 15min, 30min, 60min, 90min, 2h, 3h, 4h, 6h, 8h, 24h after dosing (Cohorts 1, 2, and 4: Day 1 and Day 5, Cohort 3: Day 1 and Day 12)]
- Time to Maximum Plasma Concentration (Tmax) of SGI-110 and Its Active Metabolite Decitabine Following Single and Multiple Administration of SGI-110 [Pre-dose, 15min, 30min, 60min, 90min, 2h, 3h, 4h, 6h, 8h, 24h after dosing (Cohorts 1, 2, and 4: Day 1 and Day 5, Cohort 3: Day 1 and Day 12)]
- Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC24h) of SGI-110 and Its Active Metabolite Decitabine Following Single and Multiple Administration of SGI-110 [Pre-dose, 15min, 30min, 60min, 90min, 2h, 3h, 4h, 6h, 8h, 24h after dosing (Cohorts 1, 2, and 4: Day 1 and Day 5, Cohort 3: Day 1 and Day 12)]
- Terminal-phase Elimination Half-life (T1/2,z) of SGI-110 and Its Active Metabolite Decitabine Following Single and Multiple Administration of SGI-110 [Pre-dose, 15min, 30min, 60min, 90min, 2h, 3h, 4h, 6h, 8h, 24h after dosing (Cohorts 1, 2, and 4: Day 1 and Day 5, Cohort 3: Day 1 and Day 12)]
Eligibility Criteria
Criteria
Ages Eligible for Study:
20 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Male or female patients with a diagnosis of AML (WHO classification 2008).
-
Patients, 20 years of age or older, who are unresponsive to standard chemotherapy or have relapsed following standard chemotherapy
-
Patients, 65 years of age or older, who are not eligible for standard intensive chemotherapy
-
Patients with ECOG performance status (PS) of 0 to 2
-
Patients with adequate organ function
-
Women of child-bearing potential must not be pregnant or breast feeding (pregnancy test will be performed at Screening). Women of child bearing potential and all men with female partners of child bearing potential must practice two medically acceptable methods of birth control and must not become pregnant or father a child while receiving treatment with SGI-110 and for 3 months following last dosing.
-
Patients who have undergone prior allogeneic hematopoietic stem cell transplantation must have no evidence of active graft-versus host disease (GVHD) and must be off immunosuppressive therapy by ≥2 weeks prior to IMP administration.
Exclusion Criteria:
-
Patients with acute promyelocytic leukemia accompanied by t(15;17)(q22;q12) or (PML/RARA) karyotype abnormalities (include other variant types of APL)
-
Patients with multiple cancers (except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for at least 3 years)
-
Subjects with life-threatening illnesses other than AML or MDS, uncontrolled medical conditions or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, or put the study outcomes at risk.
-
Patients with poorly controlled arrhythmias, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
-
Patients with symptomatic central nervous system involvement.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | kinki Region | Kyoto | Japan | ||
| 2 | Kanto | Region | Japan | ||
| 3 | Kyusyu | Region | Japan |
Sponsors and Collaborators
- Otsuka Pharmaceutical Co., Ltd.
Investigators
- Study Director: Junji Ikeda, Otsuka Pharmaceutical Co., Ltd.
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Otsuka Pharmaceutical Co., Ltd.
ClinicalTrials.gov Identifier:
NCT02293993
Other Study ID Numbers:
- 343-14-001
- JapicCTI-142711
First Posted:
Nov 19, 2014
Last Update Posted:
Mar 5, 2021
Last Verified:
Feb 1, 2021
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | This trial consisted of a screening period, dose limiting toxicity (DLT) evaluation period (Course 1), and withdrawal examination. Subjects who completed investigational medicinal product (IMP) administration and all observations during the DLT evaluation period, and who did not have any apparent progression of AML, were permitted to be added extended treatment period (Course 2) to continue treatment with IMP following the DLT evaluation period if they wished. |
| Arm/Group Title | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 |
|---|---|---|---|---|
| Arm/Group Description | SGI-110 36mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 10 days in total (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28). | SGI-110 90mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). |
| Period Title: Course 1 (DLT Evaluation Period) | ||||
| STARTED | 4 | 6 | 7 | 4 |
| COMPLETED | 3 | 6 | 7 | 3 |
| NOT COMPLETED | 1 | 0 | 0 | 1 |
| Period Title: Course 1 (DLT Evaluation Period) | ||||
| STARTED | 2 | 5 | 6 | 3 |
| COMPLETED | 0 | 0 | 1 | 2 |
| NOT COMPLETED | 2 | 5 | 5 | 1 |
Baseline Characteristics
| Arm/Group Title | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | Total |
|---|---|---|---|---|---|
| Arm/Group Description | SGI-110 36mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 10 days in total (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28). | SGI-110 90mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | Total of all reporting groups |
| Overall Participants | 4 | 6 | 7 | 4 | 21 |
| Age (Count of Participants) | |||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
1
25%
|
0
0%
|
0
0%
|
0
0%
|
1
4.8%
|
| >=65 years |
3
75%
|
6
100%
|
7
100%
|
4
100%
|
20
95.2%
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
2
50%
|
1
16.7%
|
5
71.4%
|
1
25%
|
9
42.9%
|
| Male |
2
50%
|
5
83.3%
|
2
28.6%
|
3
75%
|
12
57.1%
|
| Race/Ethnicity, Customized (Count of Participants) | |||||
| Japanese |
4
100%
|
6
100%
|
7
100%
|
4
100%
|
21
100%
|
| Region of Enrollment (Count of Participants) | |||||
| Japan |
4
100%
|
6
100%
|
7
100%
|
4
100%
|
21
100%
|
Outcome Measures
| Title | Dose Limiting Toxicity (DLT) |
|---|---|
| Description | DLT was defined as any of the following adverse events (AEs) occurring during Course 1 for which there was a reasonable probability or possibility of a causal relationship with the IMP. The severity of AEs was graded in accordance with Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Nonhematologic toxicity of Grade ≥3, except for (i) nausea, vomiting, or diarrhea of Grade 3 that is controllable by optimal therapy, and (ii) Grade 3 laboratory findings other than serum creatinine, bilirubin, aspartate aminotransferase, or alanine aminotransferase. Grade 4 thrombocytopenia that was not present at trial entry and that is not resolved within 7 days Grade 4 neutropenia that was not present at trial entry and that is not resolved within 7 days Febrile neutropenia (defined as a neutrophil count of <500/μL accompanied by a fever of ≥38°C) Any AE that results in a delay of >4 weeks in starting the next treatment course |
| Time Frame | 28 days (Day 1 to Day 29) |
Outcome Measure Data
| Analysis Population Description |
|---|
| DLT analysis population included subjects in whom tolerability had been assessed in Cohorts 1 to 4 (subjects who had received all doses and completed all assessments scheduled for the DLT evaluation period). |
| Arm/Group Title | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 |
|---|---|---|---|---|
| Arm/Group Description | SGI-110 36mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 10 days in total (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28). | SGI-110 90mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). |
| Measure Participants | 3 | 6 | 6 | 3 |
| Number [participants] |
0
0%
|
0
0%
|
1
14.3%
|
0
0%
|
| Title | Maximum Plasma Concentration (Cmax) of SGI-110 and Its Active Metabolite Decitabine Following Single and Multiple Administration of SGI-110 |
|---|---|
| Description | |
| Time Frame | Pre-dose, 15min, 30min, 60min, 90min, 2h, 3h, 4h, 6h, 8h, 24h after dosing (Cohorts 1, 2, and 4: Day 1 and Day 5, Cohort 3: Day 1 and Day 12) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis population included subjects whose plasma drug concentrations had been measured. |
| Arm/Group Title | Cohort 1 (Day 1) | Cohort 2 (Day 1) | Cohort 3 (Day 1) | Cohort 4 (Day 1) | Cohort 1 (Day 5) | Cohort 2 (Day 5) | Cohort 3 (Day 12) | Cohort 4 (Day 5) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | SGI-110 36mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 10 days in total (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28). | SGI-110 90mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 36mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 10 days in total (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28). | SGI-110 90mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). |
| Measure Participants | 4 | 6 | 7 | 4 | 4 | 6 | 7 | 4 |
| SGI-110 |
96.8
(37.3)
|
182
(59.7)
|
140
(33.1)
|
359
(220)
|
142
(97.4)
|
200
(42.4)
|
155
(58.5)
|
328
(208)
|
| decitabine |
28.6
(13.8)
|
54.1
(14.7)
|
31.8
(4.08)
|
109
(50.3)
|
38.2
(34.1)
|
67.2
(13.5)
|
44.5
(15.3)
|
95.7
(37.2)
|
| Title | Time to Maximum Plasma Concentration (Tmax) of SGI-110 and Its Active Metabolite Decitabine Following Single and Multiple Administration of SGI-110 |
|---|---|
| Description | |
| Time Frame | Pre-dose, 15min, 30min, 60min, 90min, 2h, 3h, 4h, 6h, 8h, 24h after dosing (Cohorts 1, 2, and 4: Day 1 and Day 5, Cohort 3: Day 1 and Day 12) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis population included subjects whose plasma drug concentrations had been measured. |
| Arm/Group Title | Cohort 1 (Day 1) | Cohort 2 (Day 1) | Cohort 3 (Day 1) | Cohort 4 (Day 1) | Cohort 1 (Day 5) | Cohort 2 (Day 5) | Cohort 3 (Day 12) | Cohort 4 (Day 5) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | SGI-110 36mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 10 days in total (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28). | SGI-110 90mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 36mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 10 days in total (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28). | SGI-110 90mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). |
| Measure Participants | 4 | 6 | 7 | 4 | 4 | 6 | 7 | 4 |
| SGI-110 |
1.49
|
0.98
|
1.48
|
1.51
|
0.99
|
0.97
|
1.42
|
1.27
|
| decitabine |
2.04
|
1.27
|
1.93
|
1.51
|
1.49
|
1.47
|
1.43
|
1.53
|
| Title | Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours (AUC24h) of SGI-110 and Its Active Metabolite Decitabine Following Single and Multiple Administration of SGI-110 |
|---|---|
| Description | |
| Time Frame | Pre-dose, 15min, 30min, 60min, 90min, 2h, 3h, 4h, 6h, 8h, 24h after dosing (Cohorts 1, 2, and 4: Day 1 and Day 5, Cohort 3: Day 1 and Day 12) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis population included subjects whose plasma drug concentrations had been measured. |
| Arm/Group Title | Cohort 1 (Day 1) | Cohort 2 (Day 1) | Cohort 3 (Day 1) | Cohort 4 (Day 1) | Cohort 1 (Day 5) | Cohort 2 (Day 5) | Cohort 3 (Day 12) | Cohort 4 (Day 5) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | SGI-110 36mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 10 days in total (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28). | SGI-110 90mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 36mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 10 days in total (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28). | SGI-110 90mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). |
| Measure Participants | 4 | 6 | 7 | 4 | 4 | 6 | 7 | 4 |
| SGI-110 |
207
(36.1)
|
398
(75.7)
|
332
(61.5)
|
710
(119)
|
206
(11.7)
|
410
(57.9)
|
311
(87.2)
|
581
(124)
|
| decitabine |
70.0
(13.4)
|
151
(42.7)
|
95.7
(11.7)
|
248
(39.9)
|
67.0
(18.6)
|
150
(34.1)
|
101
(10.7)
|
240
(41.6)
|
| Title | Terminal-phase Elimination Half-life (T1/2,z) of SGI-110 and Its Active Metabolite Decitabine Following Single and Multiple Administration of SGI-110 |
|---|---|
| Description | |
| Time Frame | Pre-dose, 15min, 30min, 60min, 90min, 2h, 3h, 4h, 6h, 8h, 24h after dosing (Cohorts 1, 2, and 4: Day 1 and Day 5, Cohort 3: Day 1 and Day 12) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis population included subjects whose plasma drug concentrations had been measured. |
| Arm/Group Title | Cohort 1 (Day 1) | Cohort 2 (Day 1) | Cohort 3 (Day 1) | Cohort 4 (Day 1) | Cohort 1 (Day 5) | Cohort 2 (Day 5) | Cohort 3 (Day 12) | Cohort 4 (Day 5) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | SGI-110 36mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 10 days in total (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28). | SGI-110 90mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 36mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 10 days in total (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28). | SGI-110 90mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). |
| Measure Participants | 4 | 6 | 7 | 4 | 4 | 6 | 7 | 4 |
| SGI-110 |
0.698
(0.393)
|
0.833
(0.493)
|
0.740
(0.212)
|
0.656
(0.155)
|
0.599
(0.332)
|
0.503
(0.144)
|
0.685
(0.341)
|
0.623
(0.153)
|
| decitabine |
1.04
(0.467)
|
1.12
(0.564)
|
1.09
(0.148)
|
0.891
(0.0990)
|
0.905
(0.385)
|
0.821
(0.231)
|
1.14
(0.486)
|
0.875
(0.107)
|
Adverse Events
| Time Frame | From the start of IMP administration up to 5 days after withdrawal | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | A treatment-emergent adverse event (TEAE) was defined as an AE occurring after the start of IMP administration. | |||||||
| Arm/Group Title | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | ||||
| Arm/Group Description | SGI-110 36mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | SGI-110 60mg/m2 was administered subcutaneously once daily for 10 days in total (Day 1 to Day 5 and Day 8 to Day 12 with dosing, Day 6 and 7 with non-dosing), followed by a 16-day non-dosing period (Day 13 to Day 28). | SGI-110 90mg/m2 was administered subcutaneously once daily for 5 consecutive days (Day 1 to Day 5), followed by a 23-day non-dosing period (Day 6 to Day 28). | ||||
All Cause Mortality |
||||||||
| Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/4 (0%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
Serious Adverse Events |
||||||||
| Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/4 (50%) | 5/6 (83.3%) | 4/7 (57.1%) | 1/4 (25%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Febrile neutropenia | 2/4 (50%) | 3/6 (50%) | 1/7 (14.3%) | 1/4 (25%) | ||||
| Cardiac disorders | ||||||||
| Cardiac failure | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/4 (0%) | ||||
| Endocrine disorders | ||||||||
| Diabetes insipidus | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Gastrointestinal disorders | ||||||||
| Gastrointestinal haemorrhage | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| General disorders | ||||||||
| Malaise | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Pyrexia | 0/4 (0%) | 0/6 (0%) | 0/7 (0%) | 1/4 (25%) | ||||
| Infections and infestations | ||||||||
| Lung infection | 0/4 (0%) | 2/6 (33.3%) | 2/7 (28.6%) | 0/4 (0%) | ||||
| Cellulitis | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Clostridium difficile colitis | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Encephalitis | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Influenza | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Periodontitis | 0/4 (0%) | 0/6 (0%) | 0/7 (0%) | 1/4 (25%) | ||||
| Pneumonia | 0/4 (0%) | 1/6 (16.7%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Bronchopulmonary aspergillosis | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Sepsis | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Subdural haematoma | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/4 (0%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Dehydration | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Nervous system disorders | ||||||||
| Cerebral infarction | 0/4 (0%) | 1/6 (16.7%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Hypoxia | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Organising pneumonia | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
| Cohort 1 | Cohort 2 | Cohort 3 | Cohort 4 | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 4/4 (100%) | 6/6 (100%) | 7/7 (100%) | 4/4 (100%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Febrile neutropenia | 2/4 (50%) | 3/6 (50%) | 2/7 (28.6%) | 1/4 (25%) | ||||
| Anaemia | 1/4 (25%) | 1/6 (16.7%) | 4/7 (57.1%) | 1/4 (25%) | ||||
| Lymphadenitis | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Cardiac disorders | ||||||||
| Cardiac failure congestive | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Endocrine disorders | ||||||||
| Autoimmune thyroiditis | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Eye disorders | ||||||||
| Blepharitis | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Dry eye | 1/4 (25%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Photophobia | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Trichiasis | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Vitreous floaters | 0/4 (0%) | 1/6 (16.7%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Gastrointestinal disorders | ||||||||
| Diarrhoea | 2/4 (50%) | 2/6 (33.3%) | 0/7 (0%) | 0/4 (0%) | ||||
| Nausea | 0/4 (0%) | 3/6 (50%) | 2/7 (28.6%) | 1/4 (25%) | ||||
| Haemorrhoids | 0/4 (0%) | 2/6 (33.3%) | 2/7 (28.6%) | 1/4 (25%) | ||||
| Stomatitis | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 1/4 (25%) | ||||
| Vomiting | 0/4 (0%) | 3/6 (50%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Abdominal discomfort | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/4 (0%) | ||||
| Constipation | 2/4 (50%) | 0/6 (0%) | 2/7 (28.6%) | 0/4 (0%) | ||||
| Dry mouth | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/4 (0%) | ||||
| Gastrointestinal haemorrhage | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Lip dry | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/4 (0%) | ||||
| Abdominal pain upper | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Glossodynia | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Mouth haemorrhage | 0/4 (0%) | 0/6 (0%) | 0/7 (0%) | 1/4 (25%) | ||||
| Mouth ulceration | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Oral mucosa erosion | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Proctalgia | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| General disorders | ||||||||
| Fatigue | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 1/4 (25%) | ||||
| Injection site induration | 0/4 (0%) | 3/6 (50%) | 0/7 (0%) | 0/4 (0%) | ||||
| Injection site pain | 0/4 (0%) | 1/6 (16.7%) | 1/7 (14.3%) | 2/4 (50%) | ||||
| Malaise | 0/4 (0%) | 2/6 (33.3%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Pyrexia | 0/4 (0%) | 1/6 (16.7%) | 2/7 (28.6%) | 1/4 (25%) | ||||
| Injection site erythema | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/4 (0%) | ||||
| Injection site pruritus | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Injection site reaction | 1/4 (25%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Oedema peripheral | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Pain | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Injection site vesicles | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Oedema | 0/4 (0%) | 0/6 (0%) | 3/7 (42.9%) | 0/4 (0%) | ||||
| Hepatobiliary disorders | ||||||||
| Hepatic function abnormal | 2/4 (50%) | 0/6 (0%) | 3/7 (42.9%) | 0/4 (0%) | ||||
| Immune system disorders | ||||||||
| Drug hypersensitivity | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Hypersensitivity | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Infections and infestations | ||||||||
| Upper respiratory tract infection | 2/4 (50%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Atypical mycobacterial infection | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Herpes simplex | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Infection | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Oral candidiasis | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Trichophytosis | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Viral upper respiratory tract infection | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Injury, poisoning and procedural complications | ||||||||
| Fall | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/4 (0%) | ||||
| Skin abrasion | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/4 (0%) | ||||
| Subdural haematoma | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/4 (0%) | ||||
| Allergic transfusion reaction | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Compression fracture | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Contusion | 0/4 (0%) | 0/6 (0%) | 0/7 (0%) | 1/4 (25%) | ||||
| Fracture | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Infusion related reaction | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Wound | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Investigations | ||||||||
| Lymphocyte count decreased | 1/4 (25%) | 5/6 (83.3%) | 6/7 (85.7%) | 3/4 (75%) | ||||
| Platelet count decreased | 2/4 (50%) | 1/6 (16.7%) | 6/7 (85.7%) | 3/4 (75%) | ||||
| White blood cell count decreased | 2/4 (50%) | 1/6 (16.7%) | 4/7 (57.1%) | 2/4 (50%) | ||||
| Neutrophil count decreased | 2/4 (50%) | 1/6 (16.7%) | 2/7 (28.6%) | 1/4 (25%) | ||||
| Weight decreased | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 1/4 (25%) | ||||
| Alanine aminotransferase increased | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 1/4 (25%) | ||||
| Aspartate aminotransferase increased | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 1/4 (25%) | ||||
| Blood alkaline phosphatase increased | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 1/4 (25%) | ||||
| Gamma-glutamyltransferase increased | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 1/4 (25%) | ||||
| Blood creatinine increased | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 1/4 (25%) | ||||
| C-reactive protein increased | 0/4 (0%) | 0/6 (0%) | 2/7 (28.6%) | 1/4 (25%) | ||||
| Reticulocyte count decreased | 0/4 (0%) | 0/6 (0%) | 0/7 (0%) | 1/4 (25%) | ||||
| Serum ferritin increased | 0/4 (0%) | 0/6 (0%) | 0/7 (0%) | 1/4 (25%) | ||||
| Antithrombin III decreased | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Blood bilirubin increased | 0/4 (0%) | 0/6 (0%) | 2/7 (28.6%) | 0/4 (0%) | ||||
| Prothrombin level decreased | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Metabolism and nutrition disorders | ||||||||
| Hypoalbuminaemia | 0/4 (0%) | 1/6 (16.7%) | 4/7 (57.1%) | 2/4 (50%) | ||||
| Hypokalaemia | 0/4 (0%) | 3/6 (50%) | 2/7 (28.6%) | 0/4 (0%) | ||||
| Decreased appetite | 0/4 (0%) | 2/6 (33.3%) | 5/7 (71.4%) | 0/4 (0%) | ||||
| Dehydration | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Hyperkalaemia | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Hyperuricaemia | 0/4 (0%) | 1/6 (16.7%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Hyponatraemia | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Hypophosphataemia | 0/4 (0%) | 0/6 (0%) | 2/7 (28.6%) | 0/4 (0%) | ||||
| Iron overload | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthralgia | 0/4 (0%) | 0/6 (0%) | 0/7 (0%) | 1/4 (25%) | ||||
| Back pain | 1/4 (25%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Joint swelling | 0/4 (0%) | 0/6 (0%) | 0/7 (0%) | 1/4 (25%) | ||||
| Musculoskeletal pain | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Osteoporosis | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Chondrocalcinosis pyrophosphate | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Myalgia | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Nervous system disorders | ||||||||
| Headache | 0/4 (0%) | 2/6 (33.3%) | 1/7 (14.3%) | 2/4 (50%) | ||||
| Dizziness | 1/4 (25%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Amnesia | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Depressed level of consciousness | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Restless legs syndrome | 0/4 (0%) | 0/6 (0%) | 0/7 (0%) | 1/4 (25%) | ||||
| Sciatica | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Dysgeusia | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Psychiatric disorders | ||||||||
| Delirium | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/4 (0%) | ||||
| Insomnia | 0/4 (0%) | 1/6 (16.7%) | 3/7 (42.9%) | 0/4 (0%) | ||||
| Sleep disorder due to a general medical condition | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Renal and urinary disorders | ||||||||
| Chronic kidney disease | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Renal impairment | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Urinary retention | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Reproductive system and breast disorders | ||||||||
| Genital erosion | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Genital ulceration | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Oropharyngeal pain | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 1/4 (25%) | ||||
| Nasal inflammation | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Organising pneumonia | 0/4 (0%) | 0/6 (0%) | 0/7 (0%) | 1/4 (25%) | ||||
| Chronic obstructive pulmonary disease | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Hypoxia | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Pleural effusion | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Respiratory depression | 0/4 (0%) | 0/6 (0%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Skin and subcutaneous tissue disorders | ||||||||
| Pruritus | 1/4 (25%) | 1/6 (16.7%) | 0/7 (0%) | 1/4 (25%) | ||||
| Dermatitis contact | 1/4 (25%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Petechiae | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 1/4 (25%) | ||||
| Skin ulcer | 0/4 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/4 (0%) | ||||
| Drug eruption | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Dry skin | 0/4 (0%) | 1/6 (16.7%) | 1/7 (14.3%) | 0/4 (0%) | ||||
| Erythema | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Rash | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Senile pruritus | 1/4 (25%) | 0/6 (0%) | 0/7 (0%) | 0/4 (0%) | ||||
| Skin induration | 0/4 (0%) | 0/6 (0%) | 0/7 (0%) | 1/4 (25%) | ||||
| Vascular disorders | ||||||||
| Hypertension | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (0%) | ||||
| Internal haemorrhage | 0/4 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/4 (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 | Director of Clinical Trials |
|---|---|
| Organization | Otsuka Pharmaceutical Co., LTD. |
| Phone | +81-3-6361-7366 |
| CL_OPCJ_RDA_Team@otsuka.jp |
Responsible Party:
Otsuka Pharmaceutical Co., Ltd.
ClinicalTrials.gov Identifier:
NCT02293993
Other Study ID Numbers:
- 343-14-001
- JapicCTI-142711
First Posted:
Nov 19, 2014
Last Update Posted:
Mar 5, 2021
Last Verified:
Feb 1, 2021