Clinical Trial Results:
A Phase 2 Open-Label Study to Determine the Effect of Blinatumomab on Minimal Residual Disease in Subjects With High-risk Diffuse Large B-cell Lymphoma Post-autologous Hematopoietic Stem-cell Transplantation
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Summary
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EudraCT number |
2016-003255-30 |
Trial protocol |
GR BE IT |
Global end of trial date |
30 Sep 2019
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Results information
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Results version number |
v2(current) |
This version publication date |
10 Oct 2020
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First version publication date |
19 Sep 2020
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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 |
20150291
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03298412 | ||
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,
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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 |
30 Sep 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 |
30 Sep 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 primary objective of this study is to determine minimal residual disease (MRD) negative rate following blinatumomab treatment in high-risk Diffuse Large B-cell Lymphoma (DLBCL) subjects who are MRD-positive post-autologous hematopoietic stem cell transplantation (aHSCT).
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Protection of trial subjects |
This study was conducted in accordance with International Council for 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 |
23 May 2018
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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 |
Switzerland: 2
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Country: Number of subjects enrolled |
United States: 1
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Country: Number of subjects enrolled |
Australia: 2
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Country: Number of subjects enrolled |
France: 2
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Country: Number of subjects enrolled |
Greece: 1
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Country: Number of subjects enrolled |
Italy: 2
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Worldwide total number of subjects |
10
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EEA total number of subjects |
5
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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) |
7
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
The study enrolled participants from Australia, France, Greece, Italy, Switzerland, and the United States. The first participant enrolled on 23 May 2018, and the last participant enrolled on 05 August 2019. | ||||||||||||||||
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Pre-assignment
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Screening details |
The study included a Screening period (up to 28 days), and a run-in period of up to 24 months to evaluate minimal residual disease (MRD) status and assess eligibility for treatment assignment. | ||||||||||||||||
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Period 1
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Period 1 title |
Run-in 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 |
After a run-in period of up to 24 months to evaluate MRD status and assess eligibility for treatment assignment, participants received blinatumomab intravenous (IV) infusion at an initial dose of 9 μg/day for the first 7 days of treatment, escalated (dose-step) to 28 μg/day starting on Day 8 (Week 2), followed by a dose-step to 112 μg/day starting on Day 15 (Week 3) and continuing until completion of therapy (Day 57 of Cycle 1). Cycle 1 of blinatumomab treatment is 12 weeks (84 days) in duration and includes 8 weeks (56 days) of blinatumomab IV infusion followed by a 4-week (28-day) treatment-free interval. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
blinatumomab (given after the run-in period)
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Investigational medicinal product code |
AMG 103, MT103
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Other name |
Blincyto
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Pharmaceutical forms |
Powder for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Per protocol, blinatumomab was given after the run-in period (at the start of the treatment period).
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Period 2
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Period 2 title |
Treatment Period
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Is this the baseline period? |
No | ||||||||||||||||
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 intravenous (IV) infusion at an initial dose of 9 μg/day for the first 7 days of treatment, escalated (dose-step) to 28 μg/day starting on Day 8 (Week 2), followed by a dose-step to 112 μg/day starting on Day 15 (Week 3) and continuing until completion of therapy (Day 57 of Cycle 1). Cycle 1 of blinatumomab treatment is 12 weeks (84 days) in duration and includes 8 weeks (56 days) of blinatumomab IV infusion followed by a 4-week (28-day) treatment-free interval. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
blinatumomab
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Investigational medicinal product code |
AMG 103, MT103
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Other name |
Blincyto
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Pharmaceutical forms |
Powder for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Blinatumomab wa administered as a continuous intravenous (IV) infusion.
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Baseline characteristics reporting groups
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Reporting group title |
Blinatumomab
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Reporting group description |
After a run-in period of up to 24 months to evaluate MRD status and assess eligibility for treatment assignment, participants received blinatumomab intravenous (IV) infusion at an initial dose of 9 μg/day for the first 7 days of treatment, escalated (dose-step) to 28 μg/day starting on Day 8 (Week 2), followed by a dose-step to 112 μg/day starting on Day 15 (Week 3) and continuing until completion of therapy (Day 57 of Cycle 1). Cycle 1 of blinatumomab treatment is 12 weeks (84 days) in duration and includes 8 weeks (56 days) of blinatumomab IV infusion followed by a 4-week (28-day) treatment-free interval. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Blinatumomab
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Reporting group description |
After a run-in period of up to 24 months to evaluate MRD status and assess eligibility for treatment assignment, participants received blinatumomab intravenous (IV) infusion at an initial dose of 9 μg/day for the first 7 days of treatment, escalated (dose-step) to 28 μg/day starting on Day 8 (Week 2), followed by a dose-step to 112 μg/day starting on Day 15 (Week 3) and continuing until completion of therapy (Day 57 of Cycle 1). Cycle 1 of blinatumomab treatment is 12 weeks (84 days) in duration and includes 8 weeks (56 days) of blinatumomab IV infusion followed by a 4-week (28-day) treatment-free interval. | ||
Reporting group title |
Blinatumomab
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Reporting group description |
Blinatumomab intravenous (IV) infusion at an initial dose of 9 μg/day for the first 7 days of treatment, escalated (dose-step) to 28 μg/day starting on Day 8 (Week 2), followed by a dose-step to 112 μg/day starting on Day 15 (Week 3) and continuing until completion of therapy (Day 57 of Cycle 1). Cycle 1 of blinatumomab treatment is 12 weeks (84 days) in duration and includes 8 weeks (56 days) of blinatumomab IV infusion followed by a 4-week (28-day) treatment-free interval. | ||
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End point title |
MRD-Negative Rate at the End of Cycle 1 [1] | ||||||||
End point description |
The estimated MRD-negative rate, calculated as the percentage of participants with MRD-negative status after treatment with blinatumomab. MRD-negative status was assessed by positron emission tomography-computed tomography (PET-CT) or computed tomography (CT).
Full analysis set (all participants who received any infusion of blinatumomab).
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End point type |
Primary
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End point timeframe |
12 weeks (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: One participant received/completed treatment; available data is presented in the data table. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Kaplan-Meier Estimate: Progression-Free Survival (PFS) | ||||||||
End point description |
PFS, calculated as the time from the date of first dose of blinatumomab until the date of diagnosis of relapse of lymphoma (by PET-CT, CT, clinical assessment or relapse biopsy, whichever was the preferred method), or date of death, whichever was earliest. Participants who were alive and who did not have progression or new anti-tumor treatment (excluding any stem cell transplantation) were to be censored at last date of tumor assessment.
Full analysis set (all participants who received any infusion of blinatumomab).
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End point type |
Secondary
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End point timeframe |
up to 1 year from first dose of blinatumomab
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| Notes [2] - 99999=Not estimable (1 participant in analysis set). |
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| No statistical analyses for this end point | |||||||||
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End point title |
Kaplan-Meier Estimate: Duration of MRD-Negative Status | ||||||||
End point description |
The duration of MRD-negative status, assessed only in participants who achieve MRD-negative status after blinatumomab treatment, was defined as the time when a negative MRD result was first established until documented MRD-positive re-occurrence, disease progression or, death due to any cause. Participants without any of these events at the time of the analysis were to be censored at their last disease assessment date. MRD-negative status was assessed by PET-CT or CT.
Full analysis set (all participants who received any infusion of blinatumomab).
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End point type |
Secondary
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End point timeframe |
up to 1 year from first dose of blinatumomab
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| Notes [3] - -/+99999=Not estimable (1 participant analyzed). |
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| No statistical analyses for this end point | |||||||||
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End point title |
Kaplan-Meier Estimate: Overall Survival (OS) | ||||||||
End point description |
OS, defined as time from the first dose of blinatumomab treatment until death due to any cause. Participants still alive at the time of the analysis were censored at date last known to be alive.
Full analysis set (all participants who received any infusion of blinatumomab).
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End point type |
Secondary
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End point timeframe |
up to 1 year from first dose of blinatumomab
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| Notes [4] - 99999=Not estimable (1 participant in analysis set). |
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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 (TEAEs) | ||||||||||||||
End point description |
An adverse event (AE) is defined as any untoward medical occurrence. A serious AE is defined as an AE that is: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; a congenital anomaly/birth defect; other medically important serious event. TEAEs are events with an onset after the administration of the first dose of blinatumomab treatment through 30 days after the end of blinatumomab treatment. Events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE): Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), Grade 5 (death).
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End point type |
Secondary
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End point timeframe |
From first dose of study drug through 30 days after the last dose of study drug. The treatment duration for the participant who received blinatumomab was 57 days.
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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 |
Serious adverse events and other adverse events were collected from first dose of study drug through 30 days after the last dose of study drug. The treatment duration for the participant who received blinatumomab was 57 days.
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Adverse event reporting additional description |
Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.
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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 |
- | ||||||||||||||
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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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23 May 2017 |
This protocol is being amended to:
• Include stopping rules for excessive toxicity, define dose limiting toxicity (DLT) evaluable subjects, and add interim analyses to review DLT rate
• Clarify timing and purpose of MRD tests that occur before treatment and on cycle 1 day 1
• Remove language related to sensitivity analysis performed on the MRD-negative rate at the end of cycle 1 of blinatumomab
• Make administrative and editorial updates (this includes an update to the Schedule of Assessments table to re-add 2 PET assessments that were mistakenly deleted during publication of original protocol) |
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24 Aug 2017 |
This protocol is being amended to:
• include stopping rules for disease progression.
• add hepatitis serology and human immunodeficiency virus testing.
• add benefit/risk assessment language.
• make administrative and editorial updates. |
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18 Jul 2018 |
This protocol is being amended to:
• Increase the screening window to 28 days.
• Clarify when pathology tumor block/slides should be collected and MRD tests should be performed during screening.
• Clarify that the MRD plasma sample needs to be drawn after the post aHSCT PET-CT scan.
• Clarify that subjects will be excluded from receiving blinatumomab if there is evidence of central nervous system (CNS) involvement with DLBCL at disease evaluation prior to starting blinatumomab.
• Clarify that grade 4 hematologic toxicity and grade 4 laboratory abnormalities lasting
≥ 7 days exclude lymphopenia. This lymphopenia is reported to last for 6 months or as long as a year after therapy completion (Chiappella et al, 2017; Coffier, 2007; Plosker and Figgitt, 2003). Lymphopenia is also a known adverse event with blinatumomab that does resolve after the therapy is completed. Lymphopenia is not an immediately life-threatening threatening event, is treated well with supportive care, and reverses after completion of R-chemotherapy and blinatumomab infusion.
• Clarify when vital signs will be obtained for hospitalized subjects versus subjects in the outpatient clinic.
• Make administrative and editorial updates. |
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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 | |||
