Clinical Trial Results:
A Phase 2/3 Multicenter Study to Evaluate the Safety and Efficacy of Blinatumomab in Subjects With Relapsed/Refractory Aggressive B-cell Non Hodgkin Lymphoma
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Summary
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EudraCT number |
2016-002044-16 |
Trial protocol |
GB BE ES IT |
Global end of trial date |
12 Mar 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Mar 2021
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First version publication date |
10 Mar 2021
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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 |
20150292
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02910063 | ||
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, medinfo@amgen.com
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Scientific contact |
IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, medinfo@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 |
12 Mar 2020
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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 |
12 Mar 2020
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The main objective of this trial was to estimate the complete metabolic response (CMR) rate after blinatumomab monotherapy administered in the second salvage treatment of transplant-eligible participants with relapsed/refractory (R/R) aggressive B cell non Hodgkin lymphoma who have not achieved CMR after standard platinum based first salvage chemotherapy.
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Protection of trial subjects |
This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) and other regulations/guidelines as applicable.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Jan 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 |
Belgium: 3
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Country: Number of subjects enrolled |
Italy: 7
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
United Kingdom: 8
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Country: Number of subjects enrolled |
United States: 6
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Country: Number of subjects enrolled |
Australia: 14
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Worldwide total number of subjects |
41
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EEA total number of subjects |
13
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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) |
33
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From 65 to 84 years |
8
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants were enrolled at 19 research centers in Australia, Belgium, Italy, Spain, the United Kingdom, and the United States from 23 January 2017 to 15 January 2018. | ||||||||||||||||||||||
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Pre-assignment
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Screening details |
Phase 3 part of the study was not initiated after Phase 2 data was reviewed. No participants were screened or enrolled for Phase 3. | ||||||||||||||||||||||
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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 |
Non-randomised - controlled
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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 |
Phase 2: Participants entered a single 70-day dose step cycle, and received a total of 56 days of blinatumomab continuous infusion which was administered as 7 days at 9 microgram (μg)/day, 7 days at 28 μg/day, and 42 days at 112 μg/day, followed by a treatment-free period of 14 days. Eligible participants could then enter an optional Cycle 2, 2 to 4 weeks after the end of the previous cycle. The optional Cycle 2 consisted of a 28-day cycle of blinatumomab continuous infusion administered as 7 days at 9 μg/day, 7 days at 28 μg/day, and 14 days at 112 μg/day. Phase 3: The decision made to not proceed with Phase 3 and no participants were enrolled. | ||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||
Investigational medicinal product name |
Blinatumomab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Participants received doses ranging from 9 µg/day to 112 µg/day. Blinatumomab was administered as an intravenous (IV) infusion.
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| Notes [1] - 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: Cycle 2 was an optional cycle that participants did not need to complete to complete the overall study. Phase 3 part of the study was not initiated after Phase 2 data was reviewed. No participants were screened or enrolled for Phase 3. [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: Cycle 2 was an optional cycle that participants did not need to complete to complete the overall study. Phase 3 part of the study was not initiated after Phase 2 data was reviewed. No participants were screened or enrolled for Phase 3. |
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Blinatumomab
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Reporting group description |
Phase 2: Participants entered a single 70-day dose step cycle, and received a total of 56 days of blinatumomab continuous infusion which was administered as 7 days at 9 microgram (μg)/day, 7 days at 28 μg/day, and 42 days at 112 μg/day, followed by a treatment-free period of 14 days. Eligible participants could then enter an optional Cycle 2, 2 to 4 weeks after the end of the previous cycle. The optional Cycle 2 consisted of a 28-day cycle of blinatumomab continuous infusion administered as 7 days at 9 μg/day, 7 days at 28 μg/day, and 14 days at 112 μg/day. Phase 3: The decision made to not proceed with Phase 3 and no participants were enrolled. | ||
Subject analysis set title |
Phase 2: Blinatumomab 9 µg/day
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All participants who received blinatumomab 9 µg/day continuous infusion which was administered for 7 days of in Week 1 of Cycle 1 (Cycle 1 was 70 days in length).
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Subject analysis set title |
Phase 2: Blinatumomab 28 µg/day
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All participants who received blinatumomab 28 µg/day continuous infusion which was administered for 7 days in Week 2 of Cycle 1 (Cycle 1 was 70 days in length).
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Subject analysis set title |
Phase 2: Blinatumomab 112 µg/day
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All participants who received blinatumomab 112 µg/day continuous infusion which was administered for 7 days in Week 3 of Cycle 1 (Cycle 1 was 70 days in length).
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End point title |
Phase 2: Percentage of Participants who Achieved Complete Metabolic Response (CMR) [1] | ||||||||
End point description |
Complete metabolic response (CMR) was determined by central radiographic assessment of positron emission tomography and computed tomography (PET/CT) scans using the Lugano Classification.
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End point type |
Primary
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End point timeframe |
Up to 12 weeks after first dose of blinatumomab
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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 statistics were planned |
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| Notes [2] - Full analysis set (FAS): All participants who received blinatumomab |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 3: Number of Participants who Achieved Complete Metabolic Response (CMR) [3] | ||||||||
End point description |
Complete metabolic response (CMR) was determined by central radiographic assessment of positron emission tomography and computed tomography (PET/CT) scans using the Lugano Classification.
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End point type |
Primary
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End point timeframe |
Up to 12 weeks after first dose of study treatment
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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 statistics were planned. |
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| Notes [4] - No participants were enrolled in Phase 3. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 2: Overall Survival (OS) | ||||||||
End point description |
OS was defined as the time from the date of randomization until death due to any cause.
OS was calculated using Kaplan-Meier estimates.
99999 = no data to present. The upper limit was not reached.
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End point type |
Secondary
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End point timeframe |
From randomization until the end of study, up to 30 months
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| Notes [5] - FAS: All participants who received blinatumomab |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 2: Objective Response Rate (ORR) | ||||||||
End point description |
ORR is inclusive of all participants who achieved CMR or those who achieved partial metabolic response (PMR), as determined by central radiographic assessment of PET/CT scans using the Lugano Classification.
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End point type |
Secondary
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End point timeframe |
Up to 12 weeks after first dose of blinatumomab
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| Notes [6] - FAS: All participants who received blinatumomab |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 2: Progression Free Survival (PFS) | ||||||||
End point description |
PFS was defined as the time from start of treatment with blinatumomab until the date of diagnosis of progression of lymphoma, or date of death, whichever is earliest. PFS was estimated using Kaplan-Meier method.
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End point type |
Secondary
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End point timeframe |
From first dose of blinatumomab until the end of study, up to 30 months
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| Notes [7] - FAS: All participants who received blinatumomab |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 2: Duration of Response (DOR) | ||||||||
End point description |
DOR was calculated only for participants who achieve a response (CMR or PMR). The duration was calculated from the date a response, CMR or PMR, was first achieved until the earliest date of a disease assessment indicating disease progression or death, whichever occurred first. DOR was estimated using Kaplan-Meier method.
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End point type |
Secondary
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End point timeframe |
From first dose of blinatumomab up to 12 weeks
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| Notes [8] - FAS: All participants who received blinatumomab |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 2: Percentage of Participants who Experienced Successful Mobilization | ||||||||
End point description |
Successful mobilization rate was defined as the percentage of participants who initiated mobilization while in remission and without any other anti-tumor therapy where the mobilization procedure had an outcome of ‘Successful’. Successful mobilization was dictated by institutional standards and defined when the target cell dose was no less than 2 x 10^6 CD34+ cells/kg.
Responder Analysis Set: All participants who had a CMR or PMR per central review during the first 12 weeks after initiation of blinatumomab.
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End point type |
Secondary
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End point timeframe |
From first dose of blinatumomab until the end of study, up to 30 months
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| Notes [9] - Responder Analysis Set |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 2: Percentage of Participants who had Allogeneic or Autologous Post-baseline Hematopoietic Stem Cell Transplant (HSCT) | ||||||||||||
End point description |
The percentage of responders per investigator’s review (participants who achieved either CMR or PMR during the treatment) who have undergone allogeneic (allo) HSCT or autologous (auto) HSCT while in remission and without any other anti-cancer treatment.
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End point type |
Secondary
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End point timeframe |
From baseline HSCT until the end of study, up to 30 months
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| Notes [10] - FAS: All participants who received blinatumomab. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Phase 2: Cumulative Incidence Function Estimate of 100-day Mortality After HSCT Presented as Percentage of Participants that Died Not Due to Relapse, with Relapse and Death Due to Relapse as Competing Events | ||||||||
End point description |
Non-relapse mortality rate at 100 days after HSCT was calculated as the percentage of participants who died not due to relapse. Only participants who achieved a response per investigator’s review and underwent autoHSCT are included.
AutoHSCT Analysis Set: All participants who achieved a response and underwent autoHSCT while in remission and without any other anti-cancer treatment.
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End point type |
Secondary
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End point timeframe |
100 days after HSCT
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| Notes [11] - AutoHSCT Analysis Set |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 2: Blinatumomab Steady State Concentrations (Css) | ||||||||||||||||
End point description |
Pharmacokinetic (PK) parameters were estimated by non compartmental analysis. The Css of blinatumomab was summarized as the observed concentrations collected after at least 24 hours after the start of continuous IV infusion or start of dose step, where appropriate.
PK analysis Set: All participants who received blinatumomab at each individual dose and had at least one PK sample collected.
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End point type |
Secondary
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End point timeframe |
Pre-dose on Day 1, and post-dose on Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days)
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| Notes [12] - PK Analysis Set [13] - PK Analysis Set [14] - PK Analysis Set |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Phase 2: Blinatumomab Clearance (CL) | ||||||||
End point description |
Serum blinatumomab CL was calculated as CL=R0/Css,DN; where R0 is the infusion rate (μg/hr) and Css,DN is the dose normalized average Css. For the CL calculation, the Css,DN was normalized to the 112 μg/day dose in which the value of dose in units of μg/hr was used for the infusion rate.
PK analysis Set: All subjects who received blinatumomab at each individual dose and had at least one PK sample collected.
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End point type |
Secondary
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End point timeframe |
Pre-dose on Day 1, and post-dose on Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days)
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| Notes [15] - PK Analysis Set |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 2: Half-life of Blinatumomab | ||||||||
End point description |
Blinatumomab half-life was not reported as the serum blinatumomab concentration data collected for PK assessments did not support its estimation. This is in adherence with the considerations for reporting of PK assessments as detailed in Protocol Section 10.6.
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End point type |
Secondary
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End point timeframe |
Pre-dose on Day 1, and Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days)
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| Notes [16] - Insufficient data collected. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 2: Number of Participants who Experienced a Treatment-emergent Adverse Event (TEAE) | ||||||||||||||||||||||
End point description |
Treatment-emergent adverse events were events with an onset after the administration of the first dose of blinatumomab.
TEAEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE).
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limited age appropriate instrumental activities of daily life (ADL).
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limited self care ADL.
Grade 4 Life-threatening consequences; urgent interventions indicated.
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End point type |
Secondary
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End point timeframe |
From first dose of blinatumomab until 30 days after last dose. The maximum treatment duration for blinatumomab was 114 days
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| Notes [17] - FAS: All participants who received blinatumomab |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Phase 3: Objective Response Rate (ORR) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Up to 12 weeks after first dose of study treatment
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| Notes [18] - No participants were enrolled for Phase 3. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 3: Progression Free Survival (PFS) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From first dose of study treatment until the end of study, up to 30 months
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| Notes [19] - No participants were enrolled in Phase 3. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 3: Duration of Response (DOR) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From first dose of study treatment up to 12 weeks
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| Notes [20] - No participants were enrolled in Phase 3. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 3: Percentage of Participants who Experienced Successful Mobilization | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From baseline until the end of study, up to 30 months
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| Notes [21] - No participants were enrolled in Phase 3. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 3: Percentage of Participants who had Allogeneic or Autologous Post-baseline Hematopoietic Stem Cell Transplant (HSCT) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From baseline HSCT until the end of study, up to 30 months
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| Notes [22] - No participants were enrolled in Phase 3. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 3: Percentage of Participants who Died within 100 Days after Hematopoietic Stem Cell Transplantation (HSCT) that was Not Due to Relapse | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
100 days after HSCT
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| Notes [23] - No participants were enrolled in Phase 3. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 3: Change from Baseline in Patient Reported Clinical Outcome Assessments Quality of Life (QOLCOA) Scores | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Up to 30 days after last dose after study treatment
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| Notes [24] - No participants were enrolled in Phase 3. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 3: Number of Participants who Experienced a Treatment-emergent Adverse Event (TEAE) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From first dose of study treatment until 30 days after last dose
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| Notes [25] - No participants were enrolled in Phase 3. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 3: Serum Blinatumomab Steady State Concentration (Css) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
24 hours after first dose of blinatumomab
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| Notes [26] - No participants were enrolled in Phase 3. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 3: Blinatumomab Clearance (CL) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Pre-dose on Day 1, and Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days)
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| Notes [27] - No participants were enrolled in Phase 3. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase 3: Half-life of Blinatumomab | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Pre-dose on Day 1, and Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days)
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| Notes [28] - No participants were enrolled in Phase 3. |
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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 until 30 days after last dose. The maximum treatment duration for blinatumomab was 114 days
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Adverse event reporting additional description |
All-cause mortality, serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.
No data is available for Phase 3, In March 2019, the decision was made to not proceed with Phase 3 and no participants were enrolled. The data below is only inclusive of participants in Phase 2.
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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 |
Phase 2: Participants entered a single 70-day dose step cycle, and received a total of 56 days of blinatumomab continuous infusion which was administered as 7 days at 9 microgram (μg)/day, 7 days at 28 μg/day, and 42 days at 112 μg/day, followed by a treatment-free period of 14 days. Eligible participants could then enter an optional Cycle 2, 2 to 4 weeks after the end of the previous cycle. The optional Cycle 2 consisted of a 28-day cycle of blinatumomab continuous infusion administered as 7 days at 9 μg/day, 7 days at 28 μg/day, and 14 days at 112 μg/day. Phase 3: The decision made to not proceed with Phase 3 and no participants were enrolled. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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16 Mar 2017 |
The following changes were made:
• Clarified duration of cycle and dose steps for blinatumomab for consistency within the protocol
• Added specification of the duration between end of cycle 1 and beginning of optional cycle 2 of blinatumomab
• Clarified that creatinine was to be calculated using the Cockcroft Gault equation
• Added the dose and duration of each step in the dosing schema of blinatumomab optional cycle 2 to clarify procedures
• Added mantle cell lymphoma as a histology that excluded eligibility for enrollment
• Added procedure by which scans were to be submitted to determine eligibility for participants who have had only 1 cycle of previous chemotherapy
• Revised requirements for blinatumomab infusion interruptions and dose modifications per request of the Food and Drug Administration (FDA)
• Updated blinatumomab stopping and/or withholding rules to include cytokine storm
• Added time point at week 68 for collection of cell pellet sample for optional pharmacogenetic testing
• Specified that lipase samples should be collected at the investigator’s discretion if pancreatitis was suspected
• Clarified that vital signs to be monitored every 4 to 8 hours postdose
• Clarified that participants are prohibited from receiving additional chemotherapy after the last response assessment before enrollment
• Clarified that PET imagining of the neck to be done as clinically indicated
• Clarified procedures for bone marrow biopsy
• Added the EuroQol- 5 Dimension (EQ-5D) and Functional Assessment of Cancer Therapy - Lymphoma (FACT Lym) instruments as appendices |
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16 Mar 2017 |
Amendment dated 16 March 2017 continued:
• Specified that disease progression is considered a disease related event and procedures for recording as an adverse event
• Revised list of disease-related adverse events
• Added reporting of events for participants who are partial response/minor response at baseline per Lugano who do not go to transplantation within 30 days of first response assessment
• Revised procedures for reporting laboratory abnormalities as adverse events |
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07 May 2019 |
This following changes were made: • Provided post facto option of not proceeding to Phase 3 • Provided 2 years of long term follow up for Phase 2 cohort • Clarified end of study and end of follow up for Phase 2 • Redefined primary and final analyses endpoints |
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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. | |||
| Phase 3 part of the study was not initiated after Phase 2 data was reviewed. No participants were screened or enrolled for Phase 3. | |||
