Clinical Trial Results:
A Phase 1/2 Study of Venetoclax in Combination with Low-Dose Cytarabine in Treatment-Naïve Subjects with Acute Myelogenous Leukemia Who Are ≥ 60 Years of Age and Who Are Not Eligible for Standard Anthracycline-Based Induction Therapy
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Summary
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EudraCT number |
2014-002610-23 |
Trial protocol |
DE IT |
Global end of trial date |
10 Aug 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Aug 2022
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First version publication date |
19 Aug 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
M14-387
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02287233 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
AbbVie Deutschland GmbH & Co. KG
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Sponsor organisation address |
AbbVie House, Vanwall Business Park, Vanwall Road,, Maidenhead, Berkshire, United Kingdom, SL6 4UB
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Public contact |
Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
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Scientific contact |
Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 Aug 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Aug 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objectives of the Phase 1 portion are to assess the safety profile, characterize PK, determine the dose schedule, the maximum tolerated dose (MTD), and the recommended Phase 2 dose (RPTD) of venetoclax in combination with low-dose cytarabine (LDAC) in treatment-naïve subjects with AML who are ≥ 65 years of age and who are not eligible for standard induction therapy due to co-morbidity or other factors.
The primary objectives of the initial Phase 2 portion of the study are to evaluate the preliminary estimates of efficacy including the overall response rate (ORR), and to characterize the toxicities of the combination at the RPTD.
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Protection of trial subjects |
Subject read and understood the information provided about the study and gave written permission.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
31 Dec 2014
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy | ||
Long term follow-up duration |
1 Years | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 26
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Country: Number of subjects enrolled |
Germany: 8
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Country: Number of subjects enrolled |
Italy: 3
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Country: Number of subjects enrolled |
United States: 57
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Worldwide total number of subjects |
94
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EEA total number of subjects |
11
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
2
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From 65 to 84 years |
86
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85 years and over |
6
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Recruitment
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Recruitment details |
Previously untreated adults with acute myeloid leukemia (AML)who were ineligible for intensive chemotherapy were enrolled between December 2014 and May 2017. The study consisted of a dose escalation phase (Phase 1) and a dose expansion phase (Phase 2). | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Nine study sites in the United States, Australia, Germany, and Italy screened 116 subjects (most screen failures were due to inclusion/exclusion criteria), and 94 subjects at 9 sites were enrolled. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Phase 1: 600 mg Venetoclax + LDAC | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg (Day 2) and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received low-dose cytarabine (LDAC; 20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Venetoclax
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Investigational medicinal product code |
ABT-199 (GDC-0199)
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Other name |
VENCLEXTA®
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tablets taken orally once a day
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Investigational medicinal product name |
Cytarabine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Administered by subcutaneous injection on Days 1 to 10 of each 28-day cycle
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Arm title
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Phase 1: 800 mg Venetoclax + LDAC | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 100 mg (Day 2) and increased up to 800 mg by Day 6. Beginning with Cycle 2, 800 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Venetoclax
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Investigational medicinal product code |
ABT-199 (GDC-0199)
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Other name |
VENCLEXTA®
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tablets taken orally once a day
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Investigational medicinal product name |
Cytarabine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Administered by subcutaneous injection on Days 1 to 10 of each 28-day cycle
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Arm title
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Phase 2: 600 mg Venetoclax + LDAC | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg, and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Cytarabine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Administered by subcutaneous injection on Days 1 to 10 of each 28-day cycle
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Investigational medicinal product name |
Venetoclax
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Investigational medicinal product code |
ABT-199 (GDC-0199)
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Other name |
VENCLEXTA®
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tablets taken orally once a day
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Baseline characteristics reporting groups
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Reporting group title |
Phase 1: 600 mg Venetoclax + LDAC
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Reporting group description |
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg (Day 2) and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received low-dose cytarabine (LDAC; 20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 1: 800 mg Venetoclax + LDAC
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Reporting group description |
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 100 mg (Day 2) and increased up to 800 mg by Day 6. Beginning with Cycle 2, 800 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 2: 600 mg Venetoclax + LDAC
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Reporting group description |
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg, and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Phase 1: 600 mg Venetoclax + LDAC
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Reporting group description |
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg (Day 2) and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received low-dose cytarabine (LDAC; 20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. | ||
Reporting group title |
Phase 1: 800 mg Venetoclax + LDAC
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Reporting group description |
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 100 mg (Day 2) and increased up to 800 mg by Day 6. Beginning with Cycle 2, 800 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. | ||
Reporting group title |
Phase 2: 600 mg Venetoclax + LDAC
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Reporting group description |
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg, and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. | ||
Subject analysis set title |
Phase 1+2: 600 mg Venetoclax + LDAC
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg, and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle.
Participants could continue receiving treatment until disease progression or until discontinuation criteria were met.
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End point title |
Phase 1: Number of Participants With Dose-limiting Toxicities [1] [2] | |||||||||
End point description |
Dose-limiting toxicities (DLTs) were determined during cycle 1 of the dose-escalation phase and defined as Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 grade 4 (life threatening requiring urgent intervention) or 5 (resulted in death) toxicity, excluding adverse events commonly caused by AML (eg, neutropenia, fever). Hematologic DLT was defined as failure of platelet recovery to 25 × 10^9/L or greater and absolute neutrophil count (ANC) to 0.5 × 10^9/L or greater within 14 days of the last dose of venetoclax in the absence of residual AML.
The DLT-evaluable population included participants who received at least 80% of planned Cycle 1 doses during the dose-escalation phase (Phase 1)
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End point type |
Primary
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End point timeframe |
Up to 28 days (Cycle 1)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical testing was conducted. [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: DLTs were only analyzed in Phase 1. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax [3] [4] | ||||||||||||||||||
End point description |
The highest concentration that a drug achieves in the blood after administration in a dosing interval.
The pharmacokinetic (PK) population includes participants enrolled in Phase 1 who had at least one dose of venetoclax and had at least one reported PK sample concentration.
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End point type |
Primary
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End point timeframe |
Cycle 1, Day 10 at predose and 2, 4, 6, 8, and 24 hours postdose (venetoclax with LDAC); Cycle 1, Day 18 at predose, 2, 4, 6, 8, and 24 hours postdose (venetoclax alone)
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical testing was conducted. [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: PK analyses were conducted for Phase 1 only |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax [5] [6] | ||||||||||||||||||
End point description |
The time at which the maximum plasma concentration (Cmax) is observed.
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End point type |
Primary
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End point timeframe |
Cycle 1, Day 10 at predose and 2, 4, 6, 8, and 24 hours postdose (venetoclax with LDAC); Cycle 1, Day 18 at predose, 2, 4, 6, 8, and 24 hours postdose (venetoclax alone)
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical testing was conducted. [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: PK analyses were conducted for Phase 1 only |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax [7] [8] | ||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Cycle 1, Day 10 at predose and 2, 4, 6, 8, and 24 hours postdose (venetoclax with LDAC); Cycle 1, Day 18 at predose, 2, 4, 6, 8, and 24 hours postdose (venetoclax alone)
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical testing was conducted. [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: PK analyses were conducted for Phase 1 only |
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| Notes [9] - N=6 on Day 18 [10] - N=9 on Day 18 |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Cytarabine [11] [12] | ||||||||||||||||||
End point description |
The highest concentration that a drug achieves in the blood after administration in a dosing interval.
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End point type |
Primary
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End point timeframe |
Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
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| Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical testing was conducted. [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: PK analyses were conducted for Phase 1 only |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Cytarabine [13] [14] | ||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
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| Notes [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical testing was conducted. [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: PK analyses were conducted for Phase 1 only |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to Last Measurable Concentration (AUCt) of Cytarabine [15] [16] | ||||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Cycle 1, Day 1 and Day 10 at pre-dose and at 15 and 30 minutes and 1, 3, 6 hours post-dose.
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| Notes [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical testing was conducted. [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: PK analyses were conducted for Phase 1 only |
|||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||
End point title |
Overall Response Rate [17] | ||||||||
End point description |
Overall response rate (ORR) is defined as the percentage of participants who achieved a complete remission (CR), complete remission with incomplete marrow recovery (CRi), or partial remission (PR) per the International Working Group (IWG) for AML response criteria, per investigator assessment.
CR: absolute neutrophil count (ANC) ≥ 10^3 /µL, platelet counts ≥ 10^5 /µL, red blood cell (RBC) transfusion independence (a period of at least 56 days with no RBC transfusion), and bone marrow with < 5% blasts.
CRi: lack of morphologic evidence of leukemia (blasts < 5%), and platelet counts < 10^5 /µL or ANC < 10^3 /µL.
PR: all of the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
|
||||||||
| Notes [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical testing was conducted. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Participants With Treatment-emergent Adverse Events (TEAEs) [18] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Treatment-emergent events are defined as events that began or worsened in severity after the first dose of study drug. The investigator rated the severity of each AE according to the CTCAE Version 4.0 and the following:
Grade 1: The AE is transient and easily tolerated (mild).
Grade 2: The AE causes discomfort and interrupts usual activities (moderate).
Grade 3: The AE causes considerable interference with usual activities and may be incapacitating (moderate to severe).
Grade 4: The AE is life threatening requiring urgent intervention.
Grade 5: The AE resulted in death.
The investigator assessed each event as either having a reasonable possibility or no reasonable possibility of being related to the use of study drug.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
From first dose of study drug until 30 days after last dose of study drug; median (minimum, maximum) duration of treatment was 4.1 (0.2, 62.8) months overall.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical testing was conducted. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||
End point title |
Complete Remission Rate | ||||||||
End point description |
Complete remission (CR) rate is defined as the percentage of participants who achieved a complete remission at any time point during the study per the modified IWG criteria for AML and investigator assessment.
CR: absolute neutrophil count (ANC) ≥ 10^3 /µL, platelet counts ≥ 10^5 /µL, red blood cell (RBC) transfusion independence (a period of at least 56 days with no RBC transfusion), and bone marrow with < 5% blasts.
Participants who never achieved CR or had no IWG disease assessment were considered to be non-responders in the calculation of CR rate.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
CR Plus CR With Incomplete Blood Count Recovery (CRi) Rate | ||||||||
End point description |
The percentage of participants who achieved a CR or CRi at any time point during the study per the modified IWG criteria for AML and investigator assessment.
CR: absolute neutrophil count (ANC) ≥ 10^3 /µL, platelet counts ≥ 10^5 /µL, red blood cell (RBC) transfusion independence (a period of at least 56 days with no RBC transfusion), and bone marrow with < 5% blasts.
CRi: lack of morphologic evidence of leukemia (blasts < 5%), and platelet counts < 10^5 /µL or ANC < 10^3 /µL
Participants who never achieved CR or CRi or had no IWG disease assessment were considered to be non-responders in the calculation of CR + CRi rate.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
CR Plus CRi Rate by Initiation of Cycle 2 | ||||||||
End point description |
The percentage of participants who achieved a CR or CRi by initiation of Cycle 2 of study treatment per the modified IWG criteria for AML and investigator assessment.
CR: ANC ≥ 10^3 /µL, platelet counts ≥ 10^5 /µL, RBC transfusion independence (a period of at least 56 days with no RBC transfusion), and bone marrow with < 5% blasts.
CRi: Lack of morphologic evidence of leukemia (blasts < 5%), and platelet counts < 10^5 /µL or ANC < 10^3 /µL.
Participants who never achieved CR or CRi or had no IWG disease assessment by initiation of Cycle 2 were considered to be non-responders in the calculation of CR + CRi rate by initiation of Cycle 2.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Cycle 2, Day 1
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Time to First Response of CR + CRi | ||||||||
End point description |
The time to the first response of CR + CRi is defined as the time from the first date of study drug to the first response of CR or CRi.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
|
||||||||
|
|||||||||
| Notes [19] - Participants with a response of CR or CRi |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Time to Best Response of CR + CRi | ||||||||
End point description |
The time to the best response of CR + CRi is defined as the time from the first date of study drug to the best response of CR or CRi.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
|
||||||||
|
|||||||||
| Notes [20] - Participants with a response of CR or CRi |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Complete Remission With Partial Hematologic Recovery (CRh) Rate | ||||||||
End point description |
Complete remission with partial hematologic recovery) is a derived response based on bone marrow blast and hematology laboratory values. CRh rate is defined as the percentage of participants who achieved CRh as the best response at any time point during the study.
A participant achieved a CRh when meeting the following criteria:
- Bone marrow with < 5% blasts and
- Peripheral blood neutrophil count of > 0.5 × 10^3 /µL and
- Peripheral blood platelet count of > 0.5 × 10^5 /µL and
- A 1 week (≥ 7 days) platelet transfusion-free period prior to the hematology lab collection.
Participants who never achieved CRh or did not have disease assessment or hematology data were considered to be non-responders in the calculation of CRh rate.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
CR Plus CRh Rate | ||||||||
End point description |
CR + CRh rate is defined as the percentage of participants who achieved CR or CRh at any time point during the study.
CR: ANC ≥ 10^3 /µL, platelet counts ≥ 10^5 /µL, RBC transfusion independence (a period of at least 56 days with no RBC transfusion), and bone marrow with < 5% blasts.
CRh is a derived response based on bone marrow blast and hematology lab values. A participant achieved a CRh when meeting the following criteria:
- Bone marrow with < 5% blasts and
- Peripheral blood neutrophil count of > 0.5 × 10^3 /µL and
- Peripheral blood platelet count of > 0.5 × 10^5 /µL and
- A 1 week (≥ 7 days) platelet transfusion-free period prior to the hematology lab collection.
Participants who never achieved CR/CRh or did not have disease assessment or hematology data were considered to be non-responders in the calculation of CR + CRh rate.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
CR Plus CRh Rate by Initiation of Cycle 2 | ||||||||
End point description |
CR + CRh rate by initiation of Cycle 2 is defined as the percentage of participants who achieved CR or CRh by initiation of Cycle 2 of study treatment.
CR: ANC ≥ 10^3 /µL, platelet counts ≥ 10^5 /µL, RBC transfusion independence (a period of at least 56 days with no RBC transfusion), and bone marrow with < 5% blasts.
CRh is a derived response based on bone marrow blast and hematology lab values. A participant achieved a CRh when meeting the following criteria:
• Bone marrow with < 5% blasts and
• Peripheral blood neutrophil count of > 0.5 × 10^3 /µL and
• Peripheral blood platelet count of > 0.5 × 10^5 /µL and
• A 1 week (≥ 7 days) platelet transfusion-free period prior to the hematology lab collection.
Participants who never achieved CR/CRh or did not have disease assessment by initiation of Cycle 2 were considered to be non-responders in the calculation of CR + CRh rate by initiation of Cycle 2.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Cycle 2, Day 1
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Time to First Response of CR Plus CRh | ||||||||
End point description |
The time to the first response of CR + CRh is defined as the time from the first date of study drug to the first response of CR or CRh.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
|
||||||||
|
|||||||||
| Notes [21] - Participants with a reponse of CR or CRh |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Time to Best Response of CR Plus CRh | ||||||||
End point description |
The time to the best response of CR + CRh is defined as the time from the first date of study drug to the best response of CR or CRh.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
|
||||||||
|
|||||||||
| Notes [22] - Participants with a response of CR or CRh |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||
End point title |
Best Response Based on IWG Criteria | ||||||||||||||||||||
End point description |
Best response determined using the IWG-AML response criteria during the course of treatment.
-CR: ANC ≥ 10^3 /µL, platelet counts ≥ 10^5 /µL, RBC transfusion independence, and bone marrow with < 5% blasts;
-CRi: lack of morphologic evidence of leukemia (blasts < 5%), and platelet counts < 10^5 /µL or ANC < 10^3 /µL;
-PR: all of the hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to 5% to 25% in the bone marrow aspirate;
-MLFS: < 5% blasts in an aspirate and/or bone marrow core sample;
-RD: failure to achieve CR, CRi, PR; only including subjects surviving at least 7 days following completion of initial treatment cycle with evidence of persistent leukemia by blood and/or bone marrow examination;
-PD: one or more of the following: ≥ 50% decrement from maximum response levels in neutrophils or platelets; a reduction in hemoglobin by at least 2 g/dL; or transfusion dependence not due to other toxicities and bone marrow blast ≥ 5%.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Response was assessed at Cycle 2, Day 1, Cycle 4, Day 1, and every 3 cycles thereafter; median duration of treatment was 4.2 months.
|
||||||||||||||||||||
|
|||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||
|
|||||||||
End point title |
Duration of Complete Response | ||||||||
End point description |
Duration of CR is defined as the time from date that a participant achieved CR to the first date of relapse, clinical disease progression or death due to disease progression, whichever occurred earliest. Duration of CR was estimated using Kaplan-Meier methodology. If a participant was still responding at the data cutoff date, then the subject's data was censored at their last disease assessment date. Disease assessment data after the onset of any post-treatment therapy were not included in the duration of CR analysis.
"99999" indicates values that could not be estimated.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
|
||||||||
|
|||||||||
| Notes [23] - Participants with a reponse of CR |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Duration of CR Plus CRi | ||||||||
End point description |
Duration of CR + CRi is defined as the time from the date that a participant achieved CR or CRi to the first date of relapse, clinical disease progression or death due to disease progression, whichever occurred earliest. Duration of CR + CRi was estimated using Kaplan-Meier methodology. If a participant was still responding at the data cutoff date, then the participant's data were censored at their last disease assessment date. Disease assessment data after the onset of any post-treatment therapy were not included in the analysis.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
|
||||||||
|
|||||||||
| Notes [24] - Participants with a response of CR or CRi |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Duration of CRi | ||||||||
End point description |
Duration of CRi is defined as the time from date that a participant achieved CRi to the first date of relapse, clinical disease progression or death due to disease progression, whichever occurred earliest. Duration of CRi was estimated using Kaplan-Meier methodology. If a participant was still responding at the data cutoff date, then the participant's data were censored at their last disease assessment date. Disease assessment data after the onset of any post-treatment therapy were not included in the analysis.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
|
||||||||
|
|||||||||
| Notes [25] - Participants with a response of CRi |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Duration of CR Plus CRh | ||||||||
End point description |
Duration of CR + CRh is defined as the time from date that a participant achieved CR or CRh to the first date of relapse, clinical disease progression or death due to disease progression, whichever occurred earliest. Duration of CR + CRh was estimated using Kaplan-Meier methodology. If a participant was still responding at the data cutoff date, then the participant's data were censored at their last disease assessment date. Disease assessment data after the onset of any post-treatment therapy were not included in the analysis.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
|
||||||||
|
|||||||||
| Notes [26] - Participants with a response of CR or CRh |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Overall Survival (OS) | ||||||||
End point description |
Overall survival is defined as the time from the date of first dose to the date of death. All events of death were included, regardless of whether the event occurred while the participant was still taking study drug, or after the participant discontinued study drug. OS was estimated using Kaplan-Meier methodology. Participants who were still alive were censored at the analysis date.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Median duration of follow-up was 44.5 months (range: 0.3 to 63.7)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||
End point title |
Post Baseline Transfusion Independence Rate | ||||||||||||||
End point description |
Post baseline transfusion independence rate was estimated as the percentage of participants who achieved transfusion independence during the evaluation period. Post-baseline transfusion independence is defined as a period of at least 56 days (≥ 56 days) with no RBC or platelet transfusion during the evaluation period. The evaluation period is from the first dose of study drug to the last dose of study drug until the 30 day follow-up visit, disease progression (including clinical progression), or death, whichever was earlier.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
From the first dose of study drug to the last dose of study drug plus 30 days, disease progression (including clinical progression), or death, whichever was earlier; median duration of treatment was 4.2 months.
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Post Baseline Transfusion Independence Rate Among Participants Transfusion-dependent at Baseline | ||||||||||||||
End point description |
Post baseline transfusion independence rate was estimated as the percentage of participants who achieved transfusion independence during the evaluation period. Post-baseline transfusion independence is defined as a period of at least 56 days (≥ 56 days) with no RBC or platelet transfusion during the evaluation period. The evaluation period is from the first dose of study drug to the last dose of study drug until the 30 day follow-up visit, disease progression (including clinical progression), or death, whichever was earlier.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
From the first dose of study drug to the last dose of study drug plus 30 days, disease progression (including clinical progression), or death, whichever was earlier; median duration of treatment was 4.2 months.
|
||||||||||||||
|
|||||||||||||||
| Notes [27] - Participants who were transfusion-dependent at Baseline; N=53 for RBC and 23 for platelet-dependent |
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Duration of Post Baseline Transfusion Independence | ||||||||||||||
End point description |
The duration of transfusion independence is defined as the first time period that a participant received no RBC/platelet transfusions for at least 56 days during the evaluation period.
Post-baseline transfusion independence is defined as a period of at least 56 days with no RBC or platelet transfusion during the evaluation period. The evaluation period is from the first dose of study drug to the last dose of study drug until the 30 day follow-up visit, disease progression (including clinical progression), or death, whichever was earlier.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
From the first dose of study drug to the last dose of study drug plus 30 days, disease progression (including clinical progression), or death, whichever was earlier; median duration of treatment was 4.2 months.
|
||||||||||||||
|
|||||||||||||||
| Notes [28] - Participants who were post-baseline RBC or platelet transfusion independent. |
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From first dose of study drug until 30 days after last dose of study drug; median (minimum, maximum) duration of treatment was 4.1 (0.2, 62.8) months overall.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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24.0
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Reporting group title |
Phase 1: 600 mg Venetoclax + LDAC
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Reporting group description |
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg (Day 2) and increased up to 600 mg by Day 6. Beginning with Cycle 2, 600 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received low-dose cytarabine (LDAC; 20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 2: 600 mg Venetoclax + LDAC
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Reporting group description |
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 50 mg, and increased up to 600 mg by Day 6. Beginning with Cycle 2, 800 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 1: 800 mg Venetoclax + LDAC
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Reporting group description |
Venetoclax was administered orally once daily (QD) on Days 2 through 28 of Cycle 1. Dosing started at 100 mg (Day 2) and increased up to 800 mg by Day 6. Beginning with Cycle 2, 800 mg venetoclax was administered Days 1 through 28 of each 28-day cycle. Participants also received LDAC (20 mg/m²) administered by subcutaneous injection once daily on Days 1 to 10 of each cycle. Participants could continue receiving treatment until disease progression or until discontinuation criteria were met. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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11 Nov 2015 |
The purpose of this amendment is to:
● Update ABT-199 throughout protocol with venetoclax (ABT-199/GDC-0199).
● Update Introduction with the most current venetoclax information released in the Investigator's Brochure (IB) Edition 6.
● Update 95% Confidence Intervals for Assumed Observed Rates Based on Sample Size of 50 Subjects; and increase the number of subjects to be enrolled in Phase 2 to approximately 50 to improve accuracy of estimation of the Overall Response Rate (ORR).
● Update Inclusion Criteria to remove the requirement to do 24-hour urine collection for subjects whose BMI is > 25 and alert investigators to consider measuring creatinine clearance in other situations if appropriate.
● Update Exclusion Criteria, Prior and Concomitant Therapy; Excluded and Cautionary Medications and Dietary Restrictions to be consistent with updated PK findings.
● Replace Week 12 with Cycle 3 throughout the protocol.
● Change every 12 weeks to every 3 Cycles.
● Add Bone Marrow Aspirate for Bcl-2 Family Protein Analysis sample to allow investigation of the relationship between pre-treatment potential biomarkers and response to venetoclax treatment and to evaluate for the potential change of potential biomarkers after treatment.
● Add a Cycle 4 Day 1 pharmacogenetic sample.
● Update Tumor Lysis Syndrome Prophylaxis to start 24 hours prior to first dose and Confinement requirements since for some subjects hydration and allopurinol administration can be achieved equally well without hospital admission.
● Clarified sample analysis process information.
● Clarified results to be reported
● Update Deaths to note that deaths due solely to the progression of AML should not be considered an adverse event.
● Addition of AbbVie Medical Escalation Hotline information.
● Clarify definition of dose-limiting toxicity.
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28 Nov 2016 |
● Updated introduction with new venetoclax preclinical toxicology.
● Updated the primary objective and added Cohort C to the study, increasing the sample size by 20 subjects, to evaluate ORR and safety when allowing subjects who potentially require co-treatment with a strong CYP3A inhibitor.
● Added the Cohort C study population to add additional objective criteria to help define subjects with AML who are not eligible for anthracycline-based induction therapy.
● Added the Cohort C dosing instruction to simplify dosing for subjects to receive both LDC and venetoclax starting on Day 1.
● Updated Overall Study Design and Plan, Safety and Efficacy Measurement, Discontinuation of Individual Subjects with Post-treatment follow-up visit and Survival Assessment language to evaluate the disease course and survival of subjects after study treatment has concluded.
● Inclusion Criteria updated to clarify subject's age, include subjects with ECOG performance status of 3 for subjects who are 60 – 74 years of age, include subjects with Creatinine Clearance of greater or equal to 30 mL/min, clarify bilirubin requirements for subjects with different age group, and clarify the postmenopausal female population requirement for the study entry.
● Exclusion Criteria updated to allow strong and moderate CYP3A inhibitors under cautionary medication with appropriate dose reduction, allow subjects with cardiovascular disability status of New York Heart Association up to Class 2, exclude subjects with history of myeloproliferative neoplasm (MPN) including polycythemia vera, myelofibrosis, essential thrombocythemia, or chronic myelogenous leukemia.
● Updated dose modification required if moderate or strong CYP3A inhibitor is taken.
● Added Complaints section.
● Updated Dose Reduction Guidelines for Management of Persistent Neutropenia or Thrombocytopenia.
● Updated Prophylaxis and Management of Tumor Lysis Syndrome (TLS). |
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31 May 2017 |
● Updated introduction section with the new venetoclax preclinical toxicology.
● Efficacy endpoint was modified to remove Time to Progression (TTP) and Progression Free Survival (PFS) and add Event Free Survival (EFS) throughout the protocol.
● Leukemia response rate was updated to include MLFS.
● Updated Sample List of Excluded and Cautionary Medications to change the classification of diltiazem from strong to moderate CYP3A inhibitor.
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24 Jan 2018 |
● Update Efficacy Summaries section to add CRh rates and transfusion independence endpoints.
● Updated Excluded and Cautionary Medications and Dietary Restrictions Table to remove weak CYP3A inhibitors, weak CYP3A inducers and OATP1B1/B3 inhibitors as these classes of drugs are no longer considered to be cautionary.
● Updated list of Signatories for Protocol Amendment 4.
● Update Appendix C, Sample List of Excluded and Cautionary Medications to remove examples of weak CYP3A inhibitors, weak CYP3A inducers and OATP1B1/B3 inhibitors, as these drugs are no longer considered to be cautionary.
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22 Mar 2019 |
The purpose of this amendment was:
● To extend allowable treatment period from 2 to 3 years from last subject enrolled in the study.
● Update "from last subject enrolled" to "from last subject's last dose" when referring to the point at which post-treatment and survival assessments are conducted from.
● To update the Post-Treatment/Survival follow-up visits to occur every 12 weeks (± 1 week) for 1 year from last subject's last dose.
● To update survival period to occur every 12 weeks up to 1 year from last subject's last dose to reduce burden to subjects who are in long term follow up and no longer receiving study therapy.
● To update Venetoclax Preclinical Toxicology and Clinical Data Rationale to be consistent with the IB v10.0.
● Update Sample List of Excluded and Cautionary Medications to remove examples Azithromycin. The rationale for removal is the results of DDI study of azithromycin evaluating its effect on venetoclax PK, exposures of venetoclax did not change significantly.
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17 Feb 2020 |
The purpose of this amendment was to:
● To extend allowable treatment period from 3 to 4 years from last subject enrolled in the study.
● To update Venetoclax Clinical Data Rationale to be consistent with the IB v12.0.
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22 Oct 2020 |
The purpose of this amendment was to:
● Benefits and Risks - included information on the re-evaluation of the benefit and risk with consideration of Coronavirus Disease 2019 present in subject's region.
● Safety and Efficacy Measurements Assessed and Flow Chart - added instructions for necessary changes to activities or procedures in the event of temporary study [drug] interruption/halt.
● Treatments Administered - included instructions that in the event the subject cannot pick up venetoclax onsite, DTP shipment can be done as needed and permitted by local regulations.
● Protocol Deviations - clarified that protocol deviations may include modifications due to COVID-19.
● Ethical Conduct of the Study - noted that AbbVie will modify the study protocol as necessary due to the pandemic. Investigators must also notify AbbVie if any urgent safety measures are taken.
● Source Documents - noted that remote monitoring may be employed as needed.
● Modified the language for survival and post treatment follow up time frames to permit a shorter duration of follow up if all patients have discontinued and most patients have expired.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
