Safety and Efficacy of Blinatumomab in Adults With Newly Diagnosed High-risk Diffuse Large B-Cell Lymphoma

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03023878
• Collaborator: (none)
• Enrollment: 47
• Locations: 24
• Arm: 1
• Actual Duration (Months): 31.5
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A phase 2, multicenter, open-label, single arm clinical trial in adults with newly diagnosed aggressive high-risk DLBCL.

Condition or Disease	Intervention/Treatment	Phase
High-risk Diffuse Large B-Cell Lymphoma	Drug: Blinatumomab; Drug: Investigator's Choice Chemotherapy; Drug: Dexamethasone	Phase 2

Detailed Description

The safety profile of blinatumomab after frontline rituximab (R)-chemotherapy, consisting of either R-CHOP (14 or 21) (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) or R-DA-EPOCH (rituximab and dose adjusted-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), or R-CHOEP (rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide), will be determined. The study will consist of a screening period of up to 14 days, a standard of care (SOC) R-chemotherapy run-in period of approximately 21 weeks, a 12 to 16 week blinatumomab treatment period, a 30-day safety follow-up visit, and a long-term follow-up period that begins after the safety follow-up visit is completed until 1 year from the first dose blinatumomab.

Study Design

• Study Type: Interventional
• Actual Enrollment: 47 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 20150288 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)
• Actual Study Start Date: Mar 13, 2017
• Actual Primary Completion Date: Apr 4, 2019
• Actual Study Completion Date: Oct 28, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Blinatumomab 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.

Drug: Blinatumomab; Blinatumomab monotherapy was supplied in single-use sterile glass injection vials and administered as an IV infusion.; Other Names: AMG103 BlinCyto ; Drug: Investigator's Choice Chemotherapy; During the run-in period participants received 6 cycles of standard of care rituximab-chemotherapy dosed per investigator's institution standard as follows: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine,prednisone) R-DA-EPOCH (rituximab and dose adjusted-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) or R-CHOEP (rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide).; Drug: Dexamethasone; Dexamethasone 20 mg IV: within 1 hour prior to start of treatment in each treatment cycle, and within 1 hour prior to dose-step (increase).; Other Names: corticosteroid

Outcome Measures

Primary Outcome Measures

1. Participants With Treatment-Emergent (Blinatumomab) Adverse Events [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]

   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.

2. Participants With Treatment-Emergent Adverse Events Related to Blinatumomab Treatment [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]

   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.

Secondary Outcome Measures

1. 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 [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]

   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.

2. Kaplan-Meier Estimates for Duration of Response [The median (range) follow-up time was 11.5 (8.2, 14.5) months]

   Duration of response 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 stable disease 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 period. Response 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.

3. 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 [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]

   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.

4. Kaplan-Meier Estimates for Overall Survival (OS) From First Dose of Blinatumomab [The median (range) follow-up time was 12.0 (10.7, 14.5) months.]

   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.

5. Kaplan-Meier Estimates for Progression Free Survival (PFS) From First Dose of Blinatumomab [The median (range) follow-up time was 12.0 (8.2, 14.5)]

   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.

6. Percentage of Participants Who Had Hematopoietic Stem Cell Transplantation (HSCT) [Day 1 up to 14.5 months]

   Percentage of participants who had HSCT during the Long Term Follow-Up Period.

7. Pharmacokinetics (PK) Results for Blinatumomab: Steady-State Concentrations at Week 1, Week 2 and Week 3 for Cycle 1 [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]

   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.

8. Pharmacokinetics (PK) Results for Blinatumomab: Clearance for Cycle 1 [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]

   PK blood samples were analyzed in a central lab.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Subject has provided informed consent prior to initiation of any study-specific activities/procedures

• Age ≥ 18 at time of informed consent

• Subject must have untreated histologically proven high-risk DLBCL defined by atleast one of the following:

• International Prognostic Index (IPI) for Diffuse Large B-cell Lymphoma 3 to 5 (representing high intermedidate - high ratings),

• Double-hit or higher or double protein expression

• Eastern Cooperative Oncology Group performance status ≤ 2.

• Subject meets the criteria per investigator's institution to receive standard of care (SOC) rituximab-chemotherapy (ie, R-CHOP [14 or 21] or R-DA-EPOCH or R-CHOEP) of 6 cycles. Subjects may be enrolled on study prior to cycle 1 or cycle 2 of SOC R-chemotherapy

• Adequate organ and bone marrow function determined within 14 days prior to enrollment defined as:

• Hematological: Absolute neutrophil count ≥110^9/L; Platelet count ≥7510^9/L;Hemoglobin ≥8g/dL

• Renal: Creatinine clearance ≥50mL/min;

• Hepatic: Aspartate aminotransferase/Alanine aminotransferase <3upper limit of normal (ULN); Total bilirubin <2ULN (unless Gilbert's Disease or if liver involvement with lymphoma)

• Subject must have completed 6 cycles of SOC R-chemotherapy and achieved CR, PR or stable disease by PET/CT performed 3 weeks (± 3 days) after cycle 6 of SOC R-chemotherapy. Subjects with progressive disease (PD) are not eligible for treatment with blinatumomab and will end the study.

Exclusion Criteria:

• Clinically relevant central nervous system (CNS) pathology requiring treatment such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, and psychosis

• Evidence of CNS involvement with DLBCL at disease evaluation obtained prior to starting blinatumomab

• Current autoimmune disease or history of autoimmune disease with potential of CNS involvement

• Subject has active infection requiring systemic therapy

• Prior anti-CD19 therapies

• Known infection with HIV or chronic infection with hepatitis B virus or hepatitis C virus

• History of other malignancy within the past 3 years with the following exceptions:

• Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician

• Adequately treated non-melanoma skin cancer or lentigo malignancy without evidence of disease

• Adequately treated cervical carcinoma in situ without evidence of disease

• Adequately treated breast ductal carcinoma in situ without evidence of disease

• Prostatic intraepithelial neoplasia without evidence of prostate cancer

• Adequately treated urothelial papillary non-invasive carcinoma or carcinoma in situ

• Subject has known hypersensitivity to immunoglobulins or any of the products or components to be administered during dosing.

• Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject's and investigator's knowledge.

• History/evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.

• Females who are pregnant or breastfeeding or planning to become pregnant or breastfeed while receiving blinatumomab and for an additional 48 hours after the last treatment dose of blinatumomab.

• Currently receiving treatment in another investigational device or drug study or less than 30 days since ending treatment on another investigational device or drug study. Other investigational procedures while participating in this study are excluded.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Chicago	Illinois	United States	60612
2	Research Site	Maywood	Illinois	United States	60153
3	Research Site	New Orleans	Louisiana	United States	70112
4	Research Site	Baltimore	Maryland	United States	21201
5	Research Site	New Brunswick	New Jersey	United States	08903
6	Research Site	Oklahoma City	Oklahoma	United States	73104
7	Research Site	Portland	Oregon	United States	97213
8	Research Site	Greenville	South Carolina	United States	29607
9	Research Site	Edmonton	Alberta	Canada	T6G 1Z2
10	Research Site	Sault Ste. Marie	Ontario	Canada	P6B 0A8
11	Research Site	Toronto	Ontario	Canada	M5G 2M9
12	Research Site	Créteil Cedex		France	94010
13	Research Site	Paris Cedex 10		France	75475
14	Research Site	Dresden		Germany	01307
15	Research Site	Ulm		Germany	89081
16	Research Site	Sevilla	Andalucía	Spain	41013
17	Research Site	Salamanca	Castilla León	Spain	37007
18	Research Site	Barcelona	Cataluña	Spain	08003
19	Research Site	L Hospitalet De Llobregat	Cataluña	Spain	08907
20	Research Site	Valencia	Comunidad Valenciana	Spain	46026
21	Research Site	A coruña	Galicia	Spain	15006
22	Research Site	Madrid		Spain	28007
23	Research Site	Bristol		United Kingdom	BS2 8ED
24	Research Site	Sheffield		United Kingdom	S10 2JF

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Study Protocol - Jun 3, 2018
• Statistical Analysis Plan - Sep 12, 2018

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT03023878
• Other Study ID Numbers: 20150288; 2016-002190-35
• First Posted: Jan 18, 2017
• Last Update Posted: Sep 14, 2020
• Last Verified: Aug 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Dexamethasone; Blinatumomab

Study Results

Participant Flow

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.
Pre-assignment Detail	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.

Arm/Group Title	Blinatumomab
Arm/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.
Period Title: Pre-Study Run-In Period
STARTED	47
COMPLETED	30
NOT COMPLETED	17
Period Title: Pre-Study Run-In Period
STARTED	30
COMPLETED	28
NOT COMPLETED	2
Period Title: Pre-Study Run-In Period
STARTED	28
Started Cycle 1	28
Started Cycle 2	11
COMPLETED	25
NOT COMPLETED	3
Period Title: Pre-Study Run-In Period
STARTED	28
COMPLETED	26
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Blinatumomab
Arm/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.
Overall Participants	28
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.2 (11.1)
Age, Customized (Count of Participants)
< 65 years	18 64.3%
>=65 years	10 35.7%
<75 years	25 89.3%
>=75 years	3 10.7%
Sex: Female, Male (Count of Participants)
Female	18 64.3%
Male	10 35.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 25%
Not Hispanic or Latino	21 75%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	1 3.6%
Black and African American	2 7.1%
Native Hawaiian or Other Pacific Islander	0 0%
White	21 75%
Other	4 14.3%
Disease Stage at Time of Diagnosis (Count of Participants)
Stage I	0 0%
Stage IE	1 3.6%
Stage II	0 0%
Stage III	5 17.9%
Stage IV	22 78.6%
International Prognostic Index Score at Diagnosis (Count of Participants)
Score 2	2 7.1%
Score 3	17 60.7%
Score 4	7 25%
Score 5	2 7.1%

Outcome Measures

1. Primary Outcome

Title	Participants With Treatment-Emergent (Blinatumomab) Adverse Events
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Blinatumomab
Arm/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.
Measure Participants	28
TEAE	28 100%
TEAE severity grade >=3	11 39.3%
TEAE severity grade >=4	5 17.9%
Serious TEAE	7 25%
TEAE leading to interruption of IP	3 10.7%
Serious TEAE leading to interruption of IP	2 7.1%
TEAE leading to discontinuation of IP	2 7.1%
Serious TEAE leading to discontinuation of IP	1 3.6%
Fatal TEAEs	0 0%

2. Primary Outcome

Title	Participants With Treatment-Emergent Adverse Events Related to Blinatumomab Treatment
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Blinatumomab
Arm/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.
Measure Participants	28
Treatment-related TEAE	23 82.1%
Related TEAE severity grade >=3	9 32.1%
Related TEAE severity grade >=4	3 10.7%
Related Serious TEAE	5 17.9%
Related TEAE leading to interruption of IP	3 10.7%
Related Serious TEAE leading to interruption of IP	2 7.1%
Related TEAE leading to discontinuation of IP	2 7.1%
Related Serious TEAE leading to discon of IP	1 3.6%
Related and Fatal TEAEs	0 0%

3. Secondary Outcome

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
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Blinatumomab
Arm/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.
Measure Participants	28
Cycle 1	89.3 318.9%
Entire Treatment Period	92.9 331.8%

4. Secondary Outcome

Title	Kaplan-Meier Estimates for Duration of Response
Description	Duration of response 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 stable disease 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 period. Response 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.
Time Frame	The median (range) follow-up time was 11.5 (8.2, 14.5) months

Outcome Measure Data

Analysis Population Description

Responder Analysis Set includes all participants in the FAS that achieve objective response (CR or PR as per the Lugano classification) on the PET/CT scan.

Arm/Group Title	Blinatumomab
Arm/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.
Measure Participants	25
Median (95% Confidence Interval) [months]	NA

5. Secondary Outcome

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
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Blinatumomab
Arm/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.
Measure Participants	28
Cycle 1	85.7 306.1%
Entire Treatment Period	89.3 318.9%

6. Secondary Outcome

Title	Kaplan-Meier Estimates for Overall Survival (OS) From First Dose of Blinatumomab
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.
Time Frame	The median (range) follow-up time was 12.0 (10.7, 14.5) months.

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS)

Arm/Group Title	Blinatumomab
Arm/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.
Measure Participants	28
Median (95% Confidence Interval) [months]	NA

7. Secondary Outcome

Title	Kaplan-Meier Estimates for Progression Free Survival (PFS) From First Dose of Blinatumomab
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.
Time Frame	The median (range) follow-up time was 12.0 (8.2, 14.5)

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS)

Arm/Group Title	Blinatumomab
Arm/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.
Measure Participants	28
Median (95% Confidence Interval) [months]	NA

8. Secondary Outcome

Title	Percentage of Participants Who Had Hematopoietic Stem Cell Transplantation (HSCT)
Description	Percentage of participants who had HSCT during the Long Term Follow-Up Period.
Time Frame	Day 1 up to 14.5 months

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS)

Arm/Group Title	Blinatumomab
Arm/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.
Measure Participants	28
Number (95% Confidence Interval) [percentage of participants]	3.6 12.9%

9. Secondary Outcome

Title	Pharmacokinetics (PK) Results for Blinatumomab: Steady-State Concentrations at Week 1, Week 2 and Week 3 for Cycle 1
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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set: participants who received any infusion of blinatumomab and had at least one PK sample collected

Arm/Group Title	Blinatumomab
Arm/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.
Measure Participants	28
Cycle 1 Week 1: 9 mcg/day	288 (289)
Cycle 1 Week 2: 28 mcg/day	795 (280)
Cycle 1 Week 3: 112 mcg/day	3160 (782)

10. Secondary Outcome

Title	Pharmacokinetics (PK) Results for Blinatumomab: Clearance for Cycle 1
Description	PK blood samples were analyzed in a central lab.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set: participants who received any infusion of blinatumomab and had at least one PK sample collected

Arm/Group Title	Blinatumomab
Arm/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.
Measure Participants	28
Mean (Standard Deviation) [L/Hour]	1.61 (0.496)

Adverse Events

Time Frame	Mortality is reported for all enrolled participants from enrollment in the Run-in Period to the end of long-term follow-up. Adverse events are reported from the first dose of blinatumomab through 30 days after last dose; median duration of treatment was 56 days. In addition, serious adverse events related to blinatumomab collected during the long-term follow-up period are reported; median time on follow-up was 12 months.
Adverse Event Reporting Description	All-cause mortality data are reported for all participants who enrolled in the Run-in Period. Adverse events are reported for all participants who received at least one dose of blinatumomab in the Treatment Period. During the long-term follow-up period, only serious adverse events related to blinatumomab were collected.
Arm/Group Title	Blinatumomab
Arm/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.
All Cause Mortality
	Blinatumomab
	Affected / at Risk (%)	# Events
Total	3/47 (6.4%)
Serious Adverse Events
	Blinatumomab
	Affected / at Risk (%)	# Events
Total	7/28 (25%)
Blood and lymphatic system disorders
Neutropenia	1/28 (3.6%)
General disorders
Pyrexia	2/28 (7.1%)
Infections and infestations
Bacteraemia	1/28 (3.6%)
Pneumonia	1/28 (3.6%)
Sepsis	1/28 (3.6%)
Nervous system disorders
Aphasia	1/28 (3.6%)
Neurotoxicity	1/28 (3.6%)
Other (Not Including Serious) Adverse Events
	Blinatumomab
	Affected / at Risk (%)	# Events
Total	26/28 (92.9%)
Blood and lymphatic system disorders
Anaemia	2/28 (7.1%)
Neutropenia	2/28 (7.1%)
Gastrointestinal disorders
Constipation	2/28 (7.1%)
Diarrhoea	4/28 (14.3%)
Dry mouth	3/28 (10.7%)
Nausea	5/28 (17.9%)
Vomiting	3/28 (10.7%)
General disorders
Asthenia	2/28 (7.1%)
Chills	3/28 (10.7%)
Fatigue	8/28 (28.6%)
Pyrexia	10/28 (35.7%)
Immune system disorders
Cytokine release syndrome	5/28 (17.9%)
Infections and infestations
Upper respiratory tract infection	2/28 (7.1%)
Investigations
Lymphocyte count decreased	2/28 (7.1%)
Neutrophil count decreased	2/28 (7.1%)
Platelet count decreased	2/28 (7.1%)
White blood cell count decreased	3/28 (10.7%)
Metabolism and nutrition disorders
Hypophosphataemia	2/28 (7.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/28 (17.9%)
Back pain	5/28 (17.9%)
Flank pain	2/28 (7.1%)
Muscular weakness	2/28 (7.1%)
Musculoskeletal pain	3/28 (10.7%)
Myalgia	4/28 (14.3%)
Neck pain	3/28 (10.7%)
Pain in extremity	5/28 (17.9%)
Nervous system disorders
Ataxia	2/28 (7.1%)
Dizziness	2/28 (7.1%)
Headache	7/28 (25%)
Paraesthesia	2/28 (7.1%)
Tremor	10/28 (35.7%)
Psychiatric disorders
Insomnia	4/28 (14.3%)
Respiratory, thoracic and mediastinal disorders
Cough	8/28 (28.6%)
Dysphonia	2/28 (7.1%)
Nasal congestion	3/28 (10.7%)
Oropharyngeal pain	3/28 (10.7%)
Skin and subcutaneous tissue disorders
Erythema	2/28 (7.1%)
Pruritus	3/28 (10.7%)
Rash	2/28 (7.1%)
Vascular disorders
Flushing	9/28 (32.1%)
Hypotension	4/28 (14.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.