Clinical Trial Results:
A Prospective, Open-Label, Single-Arm, Phase 2, Multicenter Study Evaluating the Efficacy of Venetoclax Plus Ibrutinib in Subjects with T-Cell Prolymphocytic Leukemia
Summary
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EudraCT number |
2018-002179-17 |
Trial protocol |
AT NL FR FI GB IT |
Global end of trial date |
04 Nov 2021
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Results information
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Results version number |
v2(current) |
This version publication date |
26 Jan 2023
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First version publication date |
06 Dec 2022
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Other versions |
v1 |
Version creation reason |
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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 |
M18-803
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03873493 | ||
WHO universal trial number (UTN) |
- | ||
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 |
04 Nov 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 |
04 Nov 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 main objective of this study is to evaluate the efficacy of the combination of venetoclax plus ibrutinib for treating adults with T-cell prolymphocytic leukemia (T-PLL).
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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 |
14 Jan 2020
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Long term follow-up planned |
No
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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 |
France: 1
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Country: Number of subjects enrolled |
Australia: 1
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Country: Number of subjects enrolled |
United States: 2
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Country: Number of subjects enrolled |
Germany: 2
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Country: Number of subjects enrolled |
Italy: 3
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Country: Number of subjects enrolled |
Netherlands: 2
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Country: Number of subjects enrolled |
United Kingdom: 3
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Worldwide total number of subjects |
14
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EEA total number of subjects |
8
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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) |
5
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From 65 to 84 years |
9
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was planned as an adaptive 2-stage design with Stage 1 to enroll 14 participants and Stage 2 to enroll up to an additional 23 participants based on the number of responders in Stage 1. Stage 2 was not conducted. | ||||||||||||||||||
Pre-assignment
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Screening details |
In total, 16 adults with relapsed or refractory T-cell prolymphocytic leukemia (R/R T-PLL) were screened and 14 subjects were enrolled at 10 sites in 7 countries (Australia, France, Germany, Italy, Netherlands, United Kingdom, and United States). For one subject "study terminated by sponsor” was entered as study discontinuation reason by mistake. | ||||||||||||||||||
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 | ||||||||||||||||||
Arms
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Arm title
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Venetoclax + Ibrutinib | ||||||||||||||||||
Arm description |
Participants received 400 mg venetoclax orally once a day after a 5-day ramp-up and 420 mg ibrutinib orally once a day for up to 2 years or until progressive disease, intolerability, or they became eligible for stem cell transplantation after achieving complete remission. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Venetoclax
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Investigational medicinal product code |
ABT-199
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Other name |
Venclexta®, Venclyxto®
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Venetoclax tablets taken orally once a day (QD). Initially, venetoclax was administered utilizing a 5-step dose ramp-up over 5 days. Subjects were hospitalized and closely monitored for 7 days. The venetoclax ramp-up was administered in a daily manner: 20 mg on Week 1 Day 1, 50 mg on Week 1 Day 2, 100 mg on Week 1 Day 3, 200 mg on Week 1 Day 4, and 400 mg on Week 1 Day 5 and thereafter, once daily, until the end-of-treatment. The dose of venetoclax may have been increased to 600 mg QD at Week 8 or thereafter.
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Investigational medicinal product name |
Ibrutinib
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Investigational medicinal product code |
PCI-32765
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Other name |
Imbruvica®
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Ibrutinib capsules taken orally once a day, 420 mg/day until the end-of-treatment.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
Participants received 400 mg venetoclax orally once a day after a 5-day ramp-up and 420 mg ibrutinib orally once a day for up to 2 years or until progressive disease, intolerability, or they became eligible for stem cell transplantation after achieving complete remission. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Venetoclax + Ibrutinib
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Reporting group description |
Participants received 400 mg venetoclax orally once a day after a 5-day ramp-up and 420 mg ibrutinib orally once a day for up to 2 years or until progressive disease, intolerability, or they became eligible for stem cell transplantation after achieving complete remission. |
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End point title |
Overall Response Rate (ORR) [1] | ||||||||
End point description |
ORR is defined as the percentage of participants achieving complete remission (CR), CR with incomplete bone marrow recovery (CRi), or partial remission (PR) as their best response per investigator assessment based on the T-PLL consensus criteria 2019.
CR: All of the following response criteria must be met:
Group A:
-all lymph nodes < 1 cm;
-spleen < 13 cm;
-no constitutional symptoms;
-circulating lymphocyte count < 4 × 10^9/L;
-bone marrow T-PLL cells < 5% of mononuclear cells;
-no other specific site involvement.
Group B:
-platelets ≥ 100 × 10^9 /L;
-hemoglobin ≥ 11.0 g/dL;
-neutrophils ≥ 1.5 × 10^9 /L.
CRi: All of the CR response criteria in Group A met; at least 1 parameter in Group B not achieved unrelated to T-PLL.
PR: At least 2 of the parameters in Group A and 1 parameter in Group B need to improve if previously abnormal. If only 1 parameter of both Groups A and B is abnormal prior to therapy, only 1 parameter needs to improve.
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End point type |
Primary
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End point timeframe |
Clinical response was assessed at Weeks 4, 8, 12, 16 and 24 for ORR assessment
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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 statistical analyses were conducted. |
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Notes [2] - The full analysis set includes all participants who received at least 1 dose of study drug |
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No statistical analyses for this end point |
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End point title |
Progression-Free Survival (PFS) | ||||||||
End point description |
Progression-free survival is defined as the time from the date of first dose of any study drug to the date of earliest disease progression or death. PFS was calculated using Kaplan-Meier methods. Response was assessed by the investigator based on the T-PLL consensus criteria 2019.
Progressive disease (PD) is defined as meeting at least one of the Group A or Group B criteria below:
Group A:
-lymph nodes increase in > 20% in sum of long-axis diameters of up to 3 target lesions (SLD) from nadir;
-spleen increase ≥ 50% in vertical length beyond normal from baseline;
-circulating lymphocyte count increase ≥ 50% from baseline;
-appearance of a new lesion;
Group B:
-platelet count decrease of ≥ 50% from baseline due to T-PLL (not due to drug toxicity);
-hemoglobin decrease of ≥ 2 g/dL from baseline due to T-PLL;
-neutrophils decrease of ≥ 50% from baseline due to T-PLL.
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End point type |
Secondary
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End point timeframe |
From first dose of study drug to end of study; median time on study was 30.1 weeks.
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Notes [3] - Full analysis set |
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No statistical analyses for this end point |
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End point title |
Duration of Response (DOR) | ||||||||
End point description |
Duration of response is defined for participants who achieved a best overall response of CR, CRi, or PR as the time from the date of first response (CR, CRi, or PR) to the earliest date of disease progression or death. DOR was calculated using Kaplan-Meier methods.
Response was assessed by the investigator based on the T-PLL consensus criteria 2019.
Progressive disease is defined as meeting at least one of the Group A or Group B criteria below:
Group A:
-lymph nodes increase in > 20% in SLD from nadir;
-spleen increase ≥ 50% in vertical length beyond normal from baseline;
-circulating lymphocyte count increase ≥ 50% from baseline;
-appearance of a new lesion;
Group B:
-platelet count decrease of ≥ 50% from baseline due to T-PLL (not due to drug toxicity);
-hemoglobin decrease of ≥ 2 g/dL from baseline due to T-PLL;
-neutrophils decrease of ≥ 50% from baseline due to T-PLL.
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End point type |
Secondary
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End point timeframe |
From first dose of study drug to end of study; median time on study was 30.1 weeks.
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Notes [4] - Full analysis set participants with a best overall response of CR, CRi, or PR |
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No statistical analyses for this end point |
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End point title |
Time to Progression (TTP) | ||||||||
End point description |
TPP is defined as the time from the date of the participant's first dose of any study drug to the date of earliest disease progression. TPP was calculated using Kaplan-Meier methods.
Clinical response (laboratory and physical examination assessments) was assessed by the investigator according to the T-PLL consensus criteria 2019.
Progressive disease is defined as meeting at least one of the criteria of Group A or Group B below:
Group A:
-lymph nodes increase in > 20% in SLD from nadir;
-spleen increase ≥ 50% in vertical length beyond normal from baseline;
-circulating lymphocyte count increase ≥ 50% from baseline;
-appearance of a new lesion;
Group B:
-platelet count decrease of ≥ 50% from baseline due to T-PLL (not due to drug toxicity);
-hemoglobin decrease of ≥ 2 g/dL from baseline due to T-PLL;
-neutrophils decrease of ≥ 50% from baseline due to T-PLL.
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End point type |
Secondary
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End point timeframe |
From first dose of study drug to end of study; median time on study was 30.1 weeks.
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Notes [5] - Full analysis set |
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No statistical analyses for this end point |
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End point title |
Event-free Survival (EFS) | ||||||||
End point description |
Event-free survival is defined as time from participant's first dose of any study drug to the date of earliest disease progression, death, or start of a new anti-T-PLL therapy. EFS was calculated using Kaplan-Meier methods.
Clinical response (laboratory and physical examination assessments) was assessed by the investigator according to the T-PLL consensus criteria 2019.
Progressive disease is defined as meeting at least one of the criteria of Group A or Group B below:
Group A:
-lymph nodes increase in > 20% in SLD from nadir;
-spleen increase ≥ 50% in vertical length beyond normal from baseline;
-circulating lymphocyte count increase ≥ 50% from baseline;
-appearance of a new lesion;
Group B:
-platelet count decrease of ≥ 50% from baseline due to T-PLL (not due to drug toxicity);
-hemoglobin decrease of ≥ 2 g/dL from baseline due to T-PLL;
-neutrophils decrease of ≥ 50% from baseline due to T-PLL.
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End point type |
Secondary
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End point timeframe |
From first dose of study drug to end of study; median time on study was 30.1 weeks.
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Notes [6] - Full analysis set |
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No statistical analyses for this end point |
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End point title |
Disease Control Rate (DCR) | ||||||||
End point description |
DCR is defined as the percentage of participants who achieved CR, CRi, PR, or stable disease (SD) as best overall response per investigator assessment based on the T-PLL consensus criteria 2019.
Stable disease is defined as meeting all of the following criteria for at least 3 months:
-lymph nodes change of -29% to +20% in SLD;
-spleen change of -49% to +49% beyond normal from baseline;
-circulating lymphocyte count > 30 × 10^9 /L or change of -49% to +49%;
-platelet count change of -49% to +49%;
-hemoglobin < 11.0 g/dL or change < 50% from baseline or change < 2 g/dL;
-neutrophils change of -49% to +49%.
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End point type |
Secondary
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End point timeframe |
Clinical response was assessed at Weeks 4, 8, 12, 16, and 24 for DCR assessment
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Notes [7] - Full analysis set |
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No statistical analyses for this end point |
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End point title |
Overall Survival (OS) | ||||||||
End point description |
Overall survival is defined as the time from the date of the participant's first dose of any study drug to death from any cause. OS was calculated using Kaplan-Meier methods.
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End point type |
Secondary
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End point timeframe |
From first dose of study drug to end of study; median time on study was 30.1 weeks.
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Notes [8] - Full analysis set |
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No statistical analyses for this end point |
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End point title |
Number of Eligible Participants Reaching Autologous or Allogeneic Transplantation | ||||||
End point description |
Participants eligible for autologous or allogeneic transplantation were transplant-naïve participants who achieved complete remission.
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End point type |
Secondary
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End point timeframe |
From first dose of study drug to end of study; median time on study was 30.1 weeks.
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Notes [9] - Transplant-naive participants who achieved CR. No participants were eligible for transplant. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Treatment-emergent Adverse Events (TEAE) | ||||||||||||||||||||||||||||||||||||
End point description |
An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Treatment-emergent AEs are any event with onset after the first dose of study drug and no more than 30 days after the last dose of study drug.
A serious AE (SAE) was an event that resulted in death, was life-threatening, resulted in hospitalization or prolongation of hospitalization, persistent or significant disability/incapacity, or an important medical event requiring medical or surgical intervention to prevent a serious outcome.
The Investigator rated the severity of each AE according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening and grade 5 = death.
The Investigator assessed the relationship of the AE to the use of study drug.
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End point type |
Secondary
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End point timeframe |
From first dose of study drug up to 30 days after last dose; median time on treatment was 13.86 weeks (range 1.0 to 44.4 weeks)
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Notes [10] - All participants who received at least 1 dose of study drug (either venetoclax or ibrutinib) |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
All-cause mortality is reported from enrollment through end of study; median time on study was 30.1 weeks.
AEs are reported from first dose of study drug up to 30 days after last dose; median time on treatment was 13.86 weeks (range 1.0 to 44.4 weeks).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.0
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Reporting groups
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Reporting group title |
Venetoclax + Ibrutinib
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Reporting group description |
Participants received 400 mg venetoclax orally once a day after a 5-day ramp-up and 420 mg ibrutinib orally once a day for up to 2 years or until progressive disease, intolerability, or they became eligible for stem cell transplantation after achieving complete remission. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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02 May 2019 |
Removed nodular partial response (nPR) from the definition of ORR because nPR is not applicable for T-PLL. Added computed tomography (CT) scan for confirmation of response and updated the protocol so that CT scans for disease assessment were performed using a T-PLL-adapted version of the response evaluation criteria in lymphoma (RECIL) 2017 instead of using standard response evaluation criteria in solid tumors (RECIST). Updated the eligibility criteria to reduce the risk of dose interruptions or modifications, added safety guidelines for AEs associated with the underlying disease under investigation, and revised the toxicity management of ibrutinib to align with the company core data sheets dose modification guidelines.
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11 Nov 2020 |
Reference to the (RECIL-based) T-PLL consensus criteria 2019 was added into the primary endpoint. Revisions were made to align the secondary objectives and endpoints. Clarified that the potential continuation of therapy is subject to local regulations and to extend the post-treatment follow-up visits period in the protocol. Updated the eligibility criteria for creatinine clearance, revised the washout period for live or attenuated vaccines, clarified that seasonal flu vaccines are allowed, and revised the contraception recommendations for male subjects. Updated the eligibility criteria to exclude subjects positive for SARS-CoV-2. Added laboratory monitoring for TLS for any increase in venetoclax dose. Updated the disease assessment criteria using the (RECIL-based) T-PLL consensus criteria and clarified that disease assessment will continue after last dose of study drug.
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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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 |