Clinical Trial Results:
A Phase 2 Open-label Study Investigating the Safety and Efficacy of Blinatumomab After Frontline R-Chemotherapy in Adult Subjects With Newly Diagnosed High-risk Diffuse Large B-cell Lymphoma (DLBCL)
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Summary
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EudraCT number |
2016-002190-35 |
Trial protocol |
ES DE FR GB |
Global end of trial date |
28 Oct 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
11 Sep 2020
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First version publication date |
11 Sep 2020
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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 |
20150288
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03023878 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Amgen Inc.
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Sponsor organisation address |
One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
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Public contact |
IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
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Scientific contact |
IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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 |
28 Oct 2019
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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 |
28 Oct 2019
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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 safety profile of blinatumomab after frontline R-chemotherapy, consisting of either R-CHOP (14 or 21) or R-DA-EPOCH or R-CHOEP, will be determined.
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Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations and guidelines, and Food and Drug Administration (FDA) regulations, and guidelines set forth in 21 CFR Parts 11, 50, 54, 56, and 312. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
13 Mar 2017
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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 |
Canada: 5
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Country: Number of subjects enrolled |
France: 5
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Country: Number of subjects enrolled |
Germany: 2
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Country: Number of subjects enrolled |
Spain: 11
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Country: Number of subjects enrolled |
United Kingdom: 5
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Country: Number of subjects enrolled |
United States: 19
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Worldwide total number of subjects |
47
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EEA total number of subjects |
23
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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) |
26
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From 65 to 84 years |
21
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was conducted at 12 centers in the European Union (France, Germany, Spain, and the United Kingdom), the United States, and Canada. Of the 54 subjects screened, 47 subjects were enrolled. | ||||||||||||||||||
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Pre-assignment
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Screening details |
The study consisted of a standard of care rituximab-chemotherapy run-in period of approximately 21 weeks, a 12- to 16-week blinatumomab treatment period, a 30-day safety follow-up, and a long-term follow-up period up to 1 year from the first dose of blinatumomab, or until participant death, whichever occurred first. | ||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
47 | ||||||||||||||||||
Number of subjects completed |
28 | ||||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Protocol-specified criteria: 13 | ||||||||||||||||||
Reason: Number of subjects |
Adverse event, serious fatal: 1 | ||||||||||||||||||
Reason: Number of subjects |
Consent withdrawn by subject: 5 | ||||||||||||||||||
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Period 1
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Period 1 title |
Treatment Period (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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Arm title
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Blinatumomab | ||||||||||||||||||
Arm description |
Blinatumomab was administered as a continuous intravenous (IV) infusion. Cycle 1 was 12 weeks (84 days) in duration with step dosing of 9 µg/day for 7 days, 28 µg/day for 7 days, 112 µg/day for 6 weeks, followed by a 4-week treatment free time. An optional 4-week Cycle 2 of blinatumomab was available for participants whose disease did not progress, with step dosing of 9 µg/day for 7 days, 28 µg/day for 7 days, and 112 µg/day for 14 days. There was a safety follow-up for 30 days. And a long-term follow-up of up to 8 months for a maximum of 1 year from first dose of blinatumomab or until participant death. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Blinatumomab
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Investigational medicinal product code |
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Other name |
AMG103 BlinCyto
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Pharmaceutical forms |
Powder for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Blinatumomab monotherapy was supplied in single-use sterile glass injection vials and administered as an IV infusion.
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Investigational medicinal product name |
Dexamethasone
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Investigational medicinal product code |
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Other name |
corticosteroid
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
20 mg intravenous within 1 hour prior to start of treatment in each treatment cycle, and within 1 hour prior to dose-step (increase).
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: The number of subject reported in the baseline period reflects the number of participants who completed the run-in period and who started the blinatumomab treatment period. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Participants received Cycle 2 treatment at the Investigator's discretion. |
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Baseline characteristics reporting groups
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Reporting group title |
Blinatumomab
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Reporting group description |
Blinatumomab was administered as a continuous intravenous (IV) infusion. Cycle 1 was 12 weeks (84 days) in duration with step dosing of 9 µg/day for 7 days, 28 µg/day for 7 days, 112 µg/day for 6 weeks, followed by a 4-week treatment free time. An optional 4-week Cycle 2 of blinatumomab was available for participants whose disease did not progress, with step dosing of 9 µg/day for 7 days, 28 µg/day for 7 days, and 112 µg/day for 14 days. There was a safety follow-up for 30 days. And a long-term follow-up of up to 8 months for a maximum of 1 year from first dose of blinatumomab or until participant death. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Blinatumomab
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Reporting group description |
Blinatumomab was administered as a continuous intravenous (IV) infusion. Cycle 1 was 12 weeks (84 days) in duration with step dosing of 9 µg/day for 7 days, 28 µg/day for 7 days, 112 µg/day for 6 weeks, followed by a 4-week treatment free time. An optional 4-week Cycle 2 of blinatumomab was available for participants whose disease did not progress, with step dosing of 9 µg/day for 7 days, 28 µg/day for 7 days, and 112 µg/day for 14 days. There was a safety follow-up for 30 days. And a long-term follow-up of up to 8 months for a maximum of 1 year from first dose of blinatumomab or until participant death. | ||
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End point title |
Participants with Treatment-Emergent (Blinatumomab) Adverse Events [1] | ||||||||||||||||||||||||
End point description |
Overall incidence and severity of treatment-emergent adverse events occurring during the blinatumomab investigative product (IP) treatment period graded by investigators according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and based on the scale: Grade 1 = Mild - transient or mild discomfort; Grade 2 = Moderate - mild to moderate limitation in activity, assistance may be needed; minimal medical intervention required; Grade 3 = Severe - marked limitation in activity, assistance usually required; medical intervention required, hospitalization is possible; Grade 4 = Life threatening - extreme limitation in activity, assistance required; medical intervention, hospitalization or hospice care probable; Grade 5 = death.
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End point type |
Primary
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End point timeframe |
From the start of first infusion of IP to 30 days after the end of last infusion of IP; median (min, max) treatment duration was 56 (16, 84) days
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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: Statistical reporting of safety outcomes was entirely descriptive, with no formal statistical testing performed. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Participants with Treatment-Emergent Adverse Events Related to Blinatumomab Treatment [2] | ||||||||||||||||||||||||
End point description |
Overall incidence and severity of treatment-emergent adverse events deemed by investigators to be related to blinatumomab treatment. Severity was graded by investigators according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and based on the scale: Grade 1 = Mild - transient or mild discomfort; Grade 2 = Moderate - mild to moderate limitation in activity, assistance may be needed; minimal medical intervention required; Grade 3 = Severe - marked limitation in activity, assistance usually required; medical intervention required, hospitalization is possible; Grade 4 = Life threatening - extreme limitation in activity, assistance required; medical intervention, hospitalization or hospice care probable; Grade 5 = death.
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End point type |
Primary
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End point timeframe |
From the start of first infusion of IP to 30 days after the end of last infusion of IP; median (min, max) treatment duration was 56 (16, 84) days
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| Notes [2] - 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: Statistical reporting of safety outcomes was entirely descriptive, with no formal statistical testing performed. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Overall Objective Response Rate (ORR) Expressed as the Percentage of Participants Achieving Complete Metabolic Response (CMR) and Partial Metabolic Response (PMR) Using Lugano 2014 Criteria During Cycle 1 and During Treatment Period | ||||||||||||
End point description |
Tumor response assessment was performed by a central reader according to modified Lugano classification using PET/CT scan. Overall objective response rate (ORR) is the percentage of participants with a best overall response of complete metabolic response (CMR) or partial metabolic response (PMR). CMR: a score of 1 (no uptake above background), 2 (uptake </=mediastinum), or 3 (uptake <mediastinum but </=liver) with/without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow; and normal/IHC-negative bone marrow morphology. PMR: a score 4 (uptake moderately greater than [>] liver) or 5 (uptake markedly >liver and/or new lesions) with reduced uptake compared with baseline and residual mass(es) of any size on PET 5-PS for lymph nodes and extralymphatic sites; no new lesions; and reduced residual uptake in bone marrow compared with baseline.
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End point type |
Secondary
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End point timeframe |
Cycle 1: Day 78 (3 weeks following end of Cycle 1 IP treatment) Treatment Period: Either the Cycle 1 timeframe or approximately Day 128 (3 weeks after Cycle 2 ended) for participants who completed Cycle 2
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Kaplan-Meier Estimates for Duration of Response (DOR) | ||||||||
End point description |
DOR was calculated only for responders during cycle 1. For participants who had CR or PR on the PET/CT scan at the end of the run-in period, response was measured from the start of blinatumomab treatment. For participants who had SD at the end of the run-in period, duration was calculated from documentation of the first assessment of either PR or CR on blinatumomab.
Progression was defined as the first diagnosis of progressive metabolic response/progressive disease based on PET/CT scan per central or investigator review during the treatment period or relapse based on clinical tumor assessment during the long-term follow up. Duration was calculated until the start of new anti-tumor treatment (excluding any stem cell transplantation), PD, or death, whichever was the earliest event. Participants who did not have new anti-tumor treatment (excluding stem cell transplantation), PD, or death were censored at the last tumor assessment date.
9999=not estimable due to low number of events
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End point type |
Secondary
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End point timeframe |
The median (range) follow-up time was 11.5 (8.2, 14.5) months
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| Notes [3] - Responder Analysis Set |
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| No statistical analyses for this end point | |||||||||
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End point title |
Complete Response Rate Expressed as the Percentage of Participants Achieving Complete Metabolic Response (CMR) Using Lugano 2014 Criteria During Cycle 1 and During Treatment Period | ||||||||||||
End point description |
Tumor response assessment was performed by a central reader according to modified Lugano classification using PET/CT scan. CMR: a score of 1 (no uptake above background), 2 (uptake </=mediastinum), or 3 (uptake <mediastinum but </=liver) with/without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow; and normal/IHC-negative bone marrow morphology.
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End point type |
Secondary
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End point timeframe |
Cycle 1: Day 78 (3 weeks following end of Cycle 1 IP treatment) Treatment Period: Either the Cycle 1 timeframe or approximately Day 128 (3 weeks after Cycle 2 ended) for participants who completed Cycle 2
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Kaplan-Meier Estimates for Overall Survival (OS) from First Dose of Blinatumomab | ||||||||
End point description |
OS was calculated as the time from the date of first IP infusion until death due to any cause. Participants who are alive at the date that triggers the analysis were censored at the date last known to be alive. Months were calculated as days from the first dose date of blinatumomab to death/censor date, divided by 30.5. 9999=not estimable due to low number of events
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End point type |
Secondary
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End point timeframe |
The median (range) follow-up time was 12.0 (10.7, 14.5) months.
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| No statistical analyses for this end point | |||||||||
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End point title |
Kaplan-Meier Estimates for Progression Free Survival (PFS) from First Dose of Blinatumomab | ||||||||
End point description |
PFS was calculated as the time from the date of first IP infusion until the date of diagnosis of progression of DLBCL or the date of death, whichever was the earliest. The diagnosis of progression of DLBCL was defined as the first diagnosis of progressive metabolic response/progressive disease based on PET/CT scan per central or investigator review during the treatment period or relapse based on clinical tumor assessment during the long-term follow up period. Participants who were alive and did not have progression were censored at the last evaluable non-missing tumor assessment date prior to the analysis trigger date. 9999=not estimable due to low number of events.
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End point type |
Secondary
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End point timeframe |
The median (range) follow-up time was 12.0 (8.2, 14.5)
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Who Had Hematopoietic Stem Cell Transplantation (HSCT) | ||||||||
End point description |
Percentage of participants who had HSCT during the Long Term Follow-Up Period.
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End point type |
Secondary
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End point timeframe |
Day 1 up to 14.5 months
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| No statistical analyses for this end point | |||||||||
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End point title |
Pharmacokinetics (PK) Results for Blinatumomab: Steady-State Concentrations at Week 1, Week 2 and Week 3 for Cycle 1 | ||||||||||||||
End point description |
The steady-state serum concentration (Css), summarized as the observed concentrations collected after at least 10 hours after the start of continuous IV infusion. PK blood samples were analyzed in a central lab.
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End point type |
Secondary
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End point timeframe |
Day 2 at least 24 hours after blinatumomab was started and on Day 9 and Day 16 at least 24 hours after blinatumomab dose was increased in the cycle
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Pharmacokinetics (PK) Results for Blinatumomab: Clearance for Cycle 1 | ||||||||
End point description |
PK blood samples were analyzed in a central lab.
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End point type |
Secondary
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End point timeframe |
Day 2 at least 24 hours after blinatumomab was started and on Day 9 and Day 16 at least 24 hours after blinatumomab dose was increased in the cycle
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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 |
From first dose of blinatumomab to 30 days after last dose; median duration of treatment was 56 days. Serious adverse events related to blinatumomab and deaths were collected during the long-term follow-up period, median time on follow-up was 12 months.
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Adverse event reporting additional description |
Adverse events are reported for all participants who received at least one dose of blinatumomab in the Treatment Period. One participant died during the run-in period and is not reflected in the tables below.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.1
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Reporting groups
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Reporting group title |
Blinatumomab
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Reporting group description |
Blinatumomab was administered as a continuous intravenous (IV) infusion. Cycle 1 was 12 weeks (84 days) in duration with step dosing of 9 µg/day for 7 days, 28 µg/day for 7 days, 112 µg/day for 6 weeks, followed by a 4-week treatment free time. An optional 4-week Cycle 2 of blinatumomab was available for participants whose disease did not progress, with step dosing of 9 µg/day for 7 days, 28 µg/day for 7 days, and 112 µg/day for 14 days. There was a safety follow-up for 30 days. And a long-term follow-up of up to 8 months for a maximum of 1 year from first dose of blinatumomab or until participant death. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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28 Feb 2017 |
This amendment was not submitted to the regulatory agency. |
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11 May 2017 |
This amendment reflects changes made to the original protocol in Amendments 1 and 2.
The protocol was aligned to changes made in the other diffuse large B-cell lymphoma protocols (Studies 20150292 and 20140286) with respect to safety assessments and dose interruptions and stopping criteria.
Sample size was reduced to support consideration of the study as a pilot study. The following points were clarified:
-Run-in period treatment
-Timing and frequency for evaluation of tumor response
-Subjects with progressive disease are not eligible for treatment with blinatumomab
-Toxicity monitoring and management and permanent discontinuation criteria
-All grades 3 and 4 laboratory abnormalities were to be recorded as adverse events
The Schedule of Assessments was updated to clarify for procedures during the screening and run-in phase and to provide clear guidance for cycle 1 and cycle 2 periods.
The list of disease-related events was updated.
The assessment of blinatumomab pharmacokinetics was changed from an exploratory objective and endpoint to a secondary objective and endpoint.
The assessment of overall survival was added in the clinical hypothesis and as a secondary endpoint.
Typographical and formatting changes were made throughout the protocol. |
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03 Jun 2018 |
The following points were clarified:
-Grade 4 hematologic toxicity and grade 4 laboratory abnormalities lasting ≥ 7 days exclude lymphopenia
-Subjects would be excluded from receiving blinatumomab if there was evidence of central nervous system involvement with diffuse large B-cell lymphoma at evaluation before starting blinatumomab
-When vital signs would be obtained for hospitalized subjects versus subjects in the outpatient clinic
-What assessments in the Schedule of Assessments should be obtained after restart of continuous intravenous infusion of blinatumomab after interruption requiring dose modification.
Administration, typographical, and formatting changes were made throughout the protocol. |
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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 | |||
