Clinical trial NCT02910063
Conditions: B-Cell Non Hodgkin Lymphoma
Keywords: Relapsed/Refractory Aggressive B-Cell Non Hodgkin Lymphoma Blinatumomab Leukemia Standard of Care SOC Cancer Chemotherapy
Sponsor: Amgen
Start date: 2017-01-23; Completion date: 2020-03-12
Enrollment: 41 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This is a phase 2/3 open label, multicenter trial testing blinatumomab monotherapy for the treatment of subjects with Relapsed/Refractory (R/R) aggressive B-NHL not achieving CMR after 2 cycles of standard platinum-based chemotherapy regimens administered as S1. This study incorporates multiple interim analyses for futility, efficacy, and unblinded sample-size re-estimation. In the phase 3 part of the study, blinatumomab will be compared to Investigator's Choice chemotherapy.

In March 2019, decision made to not proceed with phase 3.

Detailed description:
This is a phase 2/3 open label, multicenter trial testing blinatumomab monotherapy for the treatment of subjects with R/R aggressive B-NHL not achieving CMR after standard platinum-based chemotherapy regimens administered as S1. This study incorporates multiple interim analyses for futility, efficacy, and unblinded sample-size re-estimation. In the phase 3 part of the study, blinatumomab will be compared to IC chemotherapy.The phase 2 component of the study will consist of up to a 28-day screening period, approximately 70 to 112 days of study treatment, a 30-day (+/- 3days) safety follow up, and long-term follow up that will conclude with the final analysis of the phase 3 component, estimated at 30 months after initiation of the phase 3 component. For the phase 3 component, the study will consist of up to a 28-day screening period, a treatment period of up to approximately 168 days, a 30-day safety follow-up visit, and long-term follow up. Long-term follow up will conclude with the final analysis.In the phase 2 component, enrolled subjects will receive blinatumomab monotherapy. In the phase 3 component, enrolled subjects will be randomized in a 1:1 ratio to blinatumomab or IC chemotherapy.

In March 2019, decision made to not proceed with phase 3.

Arms: arm 1: Blinatumomab is administered as a continuous intravenous infusion (CIVI). A single cycle of blinatumomab is continuous infusion with step dosing of 9 µg/day x 7 days, 28 µg/day x 7 days, and 112 µg/days until the end of the cycle.
Interventions: intervention 1: Blinatumomab
Intervention descriptions: intervention 1: Blinatumomab monotherapy

Protocol documents:
Prot_000.pdf: 
Product:  Blinatumomab 
Protocol Number:  20150292 
Date:  07 May 2019 
Page 1 of 115 
CONFIDENTIAL 
Title: A Phase 2/3 Multi-center Study to Evaluate the Safety and Efficacy of 
Blinatumomab in Subjects With Relapsed/Refractory Aggressive B-Cell 
Non Hodgkin Lymphoma 
Amgen Protocol Number (Product Name: Blinatumomab) 20150292 
EudraCT number 2016‐002044‐16 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
United States 
Phone: +1-805-447-1000 
Fax: +1-805-480-4978 
Key Sponsor Contact(s): 
Clinical Research Medical Director 
Email: 
Global Clinical Trial Manager 
Phone:
Email: 
 
Date: 
27 June 2016 
Amendment 1 
16 March 2017 
Superseding Amendment 1: 
27 April 2017 
Amendment 2 
07 May 2019 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number: US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN; <<for all other countries, insert the local toll-free Medical Information
number>> Amgen’s general number in the US (1-805-447-1000).
Approved
NCT Number: NCT02910063
This NCT number has been applied to the document for
purposes of posting on Clinical trials.gov


Product:  Blinatumomab 
Protocol Number:  20150292 
Date:  07 May 2019 
Page 2 of 115 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled “A Phase 2/3 Multi-center Study to Evaluate 
the Safety and Efficacy of Blinatumomab in Subjects with Relapsed/Refractory 
Aggressive B-Cell Non Hodgkin Lymphoma,” dated 07 May 2019 and agree to abide by 
all provisions set forth therein.  
I agree to comply with the International Conference on Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
• 
me (including, if applicable, my spouse [or legal partner] and dependent children) 
• 
my sub investigators (including, if applicable, their spouses [or legal partners] and 
dependent children) 
at the start of the study and for up to 1 year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20150292 
Date:  07 May 2019 
Page 3 of 115 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title: A Phase 2/3 Multi-center Study of Evaluate the Safety and Efficacy of Blinatumomab in 
Subjects with Relapsed/Refractory Aggressive B-Cell Non Hodgkin Lymphoma 
Study Phase: 2/3 
Indication: Aggressive B-Cell Non-Hodgkin Lymphoma (B-NHL) 
Primary Objective:  
Phase 2: 
• To estimate the complete metabolic response (CMR) rate following blinatumomab 
monotherapy administered in the second salvage (S2) treatment of transplant-eligible 
subjects with relapsed or refractory (R/R) aggressive B-NHL who have not achieved CMR1 
following standard platinum-based first salvage (S1) chemotherapy 
Phase 3: 
• To compare the CMR rates following blinatumomab to those following investigator’s choice 
(IC) S2 chemotherapy 
Secondary Objectives:  
Phase 2: 
• To evaluate additional efficacy parameters following blinatumomab treatment, including: 
- Duration of response (DOR) 
- Progression-free survival (PFS) 
- The rate of successful hematopoietic stem cell (HSC) mobilization  
• To evaluate the safety of blinatumomab in the S2 setting 
Phase 3: 
• To compare the efficacy of blinatumomab to IC chemotherapy with respect to:  
- Overall survival (OS) 
- DOR 
- The rate of successful HSC mobilization 
- Ability to proceed to hematopoietic stem cell transplant (HSCT) (both autologous and 
allogeneic) rates among responding subjects (CMR) or those in sustained partial 
metabolic response (PMR) 
- Objective response rate (ORR; CMR + PMR)  
- PFS 
• To compare the safety profile of blinatumomab to that of IC chemotherapy 
•  To compare the quality of life reported by subjects treated with blinatumomab and those 
treated with IC chemotherapy 
Phases 2 and 3 
• To characterize the pharmacokinetic (PK) parameters of blinatumomab administered to 
subjects with R/R aggressive B-NHL 
                                                
1 Response terminology reflect the response criteria used. The Lugano Classification response 
definitions for PET-CT evaluations of FDG-avid lymphomas uses the terminology CMR, PMR, 
NMR, or PMD. Corresponding designations from earlier response criteria include CR, PR, SD, 
or PD. 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20150292 
Date:  07 May 2019 
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CONFIDENTIAL 
 
 
Exploratory Objectives: 
Phases 2 and 3: 
• To characterize the pharmacodynamic effects of blinatumomab administered in temporal 
proximity to various S1 regimens  
• To evaluate the response rate according to disease-specific features, such as 
cell-of-origin (COO), c-myc and bcl-2 rearrangements and over expression, Revised 
International Prognostic Index (R-IPI), Secondary International Prognostic Index (IPI), 
National Comprehensive Cancer Network International Prognostic Index (NCCN IPI), 
response to frontline therapy, duration of first remission 
• To evaluate the frequency of tumor-associated mutations in cell-free (CF) circulating tumor 
DNA (CT-DNA) among subjects at various time points during and after salvage treatment 
• To determine the incidence of anti-blinatumomab antibody formation 
Hypothesis (Phase 3): Administration of blinatumomab to subjects with aggressive B-NHL 
following suboptimal response to standard platinum-containing S1 chemotherapy will increase the 
CMR rate and overall survival. 
Primary Endpoint:  
Phases 2 and 3: 
• CMR as determined by central radiographic assessment of positron emission 
tomography-computed tomography (PET/CT) scans using the Lugano Classification 
Secondary Endpoints:  
Key Secondary Endpoint: 
Phase 3: 
• OS 
Other Secondary Endpoints: 
Phase 2: 
• Objective response rate (ORR; including CMR and PMR)  
• PFS 
• DOR 
• Successful mobilization rate (defined as CD34+ cell 2x106/kg) 
• HSCT (both autologous and allogeneic) rates among subjects with post-blinatumomab 
complete response (CMR) + partial response (PMR) 
• 100-day non-relapse mortality (NRM) after autologous HSCT 
• Blinatumomab concentration steady state, clearance, and half life 
• Incidence and severity of adverse events 
Phase 3: 
• ORR (including CMR and PMR)  
• PFS 
• DOR 
• Successful mobilization rate (defined as CD34+ cell 2x106/kg) following protocol assigned 
therapy 
• HSCT (both autologous and allogeneic) rates among responding subjects (CMR or PMR) 
• 100-day NRM after HSCT rate 
• Patient-reported clinical outcome assessments quality of life (QOLCOA) using the EQ-5D and 
FACT-Lymphoma tools 
Approved 
 
 


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Protocol Number:  20150292 
Date:  07 May 2019 
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• Blinatumomab steady state concentration and clearance 
• Overall incidence and severity of treatment-emergent adverse events 
Exploratory Endpoints (Phase 2 and 3): 
• Pharmacodynamics, including descriptive analysis of quantitative and qualitative features of 
lymphocyte populations and serum or plasma concentrations of cytokines 
• Response rates and duration according to COO designation and c-myc and 
bcl-2 rearrangement and over expression, R-IPI, Secondary IPI, NCCN IPI, as determined 
from pretreatment specimens 
• Quantitative analysis of CF CT-DNA as determined by analysis of tumor-associated mutations 
in CF CT-DNA from plasma collected at various timepoints before, during, and after treatment 
Study Design: This is a phase 2/3 open label, multicenter trial testing blinatumomab 
monotherapy for the treatment of subjects with R/R aggressive B-NHL not achieving CMR after 
standard platinum-based chemotherapy regimens administered as S1.  This study incorporates 
multiple interim analyses for futility, efficacy, and unblinded sample-size re-estimation. In the 
phase 3 part of the study, blinatumomab will be compared to IC chemotherapy. 
The phase 2 component of the study will consist of up to a 28-day screening period, 
approximately 70 to 112 days of study treatment, a 30-day (± 3days) safety follow up, and 
long-term follow up that will conclude with the final analysis of the phase 3 component, estimated 
at 30 months after initiation of the phase 3 component.  In the event that phase 3 is not 
initiated, LTFU for phase 2 subjects will proceed as detailed in Section 7.2.7. 
For the phase 3 component, the study will consist of up to a 28-day screening period, a treatment 
period of up to approximately 168 days, a 30-day safety follow-up visit, and long-term follow up. 
Long-term follow up will conclude with the final analysis. 
In the phase 2 component, enrolled subjects will receive blinatumomab monotherapy.  In the 
phase 3 component, enrolled subjects will be randomized in a 1:1 ratio to blinatumomab or IC 
chemotherapy.  Randomization will be stratified according to the following criteria: 
• Response to S1 chemotherapy (PMR vs no metabolic response [NMR]/progressive 
metabolic disease [PMD]) 
• Cytarabine administered in S1 (eg, R-DHAP and R-ESHAP vs R-ICE and R-GDP) 
• Primary Mediastinal B-Cell Lymphoma (PMBCL) and B-cell lymphoma, unclassifiable, with 
features intermediate between DLBCL and classical Hodgkin lymphoma vs all other 
histologies of aggressive B-cell lymphoma 
All subjects enrolled in phase 2 and subjects in phase 3 randomized to the blinatumomab arm will 
receive a single 70-day cycle, with a total of 56 days of blinatumomab continuous infusion (7 days 
at 9 µg/day, 7 days at 28 µg/day, and 42 days at 112 µg/day), followed by a treatment-free period 
of 14 days.  Response will be assessed by central review of a PET/CT after this single cycle (ie, 
on approximately day 70).  
In phase 3, subjects randomized to the IC arm will receive no more than 3 cycles (maximum cycle 
length 28 days) of S2 chemotherapy prior to response assessment (see specific S2 requirements 
in Section 6.3).  Any change in the chemotherapy regimen prior to response assessment or 
without objective evidence of disease progression will be scored as treatment failure. 
Following the response assessment, subjects may undergo hematopoietic stem and progenitor 
cell (HSC) mobilization and autologous hematopoietic stem cell transplant or allogeneic HSCT. 
Subjects who demonstrate a response (PMR or CMR) to protocol-assigned therapy based on 
local assessment and who are not proceeding directly to autologous hematopoietic cell transplant 
or allogeneic HSCT may receive additional cycles of protocol-assigned therapy (maximum 
1 x 4-week cycle of blinatumomab given 7 days at 9 µg/day, 7 days at 28 µg/day, and 14 days at 
112 µg/day or a maximum of 3 cycles of IC S2 chemotherapy) starting at least 2 weeks, but not 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20150292 
Date:  07 May 2019 
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CONFIDENTIAL 
 
 
more than 4 weeks, after the end of Cycle 1. Non-responding subjects (NMR or PMD/ 
progressive disease [PD]) are not eligible for retreatment with blinatumomab. 
Sample Size: Approximately 332 subjects will be enrolled in the study, including 36 subjects in 
phase 2 and 296 in phase 3. Of these, approximately 184 subjects will receive blinatumomab. 
Summary of Subject Eligibility Criteria: The study will enroll subjects with aggressive B-NHL, 
including DLBCL NOS, follicular lymphoma Grade 3B, Primary Mediastinal B-Cell Lymphoma, 
T-cell rich B-cell lymphoma, or DLBCL that represents transformation of indolent NHL, (including 
follicular, marginal zone, and lymphoplasmacytoid lymphoma excluding chronic lymphocytic 
leukemia or Hodgkin Lymphoma), ≥18 years of age at the time of informed consent. Subjects 
must have a biopsy-proven diagnosis of aggressive B-cell lymphoma and have received 
appropriate therapy for aggressive B-cell lymphoma, regardless of whether there had been prior 
indolent disease.  Subjects must have refractory or relapsed disease following front line treatment 
of standard multiagent chemotherapy containing an anthracycline AND an approved 
anti-CD20 agent.  Relapsed disease (prior complete response/CMR) must have an available 
biopsy demonstrating relapse of aggressive B-cell lymphoma.  For subjects with de novo 
aggressive B-cell lymphoma and refractory disease, biopsy confirmation of persistent disease is 
preferred but persistent PET positivity is acceptable at a minimum.  Subjects must have received 
standard care platinum-based chemotherapy in S1 setting, have radiographically measurable 
disease with a clearly demarcated nodal lesion at least 1.5 cm in its largest dimension or a target 
extranodal lesion at least 1.0 cm, have an Eastern Cooperative Oncology Group (ECOG) 
performance status ≤ 2, be potentially eligible for high dose chemotherapy and autologous 
hematopoietic cell transplant per institutional standards, and have required laboratory procedures 
completed within 14 days (absolute neutrophil count ≥ 1.0 x 109/L, platelets ≥ 75 x 109/L, 
creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft Gault equation), aspartate 
aminotransferase/alanine aminotransferase/total bilirubin < 3x/3x/2x upper limit of normal [unless 
Gilbert’s disease or if liver involvement with lymphoma]). For a full list of eligibility criteria, please 
refer to Section 4.1 through Section 4.1.2.  
Investigational Product 
Amgen Investigational Product Dosage and Administration: Blinatumomab will be supplied 
as single-use sterile glass injection vials.  All subjects in phase 2 and subjects randomized to 
blinatumomab in phase 3 will receive blinatumomab by continuous intravenous (IV) infusion for 
1 cycle. The first cycle of blinatumomab is 70 days and includes 56 days of treatment, followed by 
a 14-day treatment-free interval.  The initial blinatumomab dose is 9 µg/day, and is escalated 
stepwise to 28 µg/day on day 8 and then 112 µg/day on day 15 until the completion of therapy, 
barring any dose modifications. Responding subjects (PMR or CMR) not proceeding directly to 
autologous hematopoietic cell transplant or allogeneic HSCT may receive a maximum of 
1 additional cycle of blinatumomab starting at least 2 weeks, but not more than 4 weeks, after the 
end of Cycle 1.  Optional Cycle 2 of blinatumomab is 4 weeks (28 days) in duration.  Cycle 2 dose 
escalation is 7 days at 9 µg/day, 7 days at 28 µg/day, and 14 days at 112 µg/day. 
Non-Amgen Non-investigational Product Dosage and Administration: Subjects randomized 
to the IC arm will receive no more than 3 cycles (maximum cycle length 28 days) of 
S2 chemotherapy prior to response assessment (recommended S2 chemotherapy are provided 
in Section 6.3). Subjects who demonstrate a response (PMR or CMR) to S2 chemotherapy based 
on local assessment and who are not proceeding directly to autologous hematopoietic cell 
transplant or allogeneic HSCT may receive a maximum of 3 additional cycles of IC 
S2 chemotherapy. 
Procedures: Written informed consent must be obtained from all subjects before any study 
specific screening procedures are performed. During the study, the following procedures will 
occur: medical history/current medical conditions, demographics, ECOG Performance Status, 
physical exam including neurologic examination, height, weight, vital signs, radiographic 
assessment, and bone marrow biopsy (select subjects).  Subjects will provide samples for 
coagulation, hematology with differential, blood chemistry profiles, urine sampling for pregnancy 
test, anti-blinatumomab antibodies, and immunoglobin (IgG, IgA, IgM). Subjects will further 
Approved 
 
 


Product:  Blinatumomab 
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provide samples for other specialty labs including CF CT-DNA, cytokines, lymphocyte subsets, 
PK samples, and a serum or urine pregnancy test for female subjects of childbearing potential.  
Research staff will document the use of concomitant medications and all reported adverse 
events.  After the last dose of blinatumomab or IC chemotherapy, subjects will undergo a safety 
follow-up visit and then enter long term follow-up.  For a full list of study procedures, including the 
timing of each procedure, please refer to Section 7 and the Schedule of Assessments (Table 5, 
Table 6, Table 7, Table 8, and Table 9).  
Statistical Considerations: For phase 2, the primary analysis will report the CMR rate among 
blinatumomab-treated subjects.  Phase 3 will test whether CMR/OS is superior in the group 
randomized to blinatumomab compared to the group randomized to IC.  The primary analysis 
(analysis 4) will be triggered by the date when 296 subjects have had the opportunity to complete 
at least 1 tumor assessment.  The final analysis (analysis 5) will test whether overall survival is 
superior in the group randomized to blinatumomab compared to the group randomized to IC.  The 
final analysis will be triggered by the date when the 236th death from a phase 3 subject is 
reported in the clinical trial database, or the study duration reaches 12 months from the last 
subject randomized. 
Descriptive statistics will be provided for selected demographics, safety, PK parameters, PD, and 
biomarker data by dose, dose schedule, and time as appropriate.  PK parameters will be 
estimated by non-compartmental analysis.  Descriptive statistics on continuous data will include 
means, medians, standard deviations and ranges, while categorical data will be summarized 
using frequency counts and percentages.  Graphical summaries of the data may also be 
presented. 
In phase 3, an external independent data monitoring committee (DMC) will oversee the interim 
analyses.  In addition, the DMC will assess safety approximately every 6 months provided 
enrollment is adequate. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor: Amgen Inc. 
Data Element Standards 
Version(s)/Date(s):  
Version 5.0, 20 March 2015 
 
Approved 
 
 


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CONFIDENTIAL 
 
 
Figure 1.  Phase 2 Schema 
 
CMR = complete metabolic response; HSCT = hematopoietic stem cell transplantation; PET-CT = positron emission tomography-computed tomography; PMR = partial 
metabolic response  
a. Subjects with progressive metabolic disease may be eligible after 1 cycle of S1 chemotherapy 
Primary Refractory or 1
st Relapse 
SCREENING  
S 1 
PET/
CT 
 
<CMR 
Subjects receive  
minimum of 
2 cyclesa  
platinum-based 
first salvage (S1) 
chemotherapy 
SAFETY FOLLOW UP  
LONG TERM FOLLOW UP 
ENROLMENT   
Cycle 1 Bliatumomab  
70-day cycle 
Dose step  
9 µg/day x 7 days,  
28 µg/day x 7 days, 
112 µg/day x 42 days,  
14-day rest 
HSCT  
Pre-screening 
discussions 
may be 
conducted 
prior to or 
during S1 
chemotherapy.  
Optional Cycle 2 
Blinatumomab 
28-day cycle 
Dose step  
9 µg/day x 7 days,  
28 µg/day x 7 days, 
112 µg/day x 
14 days 
Screening within 28 days 
of Cycle1 Day 1 
Optional: PMR or CMR not 
proceeding directly to HSCT 
may receive an additional 
cycle 
S 1 
PET/
CT 
 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20150292 
Date:  07 May 2019 
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Figure 2.  Phase 3 Schema 
 
CMR = complete metabolic response; PMR = partial metabolic response; HSCT = hematopoietic stem cell transplantation; IC = investigator’s choice; 
PET-CT = positron emission tomography-computed tomography; R = randomization; S2 = second salvage 
a. Subjects with progressive metabolic disease may be eligible after 1 cycle of S1 chemotherapy 
Primary Refractory or 1
st Relapse 
SCREENING  
S 1 
PET/CT 
<CMR 
Subjects receive  
a minimum of 
2 cyclesa   
first salvage (S1) 
chemotherapy 
R-platinum  
Safety Follow up 
Long-term Follow up 
ENROLMENT   
Cycle 1 
Bliatumomab  
70-day cycle 
Dose step  
9 µg/day x 7 
days,  
28 µg/day x 7 
days, 112 µg/day 
x 42 days,  
14-day rest 
Investigator 
Choice  
Salvage 2 
Up to 3 cycles  
PET/
CT 
HSCT 
R 
Pre-screening 
discussions may 
be conducted 
prior to or 
during S1 
chemotherapy 
PET/
CT 
Optional: IC S2 
chemotherapy 
Maximum of 
3 cycles 
Screening within 28 
days of Cycle 1 Day 1 
Optional: PMR or CMR not 
proceeding directly to HSCT 
may receive additional cycles 
of protocol-assigned therapy 
S 1 
Optional Cycle 2 
Blinatumomab 
28-day cycle 
Dose step  
9 µg/day x 7 days,  
28 µg/day x 7 days, 
112 µg/day x 
14 days 
 
Approved 
 
 


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Study Glossary 
Abbreviation or Term 
Definition/Explanation 
18FDG-PET 
18-fluorodeoxyglucose-positron emission tomography 
ABC 
activated B-cell 
AE 
adverse event 
ALL 
acute lymphocytic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
B-NHL 
B-cell Non-Hodgkin Lymphoma 
CBA 
cytometric bead array 
CF 
cell-free  
CT-DNA 
circulating tumor DNA 
CMR 
complete metabolic response 
CNS 
central nervous system 
COO 
cell-of-origin 
CR 
complete response 
CRF 
case report form 
CRS 
cytokine release syndrome 
CRu 
unconfirmed complete response 
CSF 
cerebro spinal fluid 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DILI 
drug induced liver injury  
DLBCL 
diffuse large B-cell lymphoma 
DMC 
data monitoring committee 
DOR 
duration of response 
EDC 
electronic data capture 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EFS 
event-free survival 
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Abbreviation or Term 
Definition/Explanation 
End of Follow-up 
defined as concluding with FA of phase 3 component, which will be 
triggered by the date when the 236th death of a phase 3 subject is 
reported in the clinical trial database, or when the study duration 
reaches 12 months from the last subject randomized, or in the 
event that the trial does not proceed to phase 3, defined as the 
date when the last phase 2 subject has had the opportunity to 
complete their 2 year follow-up after treatment. 
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject (ie, the date the subject 
withdraws full consent from the study, completes the safety follow-up 
visit or long-term follow up [whichever is later] or death). 
End of Study (primary 
completion) 
the time when the last subject enrolled in phase 2 finishes their 
2 year follow-up.   
End of Study (end of trial) the time when the last subject is assessed or receives an 
intervention for evaluation in the study; the final analysis will be 
triggered by the date when the 236th death for a phase 3 subject is 
reported in the clinical trial database, or the study duration reaches 
12 months from the last subject randomized.  In case that the 
phase 3 portion of the study is not initiated, the final analysis 
will occur when all subjects in phase 2 complete long term 
follow-up. 
End of Treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
EOI 
AEs of interest 
FAS 
full analysis set 
FSH 
follicle stimulating hormone 
GCB 
Germinal Center B-Cell 
GCP 
good clinical practice 
G-CSF 
granulocyte colony-stimulating factor 
GM-CSF 
granulocyte macrophage colony-stimulating factor  
HDT 
high dose chemotherapy 
HRT 
hormonal replacement therapy 
HSC 
hematopoietic stem cell 
HSCT 
hematopoietic stem cell transplant 
IC 
investigator’s choice 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IgA 
immunoglobin A 
IgG 
immunoglobin G 
IgM 
immunoglobin M 
INR 
international normalized ratio 
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Abbreviation or Term 
Definition/Explanation 
IP 
investigational product 
IPI 
International Prognostic Index 
IPIM 
Investigational Product Instruction Manual 
IRB/IEC 
institutional review board/independent ethics committee 
IV 
intravenous 
IVRS 
interactive voice response system, telecommunication technology 
that is linked to a central computer in real time as an interface to 
collect and process information.  
KM 
Kaplan-Meier 
LKM1 
liver kidney microsomal antibody 1 
NCCN-IPI 
National Comprehensive Cancer Network International Prognostic 
Index 
NHL 
non-Hodgkin’s lymphoma 
NMR 
no metabolic response 
NRM 
non-relapse mortality 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
P 
platinum  
PD 
progressive disease 
PET/CT 
positron emission tomography/computed tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PMBCL 
Primary Mediastinal B-cell Lymphoma 
PMD 
progressive metabolic disease 
PMR 
partial metabolic response 
PR 
partial response 
QOLCOA 
Patient-reported clinical outcome assessments quality of life 
R-IPI 
Revised International Prognostic Index 
R/R 
relapsed or refractory 
S1 
first salvage 
S2 
second salvage 
SD 
stable disease 
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Abbreviation or Term 
Definition/Explanation 
Source Data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical research. The 
information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained 
in source documents (original records or certified copies).  (ICH 
Guideline [E6]).  Examples of source data include subject 
identification, randomization identification, and stratification value. 
Study Day 1 
defined as the first day that protocol-specified investigational 
products are administered to the subject 
TBL 
total bilirubin 
TDAS 
Target Dose Analysis set 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHODRUG 
World Health Organization Drug 
Approved 
 
 


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TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Glossary ................................................................................................................ 10 
1. 
OBJECTIVES ......................................................................................................... 20 
1.1 
Primary ....................................................................................................... 20 
1.1.1 
Phase 2 ...................................................................................... 20 
1.1.2 
Phase 3 ...................................................................................... 20 
1.2 
Secondary .................................................................................................. 20 
1.2.1 
Phase 2 ...................................................................................... 20 
1.2.2 
Phase 3 ...................................................................................... 20 
1.2.3 
Phase 2 and 3 ............................................................................ 21 
1.3 
Exploratory (Phase 2 and 3) ....................................................................... 21 
2. 
BACKGROUND AND RATIONALE ........................................................................ 21 
2.1 
Disease ....................................................................................................... 21 
2.1.1 
Primary Refractory or Relapsed Disease ................................... 22 
2.1.2 
First Salvage Chemotherapy ...................................................... 22 
2.1.3 
The Importance of CR Prior to Autologous HSCT ...................... 23 
2.1.4 
Later Salvage ............................................................................. 23 
2.2 
Amgen Investigational Product Background: Blinatumomab ...................... 24 
2.3 
Rationale .................................................................................................... 26 
2.4 
Clinical Hypotheses (Phase 3) ................................................................... 26 
3. 
EXPERIMENTAL PLAN ......................................................................................... 26 
3.1 
Study Design .............................................................................................. 26 
3.2 
Number of Sites .......................................................................................... 28 
3.3 
Number of Subjects .................................................................................... 28 
3.4 
Replacement of Subjects ............................................................................ 28 
3.5 
Estimated Study Duration ........................................................................... 28 
3.5.1 
Study Duration for Subjects ........................................................ 28 
3.5.2 
End of Study ............................................................................... 29 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 29 
4.1 
Inclusion and Exclusion Criteria ................................................................. 29 
4.1.1 
Inclusion Criteria ......................................................................... 30 
4.1.2 
Exclusion Criteria ........................................................................ 31 
5. 
SUBJECT ENROLLMENT ..................................................................................... 32 
5.1 
Randomization/Treatment Assignment ...................................................... 33 
6. 
TREATMENT PROCEDURES ............................................................................... 34 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 34 
6.2 
Investigational Product: Blinatumomab ...................................................... 35 
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6.2.1 
Dosage, Administration, and Schedule ...................................... 35 
6.2.1.1 
Inpatient Dosing ....................................................... 36 
6.2.1.2 
Outpatient Dosing .................................................... 36 
6.2.1.3 
Overdose ................................................................. 37 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ...................................... 37 
6.2.2.1 
Infusion Interruption Due to 
Technical/Logistical Reasons .................................. 37 
6.2.2.2 
Infusion Interruption/Dose Modifications 
due to Adverse Events ............................................. 37 
6.2.2.3 
Permanent Discontinuation ...................................... 40 
6.3 
Non-Amgen Non-investigational Product IC Chemotherapy ...................... 41 
6.3.1 
Recommended Regimens for IC S2 Chemotherapy .................. 41 
6.3.2 
Prohibited Regimens for IC S2 Chemotherapy .......................... 42 
6.3.3 
Regimens That are Permitted but Discouraged for 
Transplant Eligible Subjects ....................................................... 42 
6.4 
Other Protocol-required Therapies ............................................................. 42 
6.5 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 43 
6.5.1 
Criteria for Withholding and/or Permanent 
Discontinuation of Amgen Investigational Product and 
Other Protocol-required Therapies due to Potential 
Hepatotoxicity ............................................................................. 43 
6.5.2 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity .............................................................. 45 
6.6 
Concomitant Therapy ................................................................................. 45 
6.7 
Medical Devices ......................................................................................... 46 
6.8 
Product Complaints .................................................................................... 46 
6.9 
Excluded Treatments, Medical Devices, and/or Procedures 
During Screening and Treatment Periods .................................................. 47 
6.10 
Contraceptive Requirements ...................................................................... 47 
6.10.1 
Female Subjects ......................................................................... 47 
6.10.2 
Male Subjects ............................................................................. 49 
6.10.3 
Unacceptable Methods of Birth Control for Female 
Subjects ..................................................................................... 49 
7. 
STUDY PROCEDURES ......................................................................................... 49 
7.1 
Schedule of Assessments .......................................................................... 50 
7.2 
General Study Procedures ......................................................................... 59 
7.2.1 
Screening, Enrollment and/or Randomization ............................ 59 
7.2.2 
Rescreening ............................................................................... 60 
7.2.3 
Treatment ................................................................................... 60 
7.2.4 
Safety Follow-up Visit(s) ............................................................. 60 
7.2.5 
Mobilization ................................................................................. 61 
7.2.6 
HSCT .......................................................................................... 61 
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7.2.7 
Long-term Follow-up ................................................................... 62 
7.2.8 
End of Study ............................................................................... 63 
7.2.9 
Early Termination Visit ................................................................ 63 
7.3 
Description of Study Procedures ................................................................ 63 
7.3.1 
Informed Consent ....................................................................... 63 
7.3.2 
Demographics ............................................................................ 64 
7.3.3 
Medical History ........................................................................... 64 
7.3.4 
Prior Therapies ........................................................................... 64 
7.3.5 
ECOG Performance Status Assessment .................................... 64 
7.3.6 
Physical Measurements ............................................................. 64 
7.3.7 
Vital Signs ................................................................................... 64 
7.3.8 
Physical Examination ................................................................. 65 
7.3.9 
Neurological Examination ........................................................... 65 
7.3.10 
Electrocardiogram ...................................................................... 65 
7.3.11 
Response Assessment ............................................................... 66 
7.3.12 
Clinical Tumor Assessment ........................................................ 66 
7.3.13 
Radiographic Assessment .......................................................... 66 
7.3.14 
Bone marrow biopsy ................................................................... 66 
7.3.15 
Concomitant Medications ........................................................... 67 
7.3.16 
Clinical Outcome Assessments for Phase 3 Subjects 
Only ............................................................................................ 67 
7.3.17 
Vital Status ................................................................................. 67 
7.4 
Laboratory Procedures ............................................................................... 67 
7.4.1 
Pharmacokinetic Samples .......................................................... 69 
7.4.2 
Cell-Free CT-DNA ...................................................................... 69 
7.4.3 
Serum Cytokines ........................................................................ 69 
7.4.4 
Lymphocyte Subsets .................................................................. 69 
7.4.5 
Antibody Testing Procedures ..................................................... 69 
7.5 
Biomarker Development ............................................................................. 70 
7.6 
Optional Pharmacogenetic Studies ............................................................ 70 
7.7 
Sample Storage and Destruction ................................................................ 70 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 72 
8.1 
Subjects’ Decision to Withdraw .................................................................. 72 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 72 
8.3 
Reasons for Removal From Treatment, or Study ....................................... 73 
8.3.1 
Reasons for Removal From Treatment ...................................... 73 
8.3.2 
Reasons for Removal From Study ............................................. 73 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 73 
9.1 
Definition of Safety Events ......................................................................... 73 
9.1.1 
Disease Related Events ............................................................. 73 
9.1.2 
Adverse Events .......................................................................... 74 
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9.1.3 
Serious Adverse Events ............................................................. 75 
9.2 
Safety Event Reporting Procedures ........................................................... 76 
9.2.1 
Reporting Procedures for Disease Related Events .................... 76 
9.2.2 
Adverse Events .......................................................................... 76 
9.2.2.1 
Reporting Procedures for Adverse Events 
That Do Not Meet Serious Criteria ........................... 76 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ...................................................................... 77 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 78 
9.2.2.4 
Serious Adverse Events That are not to be 
Reported by the Sponsors to Regulatory 
Agencies in an Expedited Manner ........................... 79 
9.2.3 
Reporting of Delayed Time to HSCT for Subjects With 
PR/PMR At Baseline .................................................................. 79 
9.3 
Pregnancy and Lactation Reporting ........................................................... 79 
10.
STATISTICAL CONSIDERATIONS ....................................................................... 80
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 80 
10.1.1 
Study Endpoints ......................................................................... 80 
10.1.1.1 
Primary Endpoint ..................................................... 80 
10.1.1.2 
Secondary Endpoint(s) ............................................ 80 
10.1.1.3 
Exploratory Endpoints .............................................. 82 
10.1.2 
Analysis Sets .............................................................................. 82 
10.1.2.1 
AutoHSCT Analysis Set ........................................... 82 
10.1.2.2 
Full Analysis Set (FAS) ............................................ 82 
10.1.2.3 
Target Dose Analysis Set (TDAS) ........................... 82 
10.1.2.4 
Responder Analysis Set ........................................... 83 
10.1.2.5 
Safety Analysis Set .................................................. 83 
10.1.3 
Covariates and Subgroups ......................................................... 83 
10.1.4 
Handling of Missing and Incomplete Data .................................. 83 
10.2 
Sample Size Considerations ...................................................................... 83 
10.2.1 
Phase 2 ...................................................................................... 83 
10.2.2 
Phase 3 ...................................................................................... 83 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees .............................................................................................. 84 
10.4 
Planned Analyses ....................................................................................... 84 
10.4.1 
Interim Analyses ......................................................................... 84 
10.4.2 
Data Monitoring Committee ........................................................ 86 
10.4.3 
Primary Analysis ......................................................................... 86 
10.4.4 
Final Analysis ............................................................................. 87 
10.5 
Planned Methods of Analysis ..................................................................... 87 
10.5.1 
General Considerations .............................................................. 87 
10.5.2 
Primary Efficacy Endpoint .......................................................... 88 
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10.5.3 
Secondary Efficacy Endpoint(s) ................................................. 88 
10.5.4 
Safety Endpoints ........................................................................ 89 
10.5.4.1 
Adverse Events ........................................................ 89 
10.5.4.2 
Laboratory Test Results ........................................... 90 
10.5.4.3 
Vital Signs ................................................................ 90 
10.5.4.4 
Electrocardiogram .................................................... 90 
10.5.4.5 
Antibody Formation .................................................. 90 
10.5.4.6 
Exposure to Investigational Product ........................ 91 
10.5.4.7 
Exposure to Concomitant Medication ...................... 91 
10.6 
Pharmacokinetic assessments ................................................................... 91 
11. 
REGULATORY OBLIGATIONS ............................................................................. 91 
11.1 
Informed Consent ....................................................................................... 91 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 92 
11.3 
Subject Confidentiality ................................................................................ 93 
11.4 
Investigator Signatory Obligations .............................................................. 93 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 94 
12.1 
Protocol Amendments and Study Termination ........................................... 94 
12.2 
Study Documentation and Archive ............................................................. 94 
12.3 
Study Monitoring and Data Collection ........................................................ 95 
12.4 
Investigator Responsibilities for Data Collection ........................................ 96 
12.5 
Language.................................................................................................... 96 
12.6 
Publication Policy ....................................................................................... 96 
12.7 
Compensation ............................................................................................ 97 
13. 
REFERENCES ....................................................................................................... 98 
14. 
APPENDICES ...................................................................................................... 101 
List of Tables 
Table 1.  Responses to First Salvage Chemotherapy ..................................................... 23 
Table 2.  Infusion Interruption/Dose Modifications of Blinatumomab due to 
Adverse Events ........................................................................................ 38 
Table 3.  Dexamethasone Predose Treatment and for Events ....................................... 43 
Table 4.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies due to Potential Hepatotoxicity ............................................... 45 
Table 5.  Schedule of Assessments for Screening (Phase 2 and Phase 3) .................... 50 
Table 6.  Schedule of Assessments for Blinatumomab Cycle 1 (Phase 2 and 
Phase 3) ................................................................................................... 51 
Table 7.  Schedule of Assessments for Blinatumomab Optional Cycle 2 
(Phase 2 and Phase 3) ............................................................................ 53 
Table 8.  Schedule of Assessments for IC Chemotherapy (Phase 3 Only) ..................... 55 
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Table 9.  Schedule of Assessments for Safety Follow-up, HSCT, and 
Long-term Follow-up ................................................................................ 57 
Table 10.  Laboratory Assessments ................................................................................ 68 
Table 11.  Disease-related Adverse Events by System Organ Class ............................. 74 
Table 12.  Timing of the Planned Phase 3 Analyses for Complete Metabolic 
Response and Overall Survival ................................................................ 85 
Table 13.  Futility Stopping Rules for Complete Metabolic Response ............................ 85 
Table 14.  Efficacy Stopping Rules for Complete Metabolic Response .......................... 86 
Table 15.  Efficacy Stopping Rules for Overall Survival .................................................. 86 
List of Figures 
Figure 1.  Phase 2 Schema ............................................................................................... 8 
Figure 2.  Phase 3 Schema ............................................................................................... 9 
List of Appendices 
Appendix A.  Additional Safety Assessment Information .............................................. 102 
Appendix B.  Sample eSerious Event Contingency Form ............................................. 104 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................. 107 
Appendix D.  Response Assessment per the Lugano Classification ............................. 109 
Appendix E.  ECOG Performance Status Scale ........................................................... 110 
Appendix F.  EQ-5D ...................................................................................................... 111 
Appendix G.  FACT-Lymphoma .................................................................................... 113 
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1. 
OBJECTIVES 
1.1 
Primary 
1.1.1 
Phase 2 
• 
To estimate the complete metabolic response (CMR) rate following blinatumomab 
monotherapy administered in the second salvage (S2) treatment of 
transplant-eligible subjects with relapsed or refractory (R/R) aggressive B-cell 
Non-Hodgkin Lymphoma (B-NHL) who have not achieved CMR1 following standard 
platinum-based first salvage (S1) chemotherapy 
1.1.2 
Phase 3 
• 
To compare the CMR rates following blinatumomab to those following investigator’s 
choice (IC) S2 chemotherapy 
1.2 
Secondary 
1.2.1 
Phase 2 
• 
To evaluate additional efficacy parameters following blinatumomab treatment, 
including: 
− 
Duration of response (DOR) 
− 
Progression-free survival (PFS) 
− 
The rate of successful hematopoietic stem cell (HSC) mobilization  
• 
To evaluate the safety of blinatumomab in the S2 setting 
1.2.2 
Phase 3 
• 
To compare the efficacy of blinatumomab to IC chemotherapy with respect to:  
− 
Overall survival (OS) 
− 
DOR 
− 
The rate of successful HSC mobilization 
− 
Ability to proceed to hematopoietic stem cell transplant (HSCT) (both autologous 
and allogeneic) rates among responding subjects (CMR) or those in sustained 
partial metabolic response (PMR) 
− 
Objective response rate (ORR; including CMR and PMR)  
− 
PFS 
• 
To compare the safety profile of blinatumomab to that of IC chemotherapy 
• 
To compare the quality of life reported by subjects treated with blinatumomab or IC 
chemotherapy 
                                                
1 Response terminology reflect the response criteria used. The Lugano Classification response 
definitions for PET-CT evaluations of FDG-avid lymphomas uses the terminology CMR, PMR, 
NMR, or PMD. Corresponding designations from earlier response criteria include CR, PR, SD, or 
PD. 
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1.2.3 
Phase 2 and 3 
• 
To characterize the pharmacokinetic (PK) parameters of blinatumomab administered 
to subjects with R/R aggressive B-NHL 
1.3 
Exploratory (Phase 2 and 3) 
• 
To characterize the pharmacodynamic effects of blinatumomab administered in 
temporal proximity to various S1 regimens  
• 
To evaluate the response rate according to disease-specific features, such as 
cell-of-origin (COO), c-myc and bcl-2 rearrangements and over expression, Revised 
International Prognostic Index (R-IPI), Secondary International Prognostic Index 
(IPI), National Comprehensive Cancer Network International Prognostic Index 
(NCCN IPI), first response, duration of first remission  
• 
To evaluate the frequency of tumor-associated mutations in cell-free (CF) circulating 
tumor (CT- DNA) among subjects at various time points during and after salvage 
treatment 
• 
To determine the incidence of anti-blinatumomab antibody formation 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
The annual incidence of Non-Hodgkin’s Lymphoma (NHL) in Europe and the United 
States is estimated to be 15 to 20 cases/100.000 (Fisher and Fisher, 2004).  Diffuse 
large B-cell lymphoma (DLBCL) is the most common subtype of NHL, accounting for 
30% to 40% of cases and 13% of all hematologic disorders.  The incidence is 
approximately 8 cases per 100 000 and rises with age; the median age at diagnosis is 
70 years (Haematological Malignancy Research Network).  Morphologically similar 
entities have historically been treated in a similar manner as DLBCL, and thus are 
collectively known as aggressive B-cell lymphomas.  DLBCL as a uniform 
diagnostic entity, makes up approximately 85% of aggressive B-cell lymphomas 
(Ziepert et al, 2010).  However, distinct patterns of gene expression are observed 
within DLBCL, with different prognostic and potentially predictive implications 
(Swerdlow et al, 2016).   
Left untreated, DLBCL is uniformly fatal.  Anthracycline-based frontline chemotherapy, 
introduced in the 1970s, resulted in the long term cure of 30% of patients 
(DeVita et al, 1975).Twenty-five years later, introduction of the human-mouse chimeric 
monoclonal anti-CD20 immunoglobin G (IgG) rituximab increased the cure rate 
significantly and is now a standard agent in frontline therapy, resulting in cure for 60% of 
patients (Sehn and Gascoyne 2015). 
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2.1.1 
Primary Refractory or Relapsed Disease 
Patients with DLBCL who do not respond to frontline therapy, or who experience 
relapse after a remission, are generally considered incurable unless able to receive high 
dose chemotherapy (HDT) plus either autologous HSCT or allogeneic HSCT 
(Robinson et al, 2016).  HSCT is preceded by a course of salvage chemotherapy.  
“Chemoresponsivess”, indicating a partial response (PR) or complete response (CR) to 
salvage chemotherapy, has been as used as 1 criterion to define HSCT eligibility, since 
early trials demonstrated the extremely poor outcomes of patients without an objective 
response to salvage chemotherapy (Philip et al, 1987).  It is not known if responsiveness 
to newer classes of therapies, such as those that are immune-based, may also be 
sufficient to permit the successful use of HDT/HSCT. 
2.1.2 
First Salvage Chemotherapy  
The most commonly used regimens in the S1 treatment of transplant-eligible patients 
contain rituximab and a platinum-based agent such as cisplatin (eg, R-DHAP, R-GDP, 
R-ESHAP) or carboplatin (eg R-ICE) (Crump et al, 2014; Martin et al, 2008; 
Witzig et al, 2008; Kewalramani et al, 2004).  Each regimen is administered over 
4-5 days every 2-4 weeks.  Two to three cycles of therapy are given before response 
assessment.  Those with PR or CR typically undergo HSC mobilization and an additional 
1-2 cycles may be given before HDT/HSCT.  Non-responders, if offered additional 
chemotherapy, typically receive an alternative regimen. 
The efficacy of salvage regimens have been compared in 2 large, multicenter 
randomized trials, CORAL (R-DHAP vs R-ICE) and NCIC Ly.12 (R-DHAP vs R-GDP) 
(Crump et al, 2014; Gisselbrecht et al, 2010).  A third trial, ORCHARRD, tested an 
alternative anti-CD20 agent, ofatumomab, versus rituximab in combination with DHAP 
(van Imhoff et al, 2014).  An overview of the results is shown in Table 1.  The different 
response and survival rates observed in these large trials may be attributed to 
heterogeneity in patient selection criteria as well as in the nature and timing of 
post-treatment assessments.  Nonetheless, these results 1) fail to demonstrate 
superiority of any specific regimen and 2) underscore the need for new agents in the 
salvage treatment of this disease. 
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Table 1.  Responses to First Salvage Chemotherapy 
Response 
to frontline 
therapy 
Regimen 
ORR 
(%) 
CR 
(%) 
EFS 
OS 
HSCT 
(%) 
Mob 
failure 
CORAL 
(Gisselbrecht et 
al. 2010) 
CR: 65% 
PR: 20% 
SD: 4% 
PD: 11% 
R-ICE 
(n = 202) 
64 
36 
3yr: 
26% 
3 yr: 
47% 
51 
10 
R-DHAP 
(n = 194 
63 
40 
3 yr: 
35% 
3 yr: 
51% 
55 
8 
NCIC LY.12 
(Crump et al. 2014) 
CR<12m 
42% 
<CR 30% 
R-GDP 
(n = 303) 
45 
14 
4yr: 
43% 
4yr: 
62% 
52.1 
12 
R-DHAP 
(n = 302) 
46 
14 
4yr: 
48% 
4 yr: 
63% 
49.3 
18 
ORCHARRD 
(van Imhoff et 
al. 2014) 
<12m 12% 
PR: 37% 
SD: 8% 
PD: 15% 
R-DHAP 
(n = 225) 
42 
22 
2yr: 
17% 
2yr: 
41% 
36 
Not 
reported 
O-DHAP 
(n = 222) 
38 
15 
2yr: 
14% 
2yr: 
46% 
33 
Not 
reported 
CR=Complete remission; PR=Partial Remission; SD=Stable Disease; PD=Progressive Disease; EFS=Event 
Free Survival; ORR=objective response rate; OS=Overall Survival; HSCT=hematopoietic stem cell 
transplantation 
2.1.3 
The Importance of CR Prior to Autologous HSCT 
Retrospective, single-institution analyses are nearly uniform in demonstrating a direct 
relationship between CMR (as defined by 18-fluorodeoxyglucose-positron emission 
tomography [18FDG-PET] scanning) prior to HSCT and superior event-free survival 
(Armand et al, 2013; Derenzini et al, 2008; Dickinson et al, 2010; Roland et al, 2011; 
Sauter et al, 2015).  Pre-transplant 18FDG-PET outperformed other well established 
prognostic factors, such as secondary age-adjusted international prognostic index for 
outcomes after autologous HSCT (Hamlin et al, 2003; Sauter et al, 2015).  Therefore, 
some centers will not mobilize patients with PMR or less after 2 cycles of chemotherapy.  
A third cycle of the same salvage regimen may be used, though the efficacy is not 
documented and many non-responders discontinue after 2 cycles (Martin et al, 2008). 
2.1.4 
Later Salvage 
Patients who do not respond to S1 may be offered alternative therapies (hereafter 
referred to as S2) and HSCT provided that there is a response to S2 and that 
performance status and organ function are relatively preserved.  There is no standard 
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S2 regimen for transplant eligible patients.  The ESMO and NCCN guidelines are 
relatively silent on appropriate S2 regimens (Zelenetz et al, 2016; Tilly et al, 2015).  ICE, 
administered after DHAP, has been reported to provide a response rate of 
52%, including 14% CR, but these responses have been observed almost exclusively in 
patients with stable disease (SD) rather than progressive disease (PD) to 
DHAP(Simpson et al, 2007).  Results of other small, single-center retrospective analyses 
support the conclusion that standard cytotoxic therapy is of limited value in patients not 
responsive to S1 chemotherapy and that novel therapies should be explored in this 
setting (Elstrom et al, 2010; Ardeshna et al, 2005;).  
A recent report from the CORAL trial has provided outcome data on the 203 subjects 
who did not undergo autologous HSCT (primarily due to treatment failure) after 
S1 chemotherapy (Van Den Neste et al, 2016).  Eighty-two percent received additional 
chemotherapy at the discretion of the treating investigator.  Of those subjects, 
13%, 15%, and 67% had CR/unconfirmed complete response (CRu), PR, or SD/PD after 
S1, with the remainder having unknown response.  Approximately 20% of those treated 
received R-DHAP-like regimens, 20% received ICE-like regimen, and 14% receiving a 
gemcitabine-based regimen.  A variety of other regimens made up the total, but each in 
fewer than 10% of subjects.  
Among subjects achieving less than CR/CRu to second line therapy (n=177), the CR/Cru 
rate to third line therapy was 22%.  The median OS  of the entire cohort (ie, including 
those that achieved CR/Cru to second line therapy) was 4.4 months.  For subjects 
achieving CR (n=55), PR (n=24), or SD/PD (n=87), OS at 1 year 77, 44, and 13%, 
respectively.  Autologous HSCT was performed in 54, 58, and 22% of subjects with CR, 
PR, and SD/PD to S2 chemotherapy.  Thirty subjects achieved CR and underwent 
HSCT; their 1 year survival was 82%.  These results confirm that the majority of patients 
who do not respond to S1 chemotherapy are unlikely to respond to additional 
conventional chemotherapy.  However, the survival experienced by responding subjects, 
particularly those in CMR, support the objective to introduce new agents in this setting. 
2.2 
Amgen Investigational Product Background: Blinatumomab 
Blinatumomab (BLINCYTO, AMG 103, formerly also known as MT103 or 
bscCD19xCD3) is a member of a novel class of bispecific antibody constructs called 
BiTE, or “bispecific T-cell engagers” (Schlereth et al, 2006; Dreier et al, 2002).  
Blinatumomab is a BiTE antibody construct with dual binding specificities.  T-cells are 
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bound by its anti-CD3 moiety, whereas B lymphoblasts and cells are bound by the 
anti_CD19 moiety.  This unique feature of blinatumomab allows it to transiently connect 
malignant cells with T-cells, thereby inducing T-cell mediated killing of the bound 
malignant cell.  In preclinical models, blinatumomab-mediated T-cell activation involves 
the transient release of inflammatory cytokines and proliferation of T-cells.  The 
subsequent serial lysis of multiple malignant cells by a single blinatumomab-activated 
T-cell closely resembles a natural cytotoxic T-cell reaction. 
CD19 is highly expressed throughout B-cell development and is present on > 90% of 
B-cell lineage cancers including DLBCL.  The efficacy of blinatumomab has been 
evaluated in subjects with B-cell precursor acute lymphocytic leukemia (ALL) and NHL, 
including DLBCL.  
Study MT103-104 evaluated the efficacy of blinatumomab in subjects with 
relapsed/refractory B-NHL.  In this phase 1 study, subjects with relapsed/refractory NHL 
where treated with a target blinatumomab dose of 60µg/m2.  In the subset of subjects 
with DLBCL (n = 11), 2 achieved a PR and 4 achieved CR/unconfirmed complete 
response (CRu) (ORR was 55%).  Neurologic events were the dose limiting toxicity, but 
were reversible in all cases upon interruption of the infusion (Goebeler et al, 2016).  As 
of the most recent analysis, 2 of the DLBCL subjects with CR/CRu had ongoing 
responses beyond 600 days.  Of the other 2 subjects, 1 subject underwent allogeneic 
HSCT and was censored, and the other relapsed around 7 months after therapy.  
A subsequent open-label phase 2 blinatumomab study (MT-103-208) in 
relapsed/refractory DLBCL included 25 subjects (23 subjects received stepwise dosing 
and 2 a flat dose of 112 µg/day).  At baseline, the median number of prior regimens was 
3 (range 1 to 7) and all subjects had received prior rituximab.  Seven (28%) had relapsed 
after prior autologous HSCT. This study demonstrated stepwise dosing with weekly dose 
escalation of blinatumomab (9/28/112 µg/day) was tolerable and associated with 
anti-tumor activity with an ORR after 1 cycle of blinatumomab of 43% for evaluable 
subjects, including CR in 19%.  The most common adverse events were tremor, pyrexia, 
and fatigue.  Grade 3 neurologic adverse events were reported in 22% of subjects (no 
grade 4 or 5) but were generally reversible with treatment interruption 
(Viardot et al, 2016). 
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The single agent clinical response seen in R/R DLBCL subjects suggests blinatumomab 
may be an effective therapy to improve the low PFS/OS that occurs in 
relapse/refractory subjects with present day therapies.  
Blinatumomab (BLINCYTO) is approved in multiple regions for the treatment of 
Philadelphia chromosome-negative R/R B-cell precursor ALL.  Additionally, confirmation 
of clinical benefit is a condition of approval in multiple countries.  
Refer to the specific section of the Investigator’s Brochure for additional information 
related to the physical, chemical, and pharmaceutical properties and formulation(s). 
2.3 
Rationale 
This study in subjects with R/R aggressive B-NHL will provide an opportunity to further 
define blinatumomab’s safety and efficacy profile in this population.  The single-agent 
activity of blinatumomab observed in heavily pre-treated subjects as described above, 
coupled with the need for new agents earlier in the course of salvage treatment, 
provides a strong rationale for testing blinatumomab in this setting. 
2.4 
Clinical Hypotheses (Phase 3) 
Administration of blinatumomab to subjects with aggressive B-NHL following suboptimal 
response to standard platinum-containing S1 chemotherapy will increase the CMR rate 
and OS. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 2/3 open label, multicenter trial testing blinatumomab monotherapy for 
the treatment of subjects with R/R aggressive B-NHL not achieving CMR after standard 
platinum-based chemotherapy regimens administered as S1.  In the phase 3 part of the 
study, blinatumomab will be compared to IC chemotherapy.  This study incorporates 
multiple interim analyses for futility, efficacy, and unblinded sample-size re-estimation, 
described further in Section 10.4.1.  The primary endpoint for both the phase 2 and 
3 components of this trial is CMR rate, determined during the first 12 weeks after 
initiation of blinatumomab or after initiationof IC chemotherapy for phase 3. 
Subjects with R/R aggressive B-NHL and considered by the investigator to be transplant 
eligible, but dependent upon the response to S2, will be enrolled after a minimum of 
2 cycles of platinum-based S1 chemotherapy or if with PMD after 1 cycle of 
platinum-based S1 chemotherapy.  In order to be eligible, subjects must undergo a 
restaging positron emission tomography/computed tomography (PET/CT) that is 
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interpreted centrally as demonstrating less than CMR.  To optimize subject recruitment 
and retention, pre-screening discussions may be conducted with potential subjects prior 
to the initiation of S1 chemotherapy.  However, enrollment may not occur until the 
PET/CT results are centrally reviewed and interpreted. 
Subjects who experience clinical evidence of progression following at least 1 cycle of 
platinum-based S1 chemotherapy may be eligible but will require pre-S1 imaging and 
post-S1 PET/CT scan to confirm progression and to establish a new baseline for 
subsequent response assessment.  
In the phase 2 component, enrolled subjects will receive blinatumomab monotherapy.  In 
the phase 3 component, enrolled subjects will be randomized in a 1:1 ratio to 
blinatumomab or IC chemotherapy.  Randomization will be stratified according to the 
following criteria: 
Response to S1 chemotherapy (PMR vs no metabolic response [NMR]/ progressive 
metabolic disease [PMD]) 
Cytarabine administered in S1 (eg, R-DHAP and R-ESHAP vs R-ICE and R-GDP) 
Primary Mediastinal B-Cell Lymphoma (PMBCL) and B-cell lymphoma, unclassifiable, 
with features intermediate between DLBCL and classical Hodgkin lymphoma vs all other 
histologies of aggressive B-cell lymphoma 
Subjects in the phase 2 and subjects randomized to blinatumomab in phase 3 will 
receive a single 70-day cycle, with a total of 56 days of blinatumomab continuous 
infusion of 7 days at 9 µg/day, 7 days at 28 µg/day, and 42 days at 112 µg/days, 
followed by a treatment-free period of 14 days.  Response will be assessed by central 
review of a PET/CT within 12 weeks of initiation of blinatumomab.  
In phase 3, subjects randomized to the IC arm will receive no more than 3 cycles 
(maximum cycle length 28 days) of S2 chemotherapy prior to response assessment.  
For phase 3, investigator choice of S2 chemotherapy regimens will be designated as the 
control arm of the study.  S2 chemotherapy requirements are provided in Section 6.3.1.  
Any change in the chemotherapy regimen prior to or without objective evidence of 
disease progression will be scored as treatment failure. 
In both phase 2 and 3, following response assessment, subjects may undergo HSC 
mobilization and autologous HSCT or allogeneic HSCT.  Subjects who demonstrate a 
response (PMR or CMR) to protocol-assigned therapy based on local assessment and 
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who are not proceeding directly to autologous HSCT or allogeneic HSCT may receive 
additional cycles of protocol-assigned therapy (maximum 1 x 4-week cycle of 
blinatumomab or a maximum of 3 cycles of IC S2 chemotherapy).  Optional 
Cycle 2 blinatumomab dosing must start at least 2 weeks, but not more than 4 weeks, 
after the end of the previous cycle.  Optional Cycle 2 blinatumomab consists of a 28 day 
cycle of blinatumomab continuous infusion administered 7 days at 9 µg/day, 7 days at 28 
µg/day, and 14 days at 112 µg/day. 
Non-responding subjects (NMR or PMD/PD) are not eligible for retreatment with 
blinatumomab. 
All subjects will have a safety follow-up no later than 30 (± 3) days after the last dose of 
blinatumomab or 30 days (±3 days) after the last dose of IC chemotherapy 
(see Section 7.2.4). 
The overall study design is described by a study schema in Figure 1 and Figure 2, and 
the study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
The study will be conducted at approximately 145 sites globally.  During the conduct of 
the study additional countries, regions or sites may be added if necessary. 
Sites that do not enroll subjects within 6 months of site initiation may be closed.  
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”.  
Approximately 332 subjects will participate in this study, and approximately 184 subjects 
will receive blinatumomab.  Refer to Section 10.2 for sample size considerations. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
Phase 2: The estimated maximum duration of the study for subjects component is 
approximately 30 months.  This includes a 28-day screening period, approximately 70 to 
112 days of study treatment, a 30-day safety follow up, and long-term follow up 
approximately 2 years from safety follow up.  
Phase 3: The estimated maximum duration of the study for an individual subject is 
approximately 33 months.  This includes a 28-day screening period, a treatment period 
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of up to approximately 168 days, a 30-day safety follow-up visit, and long-term follow up.  
Long-term follow up will conclude with the final analysis. 
3.5.2 
End of Study 
Primary Completion: the time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis; the 
primary analysis will be triggered when 296 subjects in phase 3 have had the opportunity 
to complete at least 1 tumor response assessment.End of Trial: triggered by the date 
when the 236th death of a phase 3 subject is reported in the clinical trial database, or the 
study duration reaches 12 months from the last subject randomized. 
This study is event-driven and will conclude when approximately 236 death events in 
phase 3 have occurred.It is anticipated that the enrollment period will be approximately 
33 months, and the study duration will be approximately 52 months from the date that 
the first subject is enrolled, randomized (approximately 12 months from the completion 
of randomization in phase 3). 
At the end of phase 2, when all phase 2 subjects have had an opportunity to have 
a tumor assessment by week 12, a data analysis will be done to facilitate the 
decision whether to proceed to phase 3.  If the study will not continue for the 
phase 3 portion, the study will conclude when phase 2 subjects have had an 
opportunity to complete long term follow-up. 
If the study only includes the phase 2 portion, the enrollment period is 
approximately 12 months, and the study duration will be approximately 24 months 
from the date the last subject completes treatment. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an Interactive Voice Response 
System (IVRS). 
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1) 
4.1 
Inclusion and Exclusion Criteria 
Eligibility criteria listed below will be evaluated during screening. 
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4.1.1 
Inclusion Criteria 
101 Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures OR subject’s legally acceptable representative has provided 
informed consent prior to any study-specific activities/procedures being initiated 
when the subject has any kind of condition that, in the opinion of the investigator, 
may compromise the ability of the subject to give written informed consent.  
102 Age ≥ 18 at the time of informed consent 
103 Biopsy proven aggressive B-NHL, including DLBCL NOS, follicular lymphoma 
Grade 3B, PMBCL, T-cell rich B-cell lymphoma, or DLBCL that represents 
transformation of indolent NHL, (including follicular, marginal zone, and 
lymphoplasmacytoid lymphoma excluding chronic lymphocytic leukemia or 
Hodgkin Lymphoma). Subjects with prior indolent lymphoma must have received 
therapy after a diagnosis of transformation that is appropriate for aggressive 
histology as described in 104. The following histologies are not eligible: 
• 
Lymphoblastic lymphoma 
• 
Burkitt lymphoma 
• 
Mantle cell lymphoma 
Any histologies not specifically mentioned must be discussed with the medical 
monitor. For subjects enrolled in the phase 3 portion of study, pathologic samples 
will be submitted for central confirmation of disease histology. 
104 Refractory (no prior CR/CMR) or relapsed (prior CMR) following front line 
treatment of standard multiagent chemotherapy containing an anthracycline AND 
an approved anti-CD20 agent. Examples of appropriate therapy include but are 
not limited to R-CHOP (14 or 21), R-CHOEP, and DA-R-EOCH. For subjects with 
refractory disease and who have received radiotherapy, PET positivity should be 
demonstrated no less than 6 weeks after the last dose of radiotherapy 
105 Biopsy-proven confirmation of relapsed disease. For subjects with de novo 
aggressive B-cell lymphoma and primary refractory disease (ie, never achieving 
CR/CMR), biopsy of persistent disease is preferred but persistent PET positivity 
(ie, Deauville ≥4) is acceptable at a minimum. For subjects with transformed 
disease that has been characterized as refractory, biopsy (core or excisional 
biopsy) with demonstration of persistent aggressive B-NHL is required 
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106 Received a minimum of 2 cycles of standard of care platinum-based 
chemotherapy in the S1 setting and had a response of PMD, NMR, PMR as 
centrally assessed by PET/CT scan or received at least 1 cycle of 
S1 chemotherapy and had evidence of PMD as centrally assessed. A 
pre-salvage scan is required to be submitted to the central reader if a subject had 
only 1 cycle of pre-salvage chemotherapy.  
107 Radiographically measurable disease with a clearly demarcated nodal lesion at 
least 1.5 cm in its largest dimension or a target extranodal lesion at least 1.0 cm 
in its largest dimension 
108 Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 
109 Intention to proceed to HDT and autologous HSCT per institutional standards 
110 Laboratory parameters (completed within 14 days prior to enrollment and after the 
last cycle of S1 chemotherapy): 
Hematology: 
• 
Absolute neutrophil count (ANC) ≥ 1.0 x 109/L 
• 
Platelets ≥ 75 x 109/L 
Chemistry: 
• 
Creatinine clearance ≥ 50 mL/min (calculated using Cockcroft Gault equation) 
• 
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) 
< 3X upper limit of normal (ULN) 
• 
Total bilirubin (TBL) < 2x ULN (unless Gilbert’s disease or if liver involvement 
with lymphoma) 
4.1.2 
Exclusion Criteria 
201 CMR following S1 chemotherapy 
202 Treatment within 30 days prior to randomization with another investigational device 
or drug study (ies). Other investigational procedures while participating in this 
study are excluded 
203 Prior anti-CD19-directed therapies 
204 Prior HDT with autologous HSCT 
205 Prior allogeneic HSCT 
206 Presence of clinically relevant central nervous system (CNS) pathology such as 
epilepsy, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson’s 
disease, cerebellar disease, organic brain syndrome, or psychosis 
207 Evidence of CNS involvement by NHL 
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208 Known infection with human immunodeficiency virus or chronic infection with 
hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus 
(anti-hepatitis C virus positive) 
209 History of malignancy other than B-NHL within the past 3 years with the exception 
of: 
• 
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 maligna 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 noninvasive carcinoma or carcinoma in 
situ 
210 Subject has known sensitivity to immunoglobulins or any of the products or 
components to be administered during dosing. 
211 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 and investigator’s knowledge. 
212 History or 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. 
213 Female subjects who are pregnant or breastfeeding or planning to become 
pregnant or breastfeed while receiving blinatumomab and for an additional 
48 hours after the last dose of blinatumomab. (Females of child bearing potential 
should only be included after a confirmed menstrual period and a negative highly 
sensitive urine or serum pregnancy test.) 
214 Female subjects of childbearing potential unwilling to use an effective method of 
contraception while receiving blinatumomab and for an additional 48 hours after 
the last dose of blinatumomab. 
Note: The pregnancy, breastfeeding and contraceptive requirements are specific 
for blinatumomab. The investigator is responsible for providing the subject (male 
and female) with pregnancy and breastfeeding (female only) avoidance 
requirements for other medications given during the study. 
5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.2). 
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The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB/IEC- and Amgen-approved ICF before the commencement of study-specific 
procedures. Upon completion of the screening period the subject is evaluated by the 
investigator and providing the subject continues to meet the inclusion/exclusion criteria, 
the subject is subsequently eligible to be enrolled in the study and either randomized or 
assigned to a treatment regimen. 
For Phase 2, a subject will be considered enrolled into the study when the investigator 
decides that the subject has met all eligibility criteria and registers enrollment via IVRS.  
In Phase 3, a subject will be considered enrolled and randomized into the study when 
the investigator decides that the subject has met all eligibility criteria and a 
randomization number is provided via IVRS.  
Enrollment will occur after the centralized response assessment to S1 chemotherapy.  
Subjects with CMR (Deauville ≤ 3) will not be enrolled.  The investigator is to document 
this decision and date, in the subject’s medical record and in/on the enrollment case 
report form (CRF). 
Each subject who enters into the screening period (defined as the date when the subject 
signs the IRB/IEC-approved main study ICF) for the study receives a unique subject 
identification number before any study-related activities/procedures are performed.  The 
subject identification number will be assigned by IVRS.  This number will be used to 
identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject.  
Subjects who fail screening will be allowed to re-screen once. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the Phase 3 part of this study. 
5.1 
Randomization/Treatment Assignment 
Subjects enrolled during the phase 2 component will be treated with blinatumomab 
monotherapy.  An authorized site representative will make the enrollment call to the 
IVRS.  A phase 2 subject will be considered enrolled into the study when the investigator 
confirms that the subject has met all eligibility criteria and an enrollment call has been 
made into IVRS.  The enrollment date is to be documented in the subject’s medical 
record and on the enrollment electronic case report form (eCRF).  
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Subjects enrolled during the phase 3 component will be randomized to blinatumomab or 
IC chemotherapy in a 1:1 ratio as assigned by the IVRS in an open-label manner.  The 
randomization will be performed by IVRS.  To randomize a subject, an authorized site 
representative will make the randomization call to the IVRS to assign a randomization 
number to the subject.  The randomization call to the IVRS is accomplished by entering 
the pertinent information detailed in the IVRS user manual.  The following information 
will be entered into IVRS for stratification: 
• 
Response to S1 (PMR vs NMR/PMD) 
• 
S1 chemotherapy (ie, Cytarabine [Ara-C] administered in S1 Yes/No) 
• 
PMBCL and B-cell lymphoma, unclassifiable, with features intermediate between 
DLBCL and classical Hodgkin lymphoma vs all other histologies of aggressive 
B-cell lymphoma 
Once data have been entered into the IVRS a confirmation fax or email will be sent to 
the site to verify that the correct information has been entered.  The site representative 
will receive a single, unique randomization number for each phase 3 subject and the 
randomization treatment assigned.  A phase 3 subject will be considered enrolled and 
randomized into the study when the investigator confirms that the subject has met all 
eligibility criteria and a randomization number is assigned.  The randomization date and 
randomization number are to be documented in the subject’s medical record and on the 
enrollment eCRF.  
Subjects should initiate their IVRS-assigned protocol required therapy within 3 days of 
enrollment confirmation for phase 2 and phase 3. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s) and/or Medical Device(s) 
The Amgen Investigational Product (IP) used in this study is blinatumomab, and 
non-Amgen non-IP is IC chemotherapy. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of blinatumomab. 
Other protocol-mandated medication (eg, dexamethasone used for pre-dose treatment 
or for treatment of adverse events) are commercially available and are not provided or 
reimbursed by Amgen (except if required by local regulation).  The investigator will be 
responsible for obtaining supplies of these protocol-specified therapies. 
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6.2 
Investigational Product: Blinatumomab 
Blinatumomab will be manufactured and packaged by Amgen and distributed using 
Amgen clinical study drug distribution procedures. 
Blinatumomab will be supplied as single-use glass injection vials as a sterile, 
preservative-free, white to off-white, lyophilized powder for reconstitution and 
administration by intravenous (IV) infusion.  Each vial contains blinatumomab with 
additional excipients and buffers including citric acid monohydrate, trehalose dihydrate, 
lysine hydrochloride and polysorbate 80, pH 7. 
To prepare blinatumomab for IV infusion, the lyophilized powder is reconstituted with 
sterile water for injection.  The reconstituted solution is added to an infusion bag 
containing 0.9% NaCl and a product-specific stabilizer (IV Solution Stabilizer).  The 
IV solution stabilizer functions to prevent adsorption of blinatumomab to surfaces of the 
infusion components.  The IV Solution Stabilizer is supplied in a single-use glass 
injection vials as a sterile, preservative-free, clear, colorless-to-slightly-yellow liquid 
concentrate. 
Sterile water for injection and supplies required for reconstitution and injection of 
blinatumomab will not be provided to clinical sites. 
For information surrounding the use of a continuous infusion pump, refer to Section 6.7. 
6.2.1 
Dosage, Administration, and Schedule 
Blinatumomab will be administered by continuous IV infusion. 
A cycle of blinatumomab is 70 days and includes treatment 56 days of treatment, 
followed by a 14-day treatment-free interval.  The initial blinatumomab dose is 9 µg/day, 
and is escalated stepwise to 28 µg/day on day 8 and then 112 µg /day on day 15 until 
the completion of therapy, barring any dose modifications.  Optional Cycle 
2 blinatumomab consists of a 28 day cycle of blinatumomab continuous infusion 
administered 7 days at 9 µg/day, 7 days at 28 µg/day, and 14 days at 112 µg/day.  The 
dosing schedule is described in the study schema in Figure 1 for phase 2 and Figure 2 
for phase 3. 
The dose, start and stop date/time, and lot number of the protocol-specified therapy are 
to be recorded on each subject’s eCRF.  
Response should be assessed 14 (+ 3) days after completion of blinatumomab infusion. 
Chemotherapy should not be administered within the 14-day treatment-free interval 
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unless clinical evidence of disease progression has occurred and therapy is indicated. 
Uniform adherence to that timeline is optimal for interpretation of results.  Subjects 
receiving additional chemotherapy prior to the response assessment will be scored as 
nonresponders.   
6.2.1.1 
Inpatient Dosing 
Subjects should be monitored in a hospital for a minimum of 72 hours following initiation 
of therapy and for a minimum of 48 hours at each step-dose increase because of the 
potential adverse events associated with T-cell redistribution and potential cytokine 
release effects triggered by the administration of blinatumomab.  Nurses/physicians 
trained in emergency medicine should be available for immediate intervention in case of 
complications.  See Section 6.2.2.1 regarding monitoring following dose interruptions. 
6.2.1.2 
Outpatient Dosing  
After a subject meets the minimum criteria for inpatient administration and monitoring as 
described in Section 6.2.1.1, and if a subject is deemed stable by the investigator, 
continuation of blinatumomab infusion may continue as an outpatient.  See 
Section 6.2.2.1 regarding monitoring following dose interruptions. 
In the outpatient setting, either the subject will return to the study center for changes of 
infusion bags or the subject will be visited by a well-trained ambulant/home care service 
provider at specific intervals to change the infusion bag.  The subject and the 
ambulant/home care provider will be trained and will receive written instructions for 
storage of the IV bags.  
For the ambulant/home care provider, study-specific requirements and recording of 
source documentation must be completed before any study-related tasks are started.  A 
comprehensive list of all home care services, including but not limited to the storage, 
handling, and administration of blinatumomab as well as mandatory procedural and data 
collection requirements will be separately provided in a home health care manual.  
Following each visit, this information will be documented on the ambulant/home care 
services visit worksheet and forwarded to the investigator.  
In case of any adverse event in the outpatient setting, the ambulant/home care provider 
should directly contact the investigator at the study center for further management.  Any 
unexpected or unusual events as well as any deviations will be communicated promptly 
to the investigator.  The ambulant/home care professionals provide 24 hour emergency 
on-call service. 
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In addition, the subject will visit the study center for the examinations according to the 
Schedule of Assessments (Table 5 to Table 9). 
6.2.1.3 
Overdose 
The effects of overdose of this product are not known.  The daily blinatumomab dose 
may be up to 10% lower or higher in order to account for possible pump inaccuracies.  A 
dose of up to 10% higher than the intended dose may not require specific intervention.  
In case of overdose or medication error, the infusion should be immediately stopped.  
Consultation with the Amgen medical monitor is strongly recommended for prompt 
reporting of clinically apparent or laboratory adverse events possibly related to 
overdosage.  Consultation with the Amgen medical monitor is also strongly 
recommended even if there are no adverse events, in order to discuss the minimal 
duration of dose interruption.  If the overdose results in clinically apparent or 
symptomatic adverse events or additional adverse events, the subject should be 
followed carefully until all signs of toxicity are resolved and the adverse event/s should 
be recorded/reported per Section 9.  Resumption of blinatumomab should adhere to the 
guidelines in Section 6.2.2. 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
6.2.2.1 
Infusion Interruption Due to Technical/Logistical Reasons 
The administration of blinatumomab should not be interrupted, if possible.  In case of 
infusion interruption due to any technical or logistic reason, the interruption should be as 
short as possible and the infusion continued at the earliest time possible.  Every 
interruption longer than 1 hour should be documented.  
If the interruption is longer than 4 hours, re-start of the infusion should be performed in 
the hospital under the supervision of the investigator.  Administration of dexamethasone 
premedication prior to resumption of blinatumomab infusion after a treatment interruption 
of more than 4 hours is described in Section 6.4. 
The reason for dose change of blinatumomab is to be recorded on each subject’s eCRF. 
6.2.2.2 
Infusion Interruption/Dose Modifications due to Adverse Events 
Infusion interruptions and dose modifications of blinatumomab due to adverse events 
are detailed in Table 2.  Infusions will be resumed according to instructions in Table 2 in 
order to complete the full treatment cycle, excluding the duration of treatment 
interruption (56 days blinatumomab in cycle 1, 28 days blinatumomab in optional 
cycle 2). 
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Table 2.  Infusion Interruption/Dose Modifications of Blinatumomab due to 
Adverse Events 
Toxicity 
Grade 
Instructions for Treatment Interruption and Restart 
Cytokine Release 
Syndrome 
3 
• 
Interrupt blinatumomab until the event improves to grade 
≤ 1 and administer corticosteroids (refer to Table 3) 
• 
Restart no less than 72 hours after the initial observation 
of the grade 3 event at the following dose levels: 
o If event occurred at 112 μg/day, resume at 28 μg/day 
o If event occurred at 9 or 28 μg/day, resume at 9 μg/day 
• 
Escalate up 1 dose level after 7 days if toxicity does not 
reoccur. Increase dose stepwise at 7-day intervals to 
target dose of 112 μg/day if toxicity does not reoccur. 
• 
Permanently discontinue if: 
o Initial grade 3 CRS does not improve to grade 
≤ 1 within 7 days, OR 
o Grade 3 CRS reoccurs at the lower dose level within 7 
days of reinitiation OR 
o Grade 3 CRS reoccurs at a dose of 9 μg/day without 
prior step-dose escalation 
4 
• 
Permanently discontinue blinatumomab 
Neurologic Events 
3 
• 
Interrupt blinatumomab until the event improves to grade 
≤ 1 and administer corticosteroids (refer to Table 3) 
• 
Restart no less than 72 hours after the initial observation 
of the grade 3 event at the following dose levels: 
o If event occurred at 112 μg/day, resume at 28 μg/day 
o If event occurred at 28 μg/day, resume at 9 μg/day 
• 
Escalate up 1 dose level after 7 days if toxicity does not 
reoccur. Increase dose stepwise at 7-day intervals to 
target dose of 112 μg/day if toxicity does not reoccur. 
• 
Permanently discontinue if: 
o Initial grade 3 neurologic event occurred at 9 μg/day, 
o Initial grade 3 neurologic event does not improve to 
grade ≤ 1 within 7 days, OR 
o Grade 3 neurologic event reoccurs at the lower dose 
level within 7 days of re-initiation 
4 
• 
Permanently discontinue blinatumomab 
Page 1 of 3 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
CRS=cytokine release syndrome; INR=international normalized ratio; MRI=magnetic resonance imaging; 
RUQ=right upper quandrant; TBL=total bilirubin; ULN=upper limit of normal 
* Obtain brain MRI and perform cerebro spinal fluid (CSF) analysis, if there are no contraindications 
Approved 
 
 


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Table 2.  Infusion Interruption/Dose Modifications of Blinatumomab due to 
Adverse Events 
Toxicity 
Grade 
Instructions for Treatment Interruption and Restart 
Seizure* 
 
• 
Interrupt blinatumomab, administer corticosteroids (refer 
to Table 3) and antiseizure medication per local practice 
• 
For restart, refer to grade 3 neurologic events above for 
dose level rules for re-instituting infusion 
• 
Do not re-initiate blinatumomab until 7 days after the last 
seizure and after therapeutic levels of antiseizure 
medication are likely to have been achieved 
• 
Permanently discontinue if a second seizure occurs with 
re-initiation of blinatumomab at any dose 
Elevated liver 
enzymes 
 
• 
Interrupt blinatumomab (refer to Table 4) if any one of the 
following occurs: 
o TBL > 3x ULN at any time 
o ALP > 8x ULN at any time 
o AST or ALT > 8x ULN at any time 
o AST or ALT > 5x ULN but < 8x ULN for ≥ 2 weeks 
o AST or ALT > 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (eg, RUQ abdominal 
pain/tenderness, fever, nausea, vomiting, jaundice) 
• 
Permanently discontinue blinatumomab if: 
o TBL > 2x ULN OR INR >1.5 (for subjects not on 
anticoagulant therapy) 
AND 
o AST or ALT > 3x ULN (when baseline was <ULN)  
AND 
o no other cause for the combination of the above 
laboratory abnormalities is immediately apparent 
Refer to Section 6.5 for additional details 
Page 2 of 3 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
CRS=cytokine release syndrome; INR=international normalized ratio; MRI=magnetic resonance imaging; 
RUQ=right upper quandrant; TBL=total bilirubin; ULN=upper limit of normal 
* Obtain brain MRI and perform cerebro spinal fluid (CSF) analysis, if there are no contraindications 
Approved 
 
 


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Table 2.  Infusion Interruption/Dose Modifications of Blinatumomab due to 
Adverse Events 
Toxicity 
Grade 
Instructions for Treatment Interruption and Restart 
Other clinically 
relevant adverse 
events 
3 
• 
Interrupt blinatumomab until event improves to grade ≤ 1 
(refer to Table 2) 
• 
Restart no less than 72 hours after the initial observation 
of the grade 3 event at the following dose levels: 
o If event occurred at 112 μg/day, resume at 28 μg/day 
o If event occurred at 9 or 28 μg/day, resume at 9 μg/day 
• 
Escalate up 1 dose level after 7 days if toxicity does not 
reoccur. Increase dose stepwise at 7-day intervals to 
target dose of 112 μg/day if toxicity does not reoccur. 
• 
Permanently discontinue blinatumomab if: 
o Initial grade 3 event does not improve to grade 
≤ 1 within 14 days, OR 
o Grade 3 event reoccurs at the lower dose level within 
7 days of re-initiation, OR 
• 
Grade 3 event reoccurs at a dose of 9 μg/day without 
prior step-dose escalation 
 
4 
• 
Permanently discontinue blinatumomab 
Page 3 of 3 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
CRS=cytokine release syndrome; INR=international normalized ratio; MRI=magnetic resonance imaging; 
RUQ=right upper quandrant; TBL=total bilirubin; ULN=upper limit of normal 
* Obtain brain MRI and perform cerebro spinal fluid (CSF) analysis, if there are no contraindications 
6.2.2.3 
Permanent Discontinuation 
Blinatumomab will be permanently discontinued for: 
• 
Cytokine Release Syndrome  
o Initial grade 3 cytokine release syndrome (CRS) that does not improve to grade ≤1 
within 7 days  
o Grade 3 CRS that reoccurs at the lower dose level within 7 days of reinitiation 
o Reoccurs at a dose of 9 μg/day 
o Grade 4 CRS. 
• 
Neurologic Event 
o Initial grade 3 neurologic event occurred at 9 μg/day  
o Initial grade 3 neurologic event does not improve to grade ≤ 1 within 7 days 
o Grade 3 neurologic event reoccurs at the lower dose level within 7 days of 
reinitiation  
o Reoccurs at a dose of 9 μg/day 
o Grade 4 neurologic event 
o A second seizure that occurs after reinitiation of blinatumomab. 
Approved 
 
 


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• 
Elevated liver enzymes 
o TBL > 2x ULN OR INR >1.5 (for subjects not on anticoagulant therapy) 
AND 
o AST/ALT > 3x ULN (when baseline was <ULN) 
AND 
o no other cause for the combination of the above laboratory abnormalities is 
immediately apparent 
• 
Other clinically relevant adverse events 
o Initial grade 3 event does not improve to grade ≤ 1 within 14 days (with the 
exception of delay in restart due to logistical difficulties, in which case the restart 
may be postponed for an additional 7 days).  
o Grade 3 event reoccurs at the lower dose level within 7 days of reinitiation 
o Reoccurs at a dose of 9 μg/day 
Subjects who discontinue blinatumomab for protocol defined reasons may be offered 
alternative standard of care chemotherapy at the discretion of the treating physician. 
Subjects shall be followed for survival endpoints.  
Subjects who permanently discontinue study medication due to adverse event should 
continue with other study procedures, including response assessment, as appropriate. 
6.3 
Non-Amgen Non-investigational Product IC Chemotherapy 
Non-Amgen non-IP IC chemotherapy will also be used in this study. 
Subjects randomized to the IC arm will receive no more than 3 cycles (maximum cycle 
length 28 days) of S2 chemotherapy prior to response assessment. Assessment of 
response shall be completed no later than at the end of the third cycle of chemotherapy.  
6.3.1 
Recommended Regimens for IC S2 Chemotherapy  
• R-ICE (Gisselbrecht et al. 2010; Kewalramani et al. 2004; Moskowitz et al. 1999) 
• R-DHAP (Gisselbrecht et al. 2010; Mey et al. 2006; Velasquez et al. 1988) 
• R-GDP (Crump et al. 2004; Crump et al. 2014) 
• R-ESHAP (Martin et al. 2008; Velasquez et al. 1994) 
• R-EPOCH (Gutierrez et al. 2000)  
Regimens not listed are permitted with the exception of those with any of the 
characteristics described in Section 6.3.2. 
Dose adjustment, cycle delays, and supportive care for IC chemotherapy are per 
institutional standards. The reason for dose change of IC chemotherapy is to be 
Approved 
 
 


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recorded on each subject’s eCRF.  Regimen, planned doses, intended cycle length, 
reason for dose reduction, and reason for cycle delays will be recorded. 
The dose, start date/time, stop date/time, frequency of IC chemotherapy, dose reduction, 
dose interruption, and cycle delay are to be recorded on each subjects eCRF.   
6.3.2 
Prohibited Regimens for IC S2 Chemotherapy 
• 
Radioimmunoconjugates such as (but not limited to) 90Y ibritumomab tiuxetan and 
131I tositumomab are prohibited. 
• 
Regimens with planned cycle durations of greater than 28 days are prohibited.  
• 
Regimens that include “maintenance” treatment that extends beyond the cycle 
duration are prohibited. 
• 
Regimens that include alternating cycles of non-identical chemotherapies are 
prohibited. 
6.3.3 
Regimens That are Permitted but Discouraged for Transplant 
Eligible Subjects 
Regimens that include fludarabine or melphalan (eg, mini-BEAM) are strongly 
discouraged due to the adverse impact on HSC mobilization. 
6.4 
Other Protocol-required Therapies 
All other protocol-required therapies, including dexamethasone, that are commercially 
available are not provided or reimbursed by Amgen (except if required by local 
regulation).  The investigator will be responsible for obtaining supplies of these 
protocol-required therapies.  Additional details regarding these protocol-required 
therapies are provided in the IPIM. 
Dexamethasone Premedication 
Premedication with dexamethasone is required before each blinatumomab treatment 
cycle for the prevention prophylaxis of CRS.  Dexamethasone premedication prior to 
resumption of blinatumomab infusion after a treatment interruption of < 4 hours is 
described in Table 3. 
Approved 
 
 


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Table 3.  Dexamethasone Predose Treatment and for Events 
Treatment Phase 
Target Subjects 
Dexamethasone Dose 
Predose 
dexamethasone prior 
to each blinatumomab 
treatment cycle and 
before each dose step 
increase 
All subjects  
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). 
Infusion 
interruption/dose 
modification due to 
adverse event or 
interruption due to 
technical/logistical 
event 
Subjects who interrupt treatment 
> 4 hours 
Dexamethasone 20 mg IV: within 
1 hour prior to re-start of 
treatment 
In case of signs of 
cytokine release 
syndrome 
Subjects with signs of cytokine 
release syndrome 
Dexamethasone orally or IV at a 
dose maximum of 3 doses of 
8 mg (24 mg/day) for up to 
3 days. The dose should then be 
reduced step-wise over 4 days. 
Infusion 
Interruption/Dose 
Modification Due to 
Neurologic Events 
Subjects with neurologic eventa 
Dexamethasone should be 
administered at a dose of at least 
24 mg/day for up to 3 days. 
Dexamethasone will then be 
reduced step-wise over 4 days. 
IV = intravenous 
a As outlined in Section 6.2.2.2. 
6.5 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
ALT, TBL) and/or international normalized ratio [INR] and/or signs/symptoms of hepatitis 
(as described below) may meet the criteria for withholding or permanent discontinuation 
of Amgen IP or other protocol-required therapies as specified in the Guidance for 
Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009). 
6.5.1 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies due 
to Potential Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified. 
Approved 
 
 


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Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
• 
Hepatobiliary tract disease 
• 
Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, Herpes 
Simplex Virus, Varicella, toxoplasmosis, and Parvovirus) 
• 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia. 
• 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
• 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
• 
Alpha-one antitrypsin deficiency 
• 
Alcoholic hepatitis 
• 
Autoimmune hepatitis 
• 
Wilson’s disease and hemochromatosis 
• 
Nonalcoholic Fatty Liver Disease including Steatohepatitis 
• 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
• 
Cytokine storm 
If IP is withheld, the subject is to be followed according to recommendations in 
Appendix A for possible drug induced liver injury (DILI).  
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (Section 6.5.2). 
Approved 
 
 


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Table 4.  Conditions for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies due to Potential 
Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x upper limit of normal (ULN) at 
any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5 (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
 
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring 
schedule 
 
> 3x ULN with clinical signs or 
symptoms that are consistent with 
hepatitis (such as right upper 
quadrant pain/tenderness, fever, 
nausea, vomiting, jaundice). 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
 
> 3x ULN (when baseline was 
< ULN) 
 
OR 
 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin. 
6.5.2 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then Amgen IP and other protocol-required 
therapies, as appropriate should be permanently discontinued.  Subjects who clearly 
meet the criteria for permanent discontinuation (as described in Table 4) should never 
be rechallenged with blinatumomab. 
6.6 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.9.  
Approved 
 
 


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All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community 
standards of medical care.  
All concomitant medication will be recorded on the eCRF including all prescription, 
over-the-counter, herbal supplements, and IV medications and fluids.  
Concomitant therapies are to be collected from signing of the consent form through the 
safety follow-up period.  Following the safety follow-up period, only medications taken for 
the treatment of NHL, including agents used for transplant conditioning, will be collected.  
Following the safety follow-up period, radiation administered will also be captured on a 
designated eCRF.  
The following should be recorded: medication name, indication, dose, route, frequency, 
start date, and stop date.  If changes occur during the study period, documentation of 
drug dosage, frequency, route, and date may also be included on the eCRF. 
6.7 
Medical Devices 
Blinatumomab must be administered using infusion pumps approved for use by the 
appropriate regulatory authorities for the country in which the subject is undergoing 
treatment, in both the inpatient and outpatient setting. 
Blinatumomab infusion for solution will be prepared in bags for IV infusion and delivered 
through infusion lines that are both compatible with the IP as described in the IPIM.  The 
blinatumomab final solution for infusion should not come into contact with the pump at 
any time. 
Additional details for the use of the above mentioned medical devices and specific set of 
device specifications are provided in the IPIM. 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care.  These other medical devices, (eg, syringes, sterile needles, 
alcohol prep pads) that are commercially available are not usually provided or 
reimbursed by Amgen (except, for example, if required by local regulation).  The 
investigator will be responsible for obtaining supplies of these devices.  
6.8 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
Approved 
 
 


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clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  
This includes any drug(s), device(s) or combination product(s) provisioned and/or 
repackaged /modified by Amgen.  Drug(s) or device(s) includes IP.  
Any product complaint(s) associated with an IP or non-IP(s) or device(s) supplied by 
Amgen are to be reported according to the instructions provided in the IPIM. 
6.9 
Excluded Treatments, Medical Devices, and/or Procedures During 
Screening and Treatment Periods 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study: 
• 
Any anti-tumor therapy other than protocol specified therapies: 
• 
Radiation therapy. Note that radiotherapy to previously bulky sites of disease that 
upon response assessment, remains metabolically inactive (Deauville ≤ 4) will not 
be counted as an event. Intrathecal chemotherapy may be administered if the 
investigator deems the subject to be at high risk of CNS relapse. Evidence of CNS 
disease will be reported as relapse or progression. 
• 
Immunotherapy other than blinatumomab 
• 
Chronic systemic (> 7 days) high-dose corticosteroid therapy (dexamethasone 
> 24 mg/day or equivalent) 
• 
Any other immunosuppressive therapies (except for transient use of corticosteroids 
for ≤ 7 days) 
• 
Any other investigational agent 
Following last response assessment and prior to trial enrollment, subjects are prohibited 
from receiving additional chemotherapy. 
The Exclusion Criteria in Section 4.1.2 describe other medications that are prohibited in 
this study. 
6.10 
Contraceptive Requirements 
6.10.1 
Female Subjects  
Female subjects of childbearing potential must agree to practice true sexual abstinence 
(refrain from heterosexual intercourse) or use an effective method of contraception 
during treatment and for an additional 48 hours after the last dose of protocol-required 
therapies.  
Acceptable methods of effective contraception include: Hormonal (combined estrogen 
and progestogen or progesterone-only hormonal contraception given via oral, 
intravaginal, transdermal, injectable, or implantable route); Intrauterine device; 
Approved 
 
 


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Intrauterine hormonal-releasing system; bilateral tubal occlusion/ligation; vasectomized 
partner (provided that partner is the sole sexual partner of the female participant who is 
of childbearing potential and that the vasectomized partner has received medical 
assessment of the surgical success); 2 barrier methods (1 by each partner) and the 
female partner must use spermicide (if spermicide is commercially available) with the 
barrier method the male must use a condom (latex or other synthetic material) and the 
female may select either a diaphragm, cervical cap or contraceptive sponge. A female 
condom is not an option because there is a risk of tearing when both partners use a 
condom.  The reliability of true sexual abstinence must be evaluated by the investigator 
and be the preferred and usual lifestyle of the subject.  
If a female subject is suspected of being pregnant, the protocol-required therapies must 
be stopped immediately and may not be resumed until absence of pregnancy has been 
medically confirmed.  
Females not of childbearing potential are defined as: Any female who is has had a 
hysterectomy, OR bilateral salpingectomy, OR bilateral oophorectomy, OR are 
post-menopausal. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  (A high follicle stimulating hormone [FSH] level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy [HRT].  However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient). 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study.  Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
Female subjects of childbearing potential must agree to practice sexual abstinence or 
use an acceptable method of effective contraception during the treatment and for an 
additional 48 hours after the last dose of blinatumomab. 
Acceptable methods of contraception include:  
• 
Combined (estrogen and progestogen) or Progestogen-only hormonal methods 
given via oral, intravaginal, transdermal, injectable, or implantable route) 
• 
Intrauterine device  
• 
Intrauterine hormonal-releasing system 
Approved 
 
 


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• 
Bilateral tubal ligation/occlusion 
• 
Vasectomized partner (Provided that partner is the sole sexual partner of the 
female subject of childbearing potential and that the vasectomized partner has 
received medical assessment of the surgical success) 
• 
Sexual abstinence (Defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatments. The reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and 
the preferred and usual lifestyle of the subject.) 
• 
Double barrier method: the male uses a condom and the female may choose 
either a cervical cap, diaphragm, or contraceptive sponge with spermicide 
(A female condom is not an option due to the risk of tearing when both partners 
use a condom.) 
Additional medications given during treatment with blinatumomab may alter the 
contraceptive requirements.  These additional medications may require female subjects 
use highly effective methods of contraception and for an increased length of time.  In 
addition, male subjects may also be required to use contraception.  The investigator is to 
discuss these contraceptive changes with the subject. 
6.10.2 
Male Subjects 
Male subjects are not required to use birth control during treatment with blinatumomab.  
However, the subject should let his female partner know he is in the study. 
6.10.3 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method. 
7. 
STUDY PROCEDURES 
Screening assessments and study procedures outlined in this section and in Table 5, 
Table 6, Table 7, Table 8, and Table 9 will be performed after obtaining a signed ICF. 
It is very important to attempt to perform study procedures and obtain samples at the 
precise timepoints stipulated below.  When it is not possible to perform the study visit at 
the exact timepoint, the visit may be performed within the acceptable visit window as 
defined in the visit-specific section below. 
Any missed visits, tests not done, or examinations that are not conducted must be 
reported as such on the eCRFs.  Subsequent study visits should resume on the original 
schedule.  Missed assessments at prior visits should not be duplicated at subsequent 
visits. 
Approved 
 
 


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Refer to the applicable supplemental laboratory IVRS, IPIM manuals for detailed 
collection and handling procedures. 
7.1 
Schedule of Assessments  
Table 5.  Schedule of Assessments for Screening (Phase 2 and Phase 3) 
Day 
-28 
-21 
-14 
General Assessments 
  
  
Informed consent 
X 
ECOG Performance Status 
X 
Eligibility determination 
X 
Demographics 
X 
Medical history and prior therapies 
X 
Physical examination 
X 
Neurological examination 
X 
Vital signs 
X 
Height 
X 
Weight 
X 
ECG 
X 
Clinical tumor assessment 
X 
Serious adverse events 
← Reported from Signing of ICF → 
Concomitant medications 
X 
Anti-cancer therapies 
X 
Clinical outcome assessmenta 
X 
Local Laboratory Assessments 
  
  
Hematology 
X 
Chemistry (including lipase and amylase) 
X 
Trigycerides 
 
 
X 
Creatinine clearance 
X 
Coagulation 
X 
Pregnancy testing 
 
X 
Central Laboratory Assessments 
Bone marrow b 
X 
Pathology tumor block or slidesc 
X 
Plasma sample 
X 
Radiographic Assessments 
PET/CT d 
Xe 
CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
ICF=informed consent form; PET=positron emission tomography 
a Phase 3 only 
b.Bone marrow evaluation (core biopsy with or without aspirate) should be performed if there has 
been previous histologic evidence of bone marrow involvement plus a negative or ambiguous 
PET/CT, or if bone marrow involvement is suspected with an ambiguous or negative PET/CT 
bone marrow evaluation is not required if the PET/CT is negative and there is no prior evidence 
of bone marrow involvement or if the PET/CT demonstrates findings consistent with bone 
marrow involvement. 
c.Sample from initial diagnosis or relapse must be available and should be submitted once the 
subject is enrolled.  In Phase 3, samples submitted at screening will be used for disease 
confirmation. 
d.Every attempt should be made to complete PET and CT within 3 days of each other, particularly 
during treatment 
e.± 3 days
Approved 
 
 


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Table 6.  Schedule of Assessments for Blinatumomab Cycle 1 (Phase 2 and Phase 3) 
Daya 
1b 
1c 
1d 
2 
3 
8 
9 
10 
15 
16 
22 
29 
36 
43 
50 
57 
68 
70 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signss 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Weight 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
Physical examination 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Neurological examination 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Clinical tumor assessment 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Serious adverse events 
← Reported from Signing of ICF → 
Disease related events 
← Reported from First Dose of Therapy → 
Adverse events 
← Reported from First Dose of Therapy → 
Concomitant medications 
← Reported from Enrollment → 
Anti-cancer therapies 
← Reported from Enrollment → 
Clinical outcome assessmentf 
← Weekly from Enrollment → 
Local Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Chemistryr 
X 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Neurologic safety 
← Collected only if neurologic toxicities are observed → 
Coagulation 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uric acidg 
Xh,i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulins 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
LDH  
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
C-reactive protein 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
 
 
CSF analysis j 
Collect if grade ≥3 neurologic event  or grade seizure 
Central Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow k  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
Plasma sample l 
Xi 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Pharmacogenetic sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacokinetics m 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Anti-blinatumomab antibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cytokines n 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
X 
 
 
Lymphocyte subsetso 
 
X 
X 
X 
X 
X 
 X 
X 
X 
X 
 
 
 
 
 
X 
 
 
Radiographic Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET/CT p 
  
 
 
  
  
  
  
 
  
  
  
  
  
  
  
  
 
Xq 
Footnotes defined on the next page. 
 
Approved 
 
 


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CT=computed tomography; CSF= cerebro spinal fluid; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; ICF=informed consent form; 
LDH=lactate dehydrogenase; PET=positron emission tomography; PK=pharmacokinetics. 
a Day refers to specific day of infusion. In the event of temporary treatment interruption, the day of therapy resumption should be 1 greater than the day of interruption, 
unless the cycle needs to be restarted from day 1 
b Procedures and labs must be completed prior to the initiation of protocol-required therapy, including dexamethasone with the exception noted below 
c Labs which must be drawn after dexamethasone premedication but no more than 15 minutes before initiation of blinatumomab therapy 
d Procedures and labs that must be completed on day 1 after initiation of blinatumomab infusion 
e If screening assessment of clinical tumor assessment was done within 14 days of day 1, testing on day 1 is not required. 
f Phase 3 only 
g If elevated, or if other findings that may increase suspicion/likelihood of tumor lysis, institute monitoring, prophylaxis, and /or treatment per local standards or 
institutional guidelines 
h Tumor lysis prophylaxis may be warranted based on results of uric acid testing 
i In the event of temporary interruption that requires initiation of a new cycle, these tests are not required  
j Collect as close as possible to time of event without endangering subject safety 
k Bone marrow biopsy is not required if PET scan is negative and if not otherwise clinically necessary by investigator discretion 
l Plasma must be collected, processed, and frozen within 4 hours of phlebotomy.  
m Blood samples for blinatumomab PK measurement will be taken on day 1 (pre-dose), day 2, day 9, and day 16 
n Blood samples for cytokine measurement will be taken in subjects receiving blinatumomab on day 1 (predose), day 2 (ie, 24 hours postdose/postdose step), 
day 8 (pre-dose step), day 9 (ie, 24 hours postdose/postdose step), day 15 (pre-dose and 6 hours post dose step), day 16, and day 57 
o Blood samples for lymphocytes will be taken in subjects receiving blinatumomab on day 1 (predose and 6 h), day 2 (ie, 24 hours postdose/postdose step) 
day 3 (ie, 48 hours postdose/postdose step), day 8 (pre-dose step and 6 hours post dose step), day 9 (ie, 24 hours postdose/postdose step), day 10 (ie, 48 hours 
postdose/postdose step), day 15 (pre-dose and 6 hours post dose step, and day 16 (ie, 48 hours postdose/postdose step), day 57 
p Every attempt should be made to complete PET and CT within 3 days of each other, particularly during treatment 
q The Day 70 visit does not necessarily have to happen on the same day as the PET/CT scan. Key endpoint; if subject discontinues study treatment for any reason, 
including toxicity or clinical evidence of disease progression, PET/CT should be conducted 14 (+ 3) days following the last dose of blinatumomab. Chemotherapy 
should not be administered within the 14-day treatment-free interval unless clinical evidence of disease progression has occurred and therapy is indicated. Restaging 
and initiation of cytotoxic chemotherapy should be performed no later than day 70 or 71 of the blinatumomab cycle, ie within 7 days of the end of the treatment-free 
interval 
r Additional lipase and amylase samples should be collected at Investigator discretion if there is suspicion of pancreatitis 
s Monitored every 4 to 8 hours dependent upon institution standard of practice and clinical scenario 
 
Approved 
 
 


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Table 7.  Schedule of Assessments for Blinatumomab Optional Cycle 2 (Phase 2 and Phase 3) 
Day 
1 
2 
3 
8 
9 
10 
15 
22 
29 
42 
General Assessments 
 
 
 
 
 
 
 
 
 
 
Vital signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
 
X 
 
 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurological examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical tumor assessment 
Xa 
 
 
 
 
 
 
 
 
X 
Serious adverse events 
← Reported from signing of ICF → 
Disease related events 
← Continuous from start of treatment → 
Adverse events 
← Continuous from start of treatment → 
Concomitant medications  
← Continuous from enrollment → 
Anti-cancer therapies 
← Continuous from enrollment → 
Subject-reported clinical outcome assessment b 
← Weekly to coincide with clinic visits/hospitalization → 
Local Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Chemistryh 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Neurologic safety d 
← Collected only if neurologic toxicities are observed → 
Coagulation 
X 
X 
 
 
 
 
 
 
 
 
LDH 
X 
 
 
 
 
 
 
 
 
X 
C-reactive protein 
X 
X 
 
X 
X 
 
X 
X 
 
 
CSF analysis d 
Collect if grade ≥3 neurologic event or grade seizure 
Central Laboratory Assessments 
 
 
 
 
 
 
 
 
 
 
Pathology tumor block  
Collect if lymphoma relapse 
Plasma sample c  
Xe 
 
 
 
 
 
 
 
 
X 
Anti-blinatumomab antibodies  
 
 
 
 
 
 
 
 
X 
 
Radiographic Assessments 
 
 
 
 
 
 
 
 
 
 
PET/CT f  
Xg 
Footnotes defined on the next page. 
 
Approved 
 
 


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CT=computed tomography; CT-DNA=circulating tumor DNA; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; ICF=informed consent form; 
LDH=lactate dehydrogenase; PET=positron emission tomography; PK=pharmacokinetics. 
Note: Optional Cycle 2 treatment must begin at least 2 weeks, but not more than 4 weeks, after the end of Cycle 1. 
a Not necessary if done within 7 days 
b Phase 3 only 
c Plasma must be collected, processed, and frozen within 4 hours of phlebotomy 
d Collect as close as possible to time of event without endangering subject safety 
e Only collect CT-DNA if last assessment was > 21 days prior 
f Every attempt should be made to complete PET and CT within 3 days of each other, particularly during treatment. PET/CT should be conducted 14 + 3 days following 
the last dose of blinatumomab 
g PET optional 
h Additional lipase samples should be collected at Investigator discretion if there is suspicion of pancreatitis 
i Monitored every 4 to 8 hours dependent upon institution standard of practice and clinical scenario 
 
Approved 
 
 


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Table 8.  Schedule of Assessments for IC Chemotherapy (Phase 3 Only) 
 
Block 1 
Block 2 
 
Cycles 1-3  
day 1a 
Cycles 1-3  
weekly from day 8 
EOT/End of  
Block 1b 
S2  
Cycles 4-6 day 1 
S2 
End of Block 2 
General Assessments 
 
 
 
 
 
Vital signsl 
X 
x 
X 
X 
X 
Weight 
X 
x 
X 
X 
X 
Physical examination 
X 
x 
X 
X 
X 
Neurological examination 
X 
x 
X 
X 
X 
Clinical tumor assessment 
Xc 
 
 
 
 
Serious adverse events 
← Continuous from signing of ICF → 
Disease related events 
← Continuous from start of treatment → 
Adverse events 
← Continuous from start of treatment → 
Concomitant medications  
← Continuous from enrollment → 
Anti-cancer therapies 
← Continuous from start of treatment → 
Subject-reported clinical outcome assessment 
Weekly to coincide with clinic visits/hospitalization 
Local Laboratory Assessments 
 
 
 
 
 
Hematology 
X 
x 
X 
X 
X 
Chemistryk 
X 
x 
X 
X 
X 
Coagulation 
X 
  
  
  
 
Uric acidj 
Xc 
 
 
 
 
Immunoglobulins 
X 
  
  
  
 
LDH 
X 
  
 X 
 
X 
C-reactive protein 
X 
  
  
  
 
Central Laboratory Assessments 
 
 
 
 
 
Bone marrow d  
 
 
X 
 
X 
Pathology tumor block f  
 collect if tumor relapsee  
 
Plasma sampleg 
X 
  
X 
  
X 
Radiographic Assessments 
 
 
 
 
 
PET/CT h  
  
  
X 
key endpoint 
  
Xi 
Footnotes defined on the next page. 
 
Approved 
 
 


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CT=computed tomography; ECOG=Eastern Cooperative Oncology Group; EOT=end of treatment; IC=investigator’s choice; ICF=informed consent form; LDH=lactate 
dehydrogenase; PET=positron emission tomography; S2=second salvage.  
a All day 1 procedures must be completed prior to the initiation of protocol-required therapy 
b Cycle 3 is the last cycle before response assessment 
c Not necessary if done within 7 days 
d Bone marrow biopsy is not required if PET scan is negative and if not otherwise clinically necessary by investigator discretion 
e Sample from relapse 
f Sample from initial diagnosis or relapse 
g Plasma must be collected, processed, and frozen within 4 hours of phlebotomy 
h Every attempt should be made to complete PET and CT within 3 days of each other, particularly during treatment. For subjects who end treatment early, timing of 
PET/CT should be done consistent with local practice for the specific IC chemotherapy 
i PET optional 
j Tumor lysis prophylaxis may be warranted based on results of uric acid testing 
k Additional lipase and  amylase samples should be collected at Investigator discretion if there is suspicion of pancreatitis 
l Monitored every 4 to 8 hours dependent upon institution standard of practice and clinical scenario 
 
Approved 
 
 


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Table 9.  Schedule of Assessments for Safety Follow-up, HSCT, and Long-term Follow-up 
 
Safety follow-up 
HSCT 
Long-term follow-up 
Approximately 30 days 
after last dose of 
blinatumomab or the last 
day of the last cycle of IC 
chemotherapy 
Within 14 days prior to 
conditioning regimen  
≤ 2 years after EOT: 
 Every 3 months 
(± 14 days)a 
> 2 years 
after EOT: 
 Every 
6 months 
(± 28 days) 
b 
General Assessments 
 
 
 
 
ECOG Performance Status 
X 
 
 
 
Medical history and prior therapies 
← Continuous from start of treatment → 
Vital signs 
X 
 
 
 
Weight 
X 
 
 
 
Physical examination 
X 
 
 
 
Neurological exam 
X 
 
 
 
Clinical tumor assessment 
X 
X 
X 
 
Serious adverse events 
X 
 
X c 
 
Disease related events 
X 
 
 
 
Concomitant medications  
X 
 
Lymphoma treatment only 
Subject-reported clinical outcome assessment d 
X 
 
 
 
HSCT Summarye 
 
 
Xf 
 
Local Laboratory Assessments 
  
  
  
  
Hematology 
X 
 
 
 
Chemistry 
X 
 
 
 
Coagulation 
X 
 
 
 
Immunoglobulins 
X 
 
 
 
LDH 
X 
X 
X 
 
Central Laboratory Assessments 
  
  
  
  
Bone Marrow g  
 
per institutional standard 
 
Pathology tumor block or slidesh 
Collect if lymphoma relapse 
 
Plasma sample i 
 
X 
X 
 
Anti-blinatumomab antibodies 
Xj 
 
 
 
Radiographic Assessments 
  
  
  
  
PET/CTk 
  
per institutional standard 
Footnotes defined on the next page. 
 
Approved 
 
 


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CT=computed tomography; CT-DNA=circulating tumor DNA; ECOG=Eastern Cooperative Oncology Group; EOT=end of treatment; IC=investigator’s choice; 
LDH=; PET=positron emission tomography; 
a To occur in person every 3 months (calculated from safety follow up) until completion of a 2-year period after treatment 
b To occur in person or by telephone call every 6 months (± 28 days) until study completion 
c Only adverse events possibly related to blinatumomab will be collected 
d Phase 3 only  
e HSCT summary will include completion of details about mobilization, engraftment, specific toxicities, infectious complications 
f HSCT summary is at first post HSCT visit 
g Bone marrow biopsy is not required if PET scan is negative and if not otherwise clinically necessary by investigator discretion 
i At the time of relapse 
j Plasma must be collected, processed, and frozen within 4 hours of phlebotomy 
k For subjects previously randomized to blinatumomab only 
l Based on any scans performed, response is to be assessed locally according to institutional standard and according to the Lugano classification. Any radiographic 
indication of progression should be followed-up by biopsy. 
 
 
Approved 
 
 


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7.2 
General Study Procedures  
The procedures performed and timing of each study visit are outlined in the Schedule of 
Assessments (Table 5 to Table 9). It is very important to attempt to perform study 
procedures and obtain samples at the precise timepoints stipulated in the Schedule of 
Assessments (Table 5 to Table 9).  When it is not possible to perform the study visit at 
the exact timepoint, the visit may be performed within the acceptable visit windows if 
applicable.  Any missed visits, tests not done, or examinations that are not conducted 
must be reported as such on the eCRFs.  Subsequent study visits should resume on the 
original schedule.  Missed assessments at prior visits should not be duplicated at 
subsequent visits. 
Details regarding each type of procedure are provided in subsequent sub-sections. 
Refer to the applicable supplemental central laboratory, IVRS, IPIM, and study manuals 
for detailed collection and handling procedures.  Refer to the eCRF completion 
guidelines for data collection requirements and documentation of study 
assessments/procedures. 
Confirmation that the most current IRB/IEC-approved ICF has been signed should occur 
before any study-specific procedures are performed.  All subjects who are enrolled and 
receive blinatumomab or undergo study-specific procedures should be reconsented with 
any updated versions of IRB/IEC-approved ICFs during study participation as applicable 
and per institutional guidelines. 
7.2.1 
Screening, Enrollment and/or Randomization 
The screening period is up to 28-days.  Screening procedures are to be completed 
during the screening period at time points designated in the Schedule of Assessments 
(Table 5).  Informed consent must be obtained before completing any study-specific 
procedures.  Procedures that are part of standard of care are not considered 
study-specific procedures and may be performed before the informed consent and used 
to determine eligibility (as described in Section 4.1), but must be done within the 
timeframe as specified in the Schedule of Assessments (Table 5).  Randomization is 
described in Section 5.1.  
After written informed consent has been obtained, subjects will be screened to assess 
eligibility for study participation.  If a subject has not met all eligibility criteria at the end of 
the 28-day window, the subject will be registered as a screen failure.  Subjects who 
screen fail may be eligible to rescreen 1 additional time.  
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All screening procedures must be performed within 28 days of day 1 (ie, 28 days of the 
start of treatment with study drug), unless otherwise noted.  Subjects who meet the 
inclusion and exclusion criteria will be eligible to be enrolled in the study.  See 
Section 6.9 regarding treatments prohibited during screening.  
7.2.2 
Rescreening 
Subjects who are unable to complete or meet eligibility at the initial screening will be 
permitted to rescreen 1 time, provided study recruitment has not closed.  Re-screen 
subjects must first be registered as screen failed in IVRS and subsequently registered as 
re-screened.  Subjects will retain the same subject identification number assigned at the 
original screening.  Upon signing a new ICF, a new 28-day screening window will begin.  
Procedures completed during prior screening may be included in the rescreening 
eligibility criteria provided that they occur within the timeframe as specified in the 
schedule of assessments. 
7.2.3 
Treatment 
Subjects satisfying eligibility requirements will be enrolled into the treatment period and 
should receive the first dose of blinatumomab or IC chemotherapy on day 1 of the study. 
Visits and procedures will occur per the Schedule of Assessments (Table 6, Table 7, and 
Table 8) during the treatment period. 
7.2.4 
Safety Follow-up Visit(s) 
For phase 2 and phase 3, all subjects, including subjects who withdraw from treatment 
early, will complete a safety follow-up visit approximately 30 (± 3) days after their last 
dose of blinatumomab or 30 (± 3) days or after the last day of the last cycle of IC 
chemotherapy.  In the event that a planned cycle of therapy is delayed beyond 30 days, 
then the safety follow-up may be delayed without a protocol deviation.  However, in the 
event that therapy is not resumed, the subject should be seen for safety follow-up as 
soon as possible.  For subjects proceeding to HSCT, the safety follow-up visit must be 
conducted before the initiation of the transplant conditioning regimen.  
If a subject starts a new anti-lymphoma treatment within 30 (± 3) days of their last dose 
of protocol-assigned therapy, a safety follow-up visit should be conducted immediately 
prior to starting any new treatment, including HSCT conditioning regimens. 
The procedures performed at the safety follow-up visit are listed in Table 9 will be 
performed. 
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7.2.5 
Mobilization 
Suitability for HSC mobilization is determined by the investigator.  For those subjects 
who have received blinatumomab and who have not undergone prior HSC mobilization, 
HSC mobilization may commence after PET/CT restaging.  Mobilization should be with 
colony stimulating factors (ie G-CSF or GM-CSF alone) and should not be preceded by 
chemotherapy (chemomobilization) or done in planned conjunction with another 
mobilizing agent, such as plerixafor.  As an example, G-CSF may be administered at 
10 µg/kg/day for at least 5 days until the completion of apheresis.  The target cell dose is 
dictated by institutional standards, but should be no less than 2 x 106 CD34+ cells/kg.  
Failure to achieve that dose will be designated as not successful on the appropriate 
eCRF. 
For subjects randomized to IC S2 in phase 3, the timing of mobilization is determined 
according to the S2 protocol chosen by the investigator.  Additional chemotherapy or 
planned plerixafor should not be used in the initial mobilization attempt. 
Leukapheresis may commence according to local standards.  If peripheral blood 
leukocyte and/or CD34+ cell counts are insufficient to initiate leukapheresis, subjects 
may receive plerixafor in the initial mobilization or undergo other rescue mobilization, 
including chemomobilization or bone marrow harvest.  Mobilization that requires 
plerixafor or additional chemotherapy will be designated as not successful on the 
appropriate eCRF. 
7.2.6 
HSCT 
Subjects may be referred for HSCT after primary endpoint assessment at the discretion 
of the treating investigator, regardless of response.  Hematopoietic stem cell transplant 
Conditioning Status eCRF must be completed for all subjects to indicate whether an 
HSCT conditioning regimen was initiated within 30 days of first response assessment.  
Transplant types (autologous vs allogeneic), conditioning regimens, etc. are at the 
discretion of the investigator or site.  
Approximately 100 days after HSCT, the center will complete an HSCT summary 
document and/or the appropriate eCRF.  For subjects receiving autologous HSCT, about 
the following information will be collected: 
• 
Conditioning regimens 
• 
Number of cells infused (CD34+/kg) on day 0 
• 
Date of neutrophil engraftment (first day that ANC > 0.5 x 109/L for 3 consecutive 
days)  
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• 
Date of platelet engraftment (first day that platelets > 20 x 109/ L) 
• 
Complications of autologous HSCT 
For subjects receiving allogeneic HSCT, the HSCT summary document will include 
information about: 
• 
Conditioning regimen, including intensity (myeloablative or reduced intensity) 
• 
Donor (matched sibling, mismatched related, matched unrelated, mismatched 
unrelated, haploidentical) 
• 
# alleles matching/# alleles typed 
• 
Cell source (peripheral blood, bone marrow, umbilical cord blood) 
• 
Primary graft-versus-host disease prophylaxis 
• 
Maximum grade of acute graft-versus-host disease 
• 
Other treatment related complications  
7.2.7 
Long-term Follow-up 
For both phase 2 and phase 3, follow-up visits for assessment of relapse, transplant 
status, and survival will take place every 3 months (calculated from the safety follow up 
visit) until completion of a 2-year period after treatment, thereafter follow-up for 
survival and transplant status will be completed in person or by telephone call every 
6 months (± 28 days) until study completion.  Study completion will occur once 
236 death events for phase 3 subjects have occurred or 12 months since last subject in 
phase 3 is randomized if 236th death in phase 3 subjects is not observed.  If the study 
will not continue for the phase 3 portion, study completion will occur when the 
last phase 2 subject has had the opportunity to complete their 2 year follow-up 
visit after treatment. 
Should a subject fail to return to the clinic for a scheduled protocol visit or neglect 
to participate in a scheduled follow up telephone call, sites will need to make 
3 attempts to contact subjects by a combination of telephone and mail.  Sites 
must document all 3 attempts to contact the subject.  If a subject does not 
respond within 1 month after the third contact, the subject will be considered lost 
to follow-up.The procedures and tests listed in Table 9 will be performed during the 
long-term follow up.  Subjects will allow Amgen continued access to medical records so 
that information related to subjects’ health condition, including disease status and overall 
survival, may be obtained.   
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7.2.8 
End of Study 
Study completion will occur once 236 death events for phase 3 subjects have occurred 
or 12 months after the last subject in phase 3 is randomized if 236th death in 
phase 3 subjects is not observed. 
If the study will not continue for the phase 3 portion, the study will conclude when 
all phase 2 subjects have had the opportunity to complete long term follow-up as 
described above.  
7.2.9 
Early Termination Visit 
Subjects (or a legally acceptable representative) can decline to continue receiving 
protocol-specified therapies or procedures at any time during the study but continue 
participation in the study.  Reasons for removal of a subject from treatment or study are 
discussed in Section 8.3. 
If a subject discontinues protocol-specified therapies or procedures, the Investigator is to 
discuss with the subject the appropriate processes for discontinuation from 
protocol-specified therapies and must discuss with the subject the options for 
continuation of the Schedule of Assessments and collection of data, including endpoints 
and adverse events.  The Investigator must document the change to the Schedule of 
Assessments (Table 5 to Table 9) and the level of follow-up that is agreed to by the 
subject (eg, in person, by telephone/mail, through family/friends, in 
correspondence/communication with other physicians, and from review of the medical 
records). 
7.3 
Description of Study Procedures 
The following study procedures will be conducted at the time points outlined in the 
Schedule of Assessments (Table 5 to Table 9). 
7.3.1 
Informed Consent 
All subjects or their legally acceptable representative (ie, legal guardian) must sign and 
date the most current IRB/EC approved ICF.  Confirmation that the ICF has been signed 
should occur before any study specific procedures are performed.  All subjects who are 
randomized and receive protocol-specified therapy or specified treatment should be 
re-consented with any updated versions of IRB/EC approved informed consents during 
study participation as applicable and per institutional guidelines. 
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7.3.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact on biomarker variability 
and PK of the protocol-required therapies. 
7.3.3 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
started 5 years prior to screening through the time of first dose.  Medical history will 
include information on the subject’s concurrent medical conditions.  In addition, 
lymphoma history must date back to the initial diagnosis of B-NHL.  
In addition to the medical history noted above, all history related to the subject’s 
diagnosis of aggressive B-NHL (eg, date of initial diagnosis, international prognostic 
index and additional risk factors at diagnosis, stage at diagnosis, COO at any timepoint if 
available [immunohistochemistry pattern, GEP/other], BCL-2 [Fluorescent in-situ 
hybridization [FISH]: translocation, immunohistochemistry expression levels], c-myc 
[FISH: translocation, immunohistochemistry expression levels]) will be recorded. 
7.3.4 
Prior Therapies 
For initial chemotherapy regimen (eg R-CHOP-21, R-CHOP-14, R-EPOCH), specify 
number of cycles, indicate if dose deviations for named regimen and specify justification 
(ie, cytopenias, organ toxicity) that prompted dose deviation, indicate if ongoing; if yes, 
then current Grade (CTCAE version 4.0); response assessment after completion of 
frontline chemotherapy (eg PMD/PD, NMR/SD, PMR, CMR); radiotherapy yes/no; if yes, 
sites and dose; and if relapsed, duration of time (months) between diagnosis and 
relapse. 
7.3.5 
ECOG Performance Status Assessment 
The subject’s performance status will be assessed using the ECOG performance status 
scale (see Appendix E). 
7.3.6 
Physical Measurements 
Height in centimeters and weight in kilograms should be measured without shoes.  
Height will only be performed at screening. 
7.3.7 
Vital Signs 
The following measurements for vital signs must be performed: systolic/diastolic blood 
pressure, heart rate, respiratory rate, and temperature.  Subject must be in a supine 
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position in a rested and calm state for at least 5 minutes before blood pressure 
assessments are conducted.  If the subject is unable to be in the supine position, the 
subject should be in most recumbent position possible.  The position selected for a 
subject should be the same throughout the study and documented on the vital signs 
eCRF.  The anatomic temperature assessment location selected for a subject should 
be the same throughout the study and documented on the vital signs eCRF.  If 
abnormalities are found and they are considered an adverse event, record on the Event 
CRF. 
7.3.8 
Physical Examination  
Physical examination will be completed as per standard of care.  Physical examination 
findings at screening will include medical and surgical history and will be recorded on the 
medical history eCRF.  Any new findings on physical examination during the course of 
the study will be considered adverse events. 
7.3.9 
Neurological Examination 
A baseline neurological examination will be performed according to institutional 
standards.  Subjects will be specifically queried for neurological symptoms observed in 
the interval since the last extended neurological examination.  Abnormalities of the 
following should be recorded: level of consciousness, orientation, vision, cranial nerves 
and brain stem functions, pyramidal and extra pyramidal motory system, reflexes, 
muscle tone and trophic findings, coordination, sensory system, neuropsychological 
findings (eg, speech, cognition and emotion).  Neurologic examination findings should be 
recorded on the appropriate eCRF (eg, medical history, event). 
7.3.10 
Electrocardiogram  
Standard of care electrocardiogram (ECG) will be performed.  Subject must be in supine 
position in a rested and calm state for at least 5 minutes before ECG assessment is 
conducted.  If the subject is unable to be in the supine position, the subject should be in 
most recumbent position as possible. 
The ECG must include the following measurements: heart rate, QRS, QT, QTc, and PR 
intervals. 
The principal investigator or designated center physician, will review all ECGs.  Once 
signed, the original ECG tracing will be retained with the subject’s source documents.  At 
the request of the sponsor, a copy of the original ECG will be made available to Amgen.  
Findings should be recorded on the ECG eCRF. 
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7.3.11 
Response Assessment 
The Lugano Classification will be used to assess treatment response as described in 
Appendix D. 
7.3.12 
Clinical Tumor Assessment 
Clinical tumor assessments will be performed as indicated in the schedule of 
assessments and are based on changes in the size of previously abnormal lymph node 
groups or extranodal sites, or the appearance of new lesions suspected to represent 
lymphoma progression or relapse.  Findings will be recorded on the clinical tumor 
assessment eCRF. 
7.3.13 
Radiographic Assessment 
PET/CT scans with whole body images, from base of skull to mid-thigh, will be 
conducted.  Examinations should be consistent across all timepoints including: the 
amount of tracer, location of injection, arm location, and scan delay.  
The following data should be collected per center: standard procedures, height, weight, 
gender, administered dose, time between dose administration and imaging, blood 
glucose level, number of cycles of S1 chemotherapy, and time between blood glucose 
level sampling and tracer injection.  Additionally, the number of cycles of chemotherapy 
and date and the use of G-CSF/GM-CSF (dose and dates administered) should also be 
provided. 
PET images should be converted to standardized uptake values maps to support 
comparison across timepoints and to standardize viewing conditions CT anatomical 
coverage: chest, abdomen, and pelvis (and neck if not visualized with chest).  
If PET and CT are acquired on the same day, it is strongly recommended that PET is 
performed prior to the CT with IV contrast.  Refer to the imaging manual for additional 
details, including requirements for submission of pre-S1 scans. 
7.3.14 
Bone marrow biopsy 
Bone marrow evaluation (core biopsy with or without aspirate) should be performed if 
there has been previous histologic evidence of bone marrow involvement plus a 
negative or ambiguous PET/CT, or if bone marrow involvement is suspected with an 
ambiguous or negative PET/CT.  Refer to the Laboratory Manual for additional 
information.  
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7.3.15 
Concomitant Medications 
All medications taken while on treatment are to be recorded on the eCRF per 
Section 6.6. 
7.3.16 
Clinical Outcome Assessments for Phase 3 Subjects Only 
Clinical outcomes assessments are to be taken for subjects enrolled into phase 3 only.  
The Clinical Outcome Assessment tools/instruments to be used in this study will include 
EQ-5D (instrument holder The EuroQol Group) (Appendix F) and FACT-Lymphoma 
(instrument holder FACT-Lym) (Appendix G).  
7.3.17 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If the subject is 
deceased, the date and reported case of death should be obtained. 
7.4 
Laboratory Procedures 
All screening and on-study laboratory samples will be collected, processed and sent to 
the investigator local laboratory or central laboratory as applicable (Table 10).  Detailed 
instructions for sample collection, processing, and shipping are provided in the central 
laboratory manual and/or Amgen-provided training materials.  The date and time of 
sample collection will be recorded in the source documents at the site.  
Blood draws should not be done via central venous access.  Exception: If a permanent 
central line with more than 1 lumen is used, blood draws can be done via the lumen that 
is not used for drug administration.  The analytes for all laboratory tests used throughout 
this study are listed in Table 10. 
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Table 10.  Laboratory Assessments 
Local Laboratory 
 
Chemistry 
Coagulation 
Hematology 
Other Labs 
Neurologic Safety  
Central Laboratory 
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or urea 
Creatinine 
Total bilirubin 
Direct bilirubin 
Alkaline 
phosphatase 
AST (SGOT) 
ALT (SGPT) 
Lipase 
Amylase 
PT/INR 
PTT 
Fibrinogen 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC 
Differential 
• 
Neutrophils 
• 
Bands/stabs 
• 
Lymphocytes 
• 
Monocytes 
LDH  
C-reactive protein 
Immunoglobulins (IgG, IgA, 
IgM) 
Serum or urine Pregnancy 
Triglycerides  
Uric acid 
CSF albumin 
CSF red blood cells 
CSF white blood cells 
CSF flow cytometry 
Additional CSF viral 
studies as clinically 
indicated 
Anti- blinatumomab 
Antibodies 
Pharmacokinetics 
Cytokines 
Lymphocyte subsets 
Bone marrow biopsy 
(if necessary) 
Tumor specimens for 
clonotype determination, cell 
of origin, c-myc and 
bcl-2 rearrangements and 
over expression 
Plasma for CF CT-DNA  
Pharmacogenetics sample 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = Aspartate aminotransferase; BUN = blood urea nitrogen; CSF = cerebral spinal fluid; CF 
CT-DNA = cell-free circulating tumor DNA; Ig = immunoglobulin; IgA = immunoglobin A; IgG = immunoglobin G; IgM = immunoglobin M;  
INR = international normalization; LDH = Lactase dehydrogenase; PT = prothrombin time ratio; PTT = partial thromboplastin time; RBC = red blood cell; WBC = white 
blood cell 
 
 
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7.4.1 
Pharmacokinetic Samples 
All subjects randomized to blinatumomab will have PK samples assessed.  Blood 
samples for PK testing are to be collected at the timepoints noted in Table 6, for the 
measurement of PK concentrations. 
7.4.2 
Cell-Free CT-DNA 
At the screening timepoint, a diagnostic tumor specimen will be collected, and sections 
will be used to determine clonotypic sequences of rearranged antigen receptor genes 
and/or mutational status of specific genes.  Samples of peripheral blood will be collected 
for plasma separation and freezing at timepoints indicated in the Schedule of 
Assessments.  Frozen plasma will be shipped to a central laboratory for high throughput 
sequencing. 
7.4.3 
Serum Cytokines 
To monitor activation of immune effector cells, blood samples for measurement of 
peripheral blood cytokine levels will be taken at the timepoints shown in Table 7 for all 
subjects in phase 2 and subjects randomized to blinatumomab in phase 3.  The following 
cytokines will be assessed by cytometric bead array (CBA) technique: IL-2, IL-6, IL-10, 
TNFα and IFNγ. 
7.4.4 
Lymphocyte Subsets 
In subjects who receive blinatumomab to monitor changes in lymphocytes (B-cell and 
T-cell populations) and leukocyte populations (leukocytes, lymphocytes, monocytes, and 
granulocytes) in peripheral blood, samples will be collected before dexamethasone 
administration, after dexamethasone administration but before blinatumomab 
administration, and at additional timepoints as outlined in the Schedule of Assessments 
Table 6.  The frequent sample collection during the treatment period will help to better 
understand the mechanism of action of the T-cell response. 
7.4.5 
Antibody Testing Procedures 
Blood samples will be collected at time points as outlined in the Schedule of 
Assessments for the measurement of anti-blinatumomab antibodies.  Samples testing 
positive for binding antibodies may be further characterized for quantity/titer, isotype, 
affinity, in-vitro neutralizing activity and presence of immune complexes.  Additional 
blood samples may be obtained to rule out anti-drug antibodies during the study.  
Subjects who test positive for binding antibodies and have clinical sequelae that are 
considered potentially related to an anti-blinatumomab antibody response may also be 
asked to return for additional follow up testing. 
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7.5 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  In oncology, there is particular interest in the molecular changes underlying 
the oncogenic processes that may identify cancer subtypes, stage of disease, assess 
the amount of tumor growth, or predict disease progression, metastasis, and responses 
to IP or protocol-required therapies.  
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to blinatumomab using the blood and bone marrow 
samples collected as outlined in the Schedule of Assessments.  Biomarker development 
may be pursued by the use of advanced biochemical analyses such as proteomic 
methods, ribonucleic acid transcript profiling and DNA sequencing.  Refer to the 
laboratory manual for detailed collection and handling procedures for all biomarker 
development samples. 
7.6 
Optional Pharmacogenetic Studies 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  A peripheral blood cell pellet will be collected at the time of 
plasma separation for genomic DNA isolation.  Frozen plasma and cell pellets will be 
shipped to a central laboratory for high throughput sequencing.  These optional 
pharmacogenetic analyses focus on inherited genetic variations to evaluate their 
possible correlation to the disease and/or responsiveness to the therapies used in this 
study.  Genomic DNA will be isolated from non-malignant as well as tumor tissue in 
order to determine if genetic polymorphisms in the tumor sample are tumor-associated 
or germline mutations.  At present, there is no plan to perform targeted analysis of 
non-tumor associated genes in order to identify predictors of efficacy, toxicity, or to 
understand drug metabolism.  No additional samples will be collected for 
pharmacogenetic studies.  
7.7 
Sample Storage and Destruction 
Any blood sample collected according to the Schedule of Assessments (Table 5 through 
Table 9) can be analyzed for any of the tests outlined in the protocol and for any tests 
necessary to minimize risks to study subjects.  This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study.  This can 
also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
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All samples and associated results will be coded prior to being shipped from the study 
center for analysis or storage.  Samples will be tracked using a unique identifier that is 
assigned to the samples for the study.  Results are stored in a secure database to 
ensure confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
disease under study, DLBCL, the dose response and/or prediction of response to 
blinatumomab, characterize antibody response, and characterize aspects of the 
molecule (eg, mechanism of action/target, metabolites).  Results from this analysis are 
to be documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.  
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of biomarker development, or other exploratory studies are 
not placed in the subject’s medical record and are not to be made available to the 
subject, members of the family, the personal physician, or other third parties, except as 
specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
samples (eg, blood, tumor) and any other components from the cells can be located and 
destroyed.  Samples will be destroyed once all protocol-defined procedures are 
completed.  However, information collected from samples prior to the request for 
destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 
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8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving IP 
and/or other protocol-required therapies or procedures at any time during the study but 
continue participation in the study.  If this occurs, the investigator is to discuss with the 
subject the appropriate processes for discontinuation from IP, device or other 
protocol-required therapies and must discuss with the subject the options for 
continuation of the Schedule of Assessments (Table 5, Table 6, Table 7, Table 8, and 
Table 9) and collection of data, including endpoints, adverse events, disease related 
events, and device related events, as applicable.  All attempts should be made to follow 
subjects through safety follow-up.  The investigator must document the change to the 
Schedule of Assessments (Table 5, Table 6, Table 7, Table 8, and Table 9) and the level 
of follow-up that is agreed to by the subject (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of 
the medical records).  
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.  
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from IP, device, 
and/or other protocol-required therapies, protocol procedures, or the study as a whole at 
any time prior to study completion.  
Subjects may be eligible for continued treatment with Amgen IP(s) and/or other 
protocol-required therapies by a separate protocol or as provided for by the local 
country’s regulatory mechanism, based on parameters consistent with Section 12.1. 
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8.3 
Reasons for Removal From Treatment, or Study 
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required IP(s) or procedural assessments include 
any of the following: 
• 
subject request  
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, protocol-specified criteria, pregnancy) 
• 
death 
• 
lost to follow-up 
• 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
• 
disease progression 
Subjects who discontinue treatment will continue to be followed on the study. 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease Related Events 
Disease Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease, eg, disease progression.  Such events 
do not meet the definition of an adverse event unless assessed to be more severe than 
expected for the subject’s condition. 
Disease Related Events that do not qualify as Adverse Events or Serious Adverse 
Events:  
• 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
reported as a Disease Related Event.  
• 
Death due to the disease under study is to be recorded on the Event CRF. 
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Disease Related Events that would qualify as an Adverse Event or Serious Adverse 
Event: 
•
An event based on the underlying disease that is worse than expected as assessed
by the investigator for the subject’s condition or if the investigator believes there is a
causal relationship between the IP(s)/study treatment/protocol-required therapies
and disease worsening, this must be reported as an Adverse Event or Serious
Adverse Event.
Table 11.  outlines the expected Disease-Related Events by System Organ Class. 
Table 11.  Disease-related Adverse Events by System Organ Class 
SOC 
Preferred Terms 
Investigations 
weight decreased 
Blood and lymphatic system disorders 
lymphadenopathy 
General disorders and administration 
site conditions 
disease progression 
fatigue 
Skin and subcutaneous tissue 
disorders 
night sweats 
Other 
hemorrhagec  
disease progression 
SOC = system organ class. 
9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.  
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.  
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event eCRF. 
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For situations when an adverse event or serious adverse event is due to lymphoma 
report all known signs and symptoms.  Death due to disease progression in the absence 
of signs and symptoms should be reported as the primary tumor type (eg, R/R indolent 
NHL).  
Note: The term “disease progression” should not be used to describe the disease 
related event or adverse event.  
An adverse device effect is any adverse event related to the use of a medical device.  
Adverse device effects include adverse events resulting from insufficient or inadequate 
instructions for use, adverse events resulting from any malfunction of the device, or 
adverse events resulting from use error or from intentional misuse of the device. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.  
9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease Related Event as 
defined in Section 9.1.1): 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
A disease related event blood and lymphatic system disorders or investigations are to be 
reported as a serious adverse event if: 
• 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, or 
• 
if the investigator believes a causal relationship exists between the investigational 
medicinal product(s)/protocol-required therapies and the event,  
• 
and the event meets at least 1 of the serious criteria. 
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An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).  
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention. 
If the criteria for grade 4 in the CTCAE grading scale for laboratory event differs from 
the regulatory criteria for serious adverse events, it is left to the investigator’s judgement 
whether to report these grade 4 abnormalities as serious adverse events. 
9.2 
Safety Event Reporting Procedures  
9.2.1 
Reporting Procedures for Disease Related Events 
The investigator is responsible for ensuring that all Disease Related Events observed by 
the investigator or reported by the subject that occur after the first dose of investigational 
medicinal product(s)/study treatment/protocol-required therapies through the safety 
follow-up visit are recorded on the Event CRF as a Disease Related Event.  
Disease Related Events assessed by the investigator to be more severe than expected 
and/or related to the investigational medicinal product(s)/study 
treatment/protocol-required therapies, and determined to be serious, must be recorded 
on the Event CRF as Serious Adverse Events.  
Additionally, the investigator is required to report a fatal Disease Related Event on the 
Event CRF.  
9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That Do Not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur from the first dose of IP through the 
safety follow-up visit are reported using the Event CRF.  Adverse events considered by 
the investigator to be possibly related to blinatumomab will be reported from the 
beginning of transplant conditioning during the long-term follow up until completion of a 
2-year period after treatment. 
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The investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Severity [and/or toxicity per protocol], 
• 
Assessment of relatedness to blinatumomab or protocol required medication or 
medical device, and 
• 
Action taken. 
The adverse event grading scale used will be the CTCAE.  The grading scale used in 
this study is described in Appendix A.  
The investigator must assess whether the adverse event is possibly related to 
blinatumomab.  This relationship is indicated by a “yes” or “no” response to the question: 
Is there a reasonable possibility that the event may have been caused by the 
investigational medicinal product?  
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, protocol-required therapies).  This relationship is indicated 
by a “yes” or “no” response to the question: “Is there a reasonable possibility that the 
event may have been caused by a study activity (eg, protocol-required therapies), and/or 
procedure”?   
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a change from the 
subject’s baseline values.  All grade 3 and grade 4 laboratory values should be recorded 
as adverse events.  In addition, if signs or symptoms are associated with a laboratory 
abnormality, the signs/symptoms and the laboratory abnormality should all be recorded 
as adverse events.  The laboratory abnormality and any signs/symptoms should be 
graded according to their own CTCAE criteria. 
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through safety follow-up are recorded in the subject’s medical record and are 
submitted to Amgen.  In addition, blinatumomab related serious adverse events will be 
reported during the long term follow-up.  All serious adverse events must be submitted to 
Amgen within 24 hours following the investigator’s knowledge of the event via the Event 
CRF.  
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If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event Contingency Report Form within 24 hours of the investigator’s 
knowledge of the event.  See Appendix B for a sample of the Serious Adverse Event 
Worksheet /electronic Serious Adverse Event Contingency Report Form.  For EDC 
studies where the first notification of a Serious Adverse Event is reported to Amgen via 
the eSerious Adverse Event Contingency Report Form, the data must be entered into 
the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
blinatumomab and/or other protocol-required therapies.  This relationship is indicated by 
a “yes” or “no” response to the question: Is there a reasonable possibility that the event 
may have been caused by the IP? 
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and GCP.  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local regulatory requirements and procedures. 
9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
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adverse events can be reported to Amgen.  In some countries (eg, European Union 
member states), investigators are required to report serious adverse events that they 
become aware of after end of study.  If serious adverse events are reported, the 
investigator is to report them to Amgen within 24 hours following the investigator’s 
knowledge of the event. 
In addition to the attributes listed in Section 9.2.2.1, the investigator must also complete 
the serious adverse event section of the Event eCRF. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
9.2.2.4 
Serious Adverse Events That are not to be Reported by the 
Sponsors to Regulatory Agencies in an Expedited Manner  
Events which are morbidities associated in general with lymphoma and lymphoma 
therapy do not require expedited reporting: 
• Planned hospitalization
9.2.3 
Reporting of Delayed Time to HSCT for Subjects With PR/PMR At 
Baseline 
The investigator is responsible for reporting delays to HSCT in subject that meet the 
following criteria: 
PR/PMR at baseline per Lugano classification and  
Do not proceed to HSCT within 30 days of the first response assessment 
These events will be recorded in the CRF and must be submitted to Amgen with 
24 hours following the investigator’s knowledge of the event.  Refer to eCRF completion 
guidelines for specific reporting directions. 
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking blinatumomab, report the pregnancy to Amgen Global Patient Safety as 
specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur 48 hours after the last dose of blinatumomab. 
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
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Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested.  
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.  If a male 
subject's female partner becomes pregnant, the investigator should discuss obtaining 
information regarding the birth outcome and health of the infant from the pregnant 
partner.  
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a Serious Adverse Event.  
If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur 48 hours after the last dose of protocol-required therapies.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
Phase 2 and Phase 3: 
• 
CMR as determined by central radiographic assessment of PET/CT scans using the 
Lugano Classification 
10.1.1.2 
Secondary Endpoint(s) 
Key Secondary Endpoints (phase 3 only): 
• 
Overall Survival (OS): calculated as the time from the date of randomization until 
death due to any cause.  Subjects who are alive at the date that triggers the analysis 
will be censored at the date last known to be alive.  If the date last known to be alive 
is after the date that triggers the analysis, the subject will be censored at the analysis 
trigger date. 
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Other Secondary Endpoints: 
Phase 2: 
• 
Objective response rates (ORR including CMR and PMR) 
• 
PFS: calculated as the time from start of blinatumomab until the date of diagnosis of 
progression of lymphoma, or date of death, whichever is earliest.  Subjects who are 
alive and did not have progression will be censored at the last date of tumor 
assessment. 
• 
DOR: calculated only for subjects who achieve an OR.  The duration will be 
calculated from the date a response, CMR or PMR, is first achieved per central 
review during the first 12 weeks after starting blinatumomab until the earliest 
date of a disease assessment indicating a relapse event or death, whichever occurs 
first.  Subjects who do not have a relapse event will be censored on their last disease 
assessment date.  If the last disease assessment date is after the date that triggers 
the analysis, the subject will be censored at the analysis trigger date.  A sensitivity 
analysis will censor subjects who receive a HSCT at the time of HSCT unless there 
is no assessment after the HSCT, in which case the last assessment prior to the 
HSCT will be used as the censoring time.  Disease assessment during LTFU will 
be reviewed by investigators only per central review agreement. 
• 
Successful mobilization rate (defined as CD34+ cell 2x106/kg) 
• 
HSCT (both autologous and allogeneic) rates among subjects with post-
blinatumomab CMR+PMR 
• 
100-day non-relapse mortality (NRM) after HSCT 
• 
Blinatumomab steady state concentration and clearance 
• 
Incidence and severity of treatment-emergent adverse events 
Phase 3: 
• 
OR (including CMR and PMR) 
• 
PFS: calculated as the time from the date of randomization until the date of diagnosis 
of progression of lymphoma, or date of death, whichever is earliest.  Subjects who 
are alive and did not have progression will be censored at the last date of tumor 
assessment. 
• 
DOR 
• 
Successful mobilization rate (defined as CD34+ cell 2x106/kg) following protocol 
assigned therapy 
• 
HSCT (both autologous and allogeneic) rates among responding subjects (CMR or 
PMR) 
• 
100-day NRM after autologous HSCT rate 
• 
Patient-reported clinical outcome assessments quality of life (QOLCOA) using the 
EQ-5D and FACT-Lymphoma tools 
• 
Blinatumomab concentration steady state, clearance, and half life 
Safety: 
• 
Incidence and severity of treatment-emergent adverse events 
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10.1.1.3 
Exploratory Endpoints 
• 
Pharmacodynamics, including descriptive analysis of quantitative and qualitative 
features of lymphocyte populations and serum or plasma concentrations of cytokines 
• 
Response rates and duration according to COO designation and c-myc and 
bcl-2 rearrangement and overexpression, R-IPI, Secondary IPI, NCCN IPI, as 
determined from pretreatment specimens 
• 
Quantitative analysis of CF CT-DNA as determined by analysis of tumor-associated 
mutations in CF CT-DNA from plasma collected at various timepoints before, during, 
and after treatment 
10.1.2 
Analysis Sets 
The primary analysis of efficacy from the phase 2 part of the study will be performed 
on all subjects who received blinatumomab.  The primary analysis of efficacy from 
the phase 3 part of the study will be performed on all randomized subjects analyzed 
according to their randomized treatment assignment (the Full Analysis Set [FAS]).  
Sensitivity analyses of efficacy will be performed on the Safety Analysis Set.  
The primary analysis of safety will be performed on the Safety Analysis Set which will 
include all subjects who received protocol-specified therapy analyzed according to the 
treatment they received. 
10.1.2.1 
AutoHSCT Analysis Set 
Includes all subjects who achieve a response and undergo autoHSCT while in 
remission and without any other anti-cancer treatment.  
10.1.2.2 
Full Analysis Set (FAS) 
For the phase 2 part of the study, the FAS includes all subjects who are treated with 
blinatumomab. 
For the phase 3 part of the study, the FAS Includes all subjects who are randomized.  
Analysis will be performed according to the randomized treatment, regardless of the 
treatment actually received. 
10.1.2.3 
Target Dose Analysis Set (TDAS) 
All subjects of the FAS who completed at least 7 days of infusion on the highest 
intended dose level will consistute Target Dose Analysis set (TDAS).  In addition, 
all subjects who discontinue the treatment due to progression of disease during 
the first cycle of treatment will be included.  The primary efficacy endpoint will be 
analyzed using TDAS. 
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10.1.2.4 
Responder Analysis Set  
Includes all subjects who had CMR or PMR during the first 12 weeks after initiation of 
blinatumomab or IC chemotherapy (for phase 3). 
10.1.2.5 
Safety Analysis Set 
Includes all subjects from both phases of the study who received protocol-specified 
therapy.  Analysis will be performed according to the treatment received. 
10.1.3 
Covariates and Subgroups 
The analysis to determine if blinatumomab is superior to IC arm with respect to the 
primary endpoint and key secondary endpoint for phase 3 will be stratified by the 
stratification factors at randomization:  
• 
Response to S1: PMR vs NMR/PMD 
• 
Cytarabine administered in S1 (eg, R-DHAP and R-ESHAP vs R-ICE and R-GDP): 
yes vs no 
• 
PMBCL and B-cell lymphoma, unclassifiable, with features intermediate between 
DLBCL and classical Hodgkin lymphoma vs all other histologies of aggressive B-cell 
lymphoma 
10.1.4 
Handling of Missing and Incomplete Data  
Subjects missing post baseline disease assessments will be considered not to have 
achieved CMR. 
Subjects not experiencing events that of interest for time-to-event endpoints (eg, deaths 
for OS) will be censored according to rules to be detailed in the statistical analysis plan. 
10.2 
Sample Size Considerations 
10.2.1 
Phase 2  
The sample size for the phase 2 part of the study is determined by a 1-sample test of the 
rate of CMR during the first 12 weeks after initiation of blinatumomab.  With the 
1-sided type I error rate (α) set at 0.025, a null hypothesis response probability (π0) of 
15%, and an alternative response probability (π1) of 40%, a sample size of 36 subjects 
will provide 90% power to reject the null hypothesis that the response probability is no 
more than 15%.  Being able to make this determination will represent evidence of clinical 
activity and warrant advancement into the phase 3 part of the study. 
10.2.2 
Phase 3 
The primary endpoint is CMR.  A CMR rate of 22% in the IC arm vs. 40% in the 
blinatumomab arm is hypothesized.  The odds ratio of CMR rate will be tested at the 
1-sided significance level of 0.025. With these assumptions and a 1:1 randomization 
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ratio, a sample size of 296 subjects will provide 89% power.  The sample size is adjusted 
for 3 interim futility analyses when 25%, 50%, and 75% of the subjects have had the 
opportunity to complete the tumor assessment and 1 interim efficacy analysis when 
75% of the subjects have had the opportunity to complete the tumor assessment.  The 
interim futility boundaries will use a Lan-DeMets beta-spending approach to an 
O’Brien-Fleming boundary and the interim efficacy boundaries will use a Lan-DeMets 
alpha-spending approach to an O’Brien-Fleming boundary.  The details of these interim 
analyses are specified in the Section 10.4.1.  
Overall survival is a key secondary endpoint and the study is also powered for overall 
survival.  If the null hypothesis for the primary endpoint is rejected, then OS will also be 
tested at a 1-sided significance level of 0.025.  Assuming the true hazard ratio is 0.65 a 
final OS analysis after 236 death events will provide 90% power.  With a median survival 
time of 4.4 months in the IC arm vs. 6.7 months in blinatumomab arm, accrual rates of 
14.5 subjects per month, a 5% drop-out rate per year, and a targeted sample size of 
296 randomized subjects, it is estimated that the 236th event will occur within 26 months 
of the start of randomization. 
Sample size re-estimation will be allowed at an interim analysis (see Section 10.4.1). 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information should not be 
distributed to the study team, investigators or subjects prior to the study being formally 
unblinded (eg, the formal unblinding may occur at the final analysis rather than during 
the primary analysis) except as specified (eg, Section 10.4.1 and Section 9.2.2.2).  
10.4 
Planned Analyses 
10.4.1 
Interim Analyses 
Table 12. specifies the timing of planned phase 3 analyses for CMR and OS. 
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Table 12.  Timing of the Planned Phase 3 Analyses for Complete Metabolic 
Response and Overall Survival 
Analysis 
Number 
Analysis Time Since 
First Subject 
Randomizeda 
(months) 
Primary Endpoint: CMR 
Key Secondary 
Endpoint: OS 
1 
8 
Interim for futility (25% of 
subjects complete treatment 
and tumor assessment, 
∼10 weeks after randomization 
- 
2 
13 
Interim for futility (50% of 
subjects complete treatment 
and tumor assessment, 
∼10 weeks after randomization) 
- 
3 
18 
Interim for efficacy, futility 
(75% subjects complete 
treatment and tumor 
assessment, ∼10 weeks after 
randomization) and sample size 
re-estimation. 
Interim for efficacy and 
sample size 
re-estimation 
(∼153 events, ∼65% of 
the total) 
 
4 
23 
Final 
- 
5 
26 
- 
Final (236 events) 
CMR=complete metabolic response; DMC=data monitoring committee; OS=overall survival 
a Time by which the required number of subjects will have had the opportunity to be assessed for the CMR 
endpoint. Actual DMC analysis may occur up to 2 months later. 
Based on the conditional power at the third interim analysis of CMR and first interim 
analysis of OS, there will be a possibility to increase the sample size by at most 
50% using the method of Gao, Ware and Mehta (2008), which will be described in detail 
in the statistical analysis plan.  The sample size will be increased if either CMR or OS 
interim results are in the pre-specified promising zone.  If the sample size is increased 
due to only OS results being in the promising zone, then the primary CMR analysis will 
occur as scheduled once 296 subjects have been assessed for CMR. 
The interim futility boundaries will use the Lan-DeMets alpha-spending approach to 
non-binding O’Brien-Fleming boundaries. 
Table 13.  Futility Stopping Rules for Complete Metabolic Response 
Analysis 
Number 
Information 
Fraction 
Number of 
Analyzed 
Subjects 
Number of 
Randomized 
Subjects* 
Futility 
Boundary 
(Z Scale) 
Cumulative 
Beta Spent 
1 
25% 
74 
111 
-1.313 
0.001 
2 
50% 
148 
185 
0.368 
0.020 
3 
75% 
222 
259 
1.307 
0.058 
4 
100% 
296 
296 
2.012 
0.100 
* Includes additional subjects randomized during the 10 weeks required prior to the response assessment 
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Table 14.  Efficacy Stopping Rules for Complete Metabolic Response 
Analysis 
Number 
Information 
Fraction 
Number of 
Analyzed 
Subjects 
Number of 
Randomized 
Subjects* 
Efficacy 
Boundary 
(Z Scale) 
Cumulative 
Alpha Spent 
3 
75% 
222 
259 
2.340 
0.010 
4 
100% 
296 
296 
2.012 
0.025 
* Includes additional subjects randomized during the 10 weeks required prior to the response assessment 
Table 15.  Efficacy Stopping Rules for Overall Survival 
Analysis 
Number 
Information 
Fractiona 
Number of 
Eventsa 
Number of 
Randomized 
Subjectsb 
Efficacy 
Boundary  
(p-Value Scale) 
Cumulative 
Alpha Spent 
3 
65% 
153 
258 
0.005 
0.005 
5 
100% 
236 
296 
0.023 
0.025 
a Estimated.  Analysis Number 3 will occur at the same time as the analysis for complete response 
b The number of subjects is calculated based on the case that the study is not stopped early. The 
sample size can be increased by up to 50% and applies to all of the above tables 
The data monitoring committee (DMC) will make recommendations regarding study 
continuation and sample size re-estimation based on interim analysis results. 
10.4.2 
Data Monitoring Committee 
An external independent DMC will oversee the interim analyses.  In addition, the DMC 
will assess safety approximately every 6 months provided enrollment is adequate.  The 
timing of safety reviews may be adjusted in order to coincide with scheduled DMC 
interim analyses for futility and efficacy.  On the basis of their reviews, the DMC will 
make recommendations to Amgen regarding the continuation of the study and sample 
size re-estimation of the study.  The DMC will consist of 3 or more members including 
2 or more clinicians with relevant specialties and 1 or more statisticians.  The DMC will 
be supported by an external independent statistician who is responsible for preparing 
reports that describe the ongoing clinical study data.  Details regarding the 
responsibilities of the DMC and the independent statistician will be described in the DMC 
Charter. 
10.4.3 
Primary Analysis 
Phase 2: The primary analysis will report the CMR rate among blinatumomab treated 
subjects. 
Phase 3: The primary analysis will test whether CMR/OS is superior in the group 
randomized to blinatumomab compared to the group randomized to IC.  The primary 
analysis will be triggered by the date when 296 subjects have had the opportunity to 
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complete at least 1 tumor assessment.  Barring a sample-size increase, the estimated 
time of this analysis is 21 months after the first subject is randomized. 
10.4.4 
Final Analysis 
The final analysis will test whether OS is superior in the group randomized to 
blinatumomab compared to the group randomized to IC.  The final analysis will be 
triggered by the date when the 236th death in phase 3 subjects is reported in the clinical 
trial database, or the study duration reaches 12 months from the last subject 
randomized.  The estimated time is 26 months to reach the OS event goal.  Barring a 
sample-size increase, since the enrollment period is expected to last 21 months, the 
estimated maximum follow up time is 33 months. 
In case that the phase 3 portion of the study is not initiated, the final analysis will 
occur when all subjects in phase 2 complete long term follow-up defined in 
Section 7.2.7. 
10.5 
Planned Methods of Analysis  
10.5.1 
General Considerations 
Continuous variables will be summarized by the non-missing sample size (n), mean, 
standard deviation, median, first and third quartiles, minimum, and maximum.  
Categorical variables will be summarized by the n and percentage in each category.  
Time to event endpoints will be summarized with hazard ratios, Kaplan-Meier (KM) 
curves, KM proportions at select time points, KM quartiles (when estimable), the number 
of subjects with events, the number of subjects censored, and the pattern of censoring.  
Point estimates for efficacy endpoints will be accompanied by 2-sided 95% confidence 
intervals including estimates of KM quartiles (Brookmeyer and Crowley, 1982), KM 
proportions (Kalbfleisch and Prentice, 1980), and binomial proportions 
(Clopper CJ and Pearson, 1934). 
The phase 3 study will have an overall alpha of 0.025 with 1-sided testing.  To preserve 
the overall significance level, statistical testing of the primary and key secondary 
endpoint will follow a hierarchical structure.  First, CMR rate will be tested.  If the 
blinatumomab arm demonstrates superiority over the IC arm for CMR, then OS will be 
tested. 
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10.5.2 
Primary Efficacy Endpoint 
Phase 2: 
The percentage of subjects with a CMR during the first 12 weeks after initiation of 
blinatumomab will be summarized with an exact binomial 95% confidence interval.  
Summary of CMR during the treatment will also be provided.  
Phase 3: 
A 1-sided Cochran-Mantel-Haensel test, which will adjust for the stratification factors at 
randomization, will be used to determine if the blinatumomab arm has a significantly 
higher CMR rate compared to the IC arm.  In addition, the percentage of subjects in 
each treatment arm with a CMR will be summarized with an exact binomial 
95% confidence interval.  Subjects missing post-baseline disease assessments will be 
considered not to have achieved CMR. 
10.5.3 
Secondary Efficacy Endpoint(s) 
Phase 2: 
Other secondary efficacy endpoints include OR after initiation of blinatumomab and 
during the treatment, PFS, duration of CMR, DOR, successful mobilization rate, 
alloHSCT rate, autoHSCT rate and 100-day NRM after autoHSCT.  
OR during the first 12 weeks after initiation of blinatumomab during the treatment will 
be summarized with an exact binomial 95% confidence interval.  
PFS will be summarized with the KM summaries.  
Duration of CMR and duration of response will be summarized with the KM summaries 
in Responders Analysis Set. 
Successful mobilization rate, autoHSCT rate and alloHSCT rate will be summarized with 
an exact binomial 95% confidence interval. AutoHSCT rate will be analyzed using 
autoHSCT Analysis Set.  
The 100-day NRM after autoHSCT rate will be summarized with the cumulative 
incidence function with relapse or deaths due to relapse treated as competing risks.  
For this endpoint, time to non-relapse deaths will be measured starting from the date of 
autologous HSCT. 
Phase 3: 
OS is the key secondary efficacy endpoint for Phase 3.  A 1-sided stratified log-rank test, 
stratified by the randomization factors, will be used to determine if OS is superior in the 
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blinatumomab arm compared to IC arm when the 236th death in phase 3 subjects is 
reported.  In addition, a hazard ratio with a 2-sided 95% confidence interval will be 
estimated from a stratified Cox regression model.  The KM summaries will be performed 
by treatment group.  
Other secondary efficacy endpoints include OR, PFS, duration of CMR and ORR, 
successful mobilization rate, HSCT rate, 100-day NRM after HSCT rate.  Overall 
response rate will be summarized by treatment group with an exact binomial 
95% confidence interval.  For descriptive purposes, a 1-sided Cochran-Mantel-Haenszel 
test, which will adjust for the stratification factors at randomization, will test if the 
blinatumomab arm has a higher ORR compared to the IC arm.  PFS, duration of CMR 
and the duration of ORR will be summarized with the KM summaries by treatment group.  
For descriptive purposes, a stratified log-rank test, stratified by the randomization 
factors, will be provided.  A hazard ratio with a 2-sided 95% confidence interval will be 
estimated from a stratified Cox regression model.  
Successful mobilization rate and HSCT rate will be summarized by treatment group with 
an exact binomial 95% confidence interval. 
The 100-day NRM after autologous HSCT rate will be summarized with the cumulative 
incidence function with non-relapse deaths treated as competing risks by treatment 
group.  For this endpoint, time to non-relapse deaths will be measured starting from the 
date of autologous HSCT. 
10.5.4 
Safety Endpoints 
10.5.4.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities will be used to code all adverse events 
(AE) to a system organ class and a preferred term.  AEs of interest (EOI) categories will 
be based on search strategies defined by Medical Coding.  All adverse event tables will 
be summarized by treatment group.  Treatment-emergent adverse events are events 
with an onset after the administration of the first dose of protocol-specified therapy. 
The subject incidence of AEs will be summarized for all treatment-emergent AEs, 
serious AEs, AEs leading to withdrawal of protocol-specified therapy, and fatal AEs. 
Subject incidence of all treatment-emergent AEs, serious AEs, AEs leading to 
withdrawal of IP, and fatal AEs will be tabulated by system organ class and preferred 
term in descending order of frequency; similar summaries will be repeated for EOIs.  
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Time to onset and duration of selected EOIs (infection and neurologic events) may also 
be summarized. 
For phase 3, a summary of treatment-emergent AEs with at least a 5% higher subject 
incidence in 1 treatment arm compared to the other will be presented by preferred term.  
This summary will be repeated for serious AEs using a 10% threshold.  
A summary of treatment-emergent AEs will be tabulated by system organ class, 
preferred term, and worst grade. 
Subgroup analyses (if there is a medical or regulatory rationale) will be presented by 
system organ class and preferred term in descending order of frequency.  All races (if 
appropriate) with less than 5% of the total subjects will be pooled together for summary 
purposes. 
10.5.4.2 
Laboratory Test Results 
Shift tables between the worst post-baseline and baseline grades for selected laboratory 
parameters will be provided.  Plots or other summaries overtime will be presented for 
selected laboratory parameters including immunoglobulins, platelets, and liver 
parameters for subjects in the Safety Analysis Set.  The summary will be done by 
treatment group for phase 3. 
10.5.4.3 
Vital Signs 
The number and percentage of subjects with abnormal changes in systolic blood 
pressure, diastolic blood pressure and heart rate will be summarized for subjects in the 
Safety Analysis Set.  The summary will be done by treatment group for phase 3. 
10.5.4.4 
Electrocardiogram 
The ECG measurements from this clinical study were performed as per standard of care 
for routine safety monitoring, rather than for purposes of assessment of potential QTc 
effect.  Since these evaluations may not necessarily be performed under the rigorous 
conditions expected to lead to meaningful evaluation of QTc data; summaries and 
statistical analyses of ECG measurements are not planned, and these data would not be 
expected to be useful for meta-analysis with data from other trials. 
10.5.4.5 
Antibody Formation 
The incidence of subjects who develop anti blinatumomab antibodies (binding and if 
positive, neutralizing) will be tabulated. 
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10.5.4.6 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to IP for subjects in the 
Safety Analysis Set.  The number of cycles of protocol-specified therapy administered 
will be summarized with an additional breakdown of the number of cycles completed, 
discontinued, and re-started.  In addition, the duration of therapy, the relative treatment 
duration, the cumulative dose, and the percent of intended dose will be summarized by 
cycle and overall.  The number and percent of subjects with dose modifications (eg, 
dose changes, dose interruptions) and reason for modification will be summarized.  The 
summary will be done by treatment group for phase 3. 
10.5.4.7 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medications from study 
day 1 through safety follow-up will be summarized by preferred term as coded by the 
World Health Organization Drug (WHODRUG) dictionary in the Safety Analysis Set.  In 
addition, the number and proportion of subjects receiving anticancer therapies (including 
HSCT conditioning regimens) during long term follow-up will be summarized by 
WHODRUG preferred term in the FAS.  The summary will be done by treatment 
group for phase 3. 
10.6 
Pharmacokinetic assessments 
Pharmacokinetic sample analysis will be performed by a central laboratory.  
Blinatumomab will be measured in all subjects who received blinatumomab at predose 
and at steady state on days 2, 9, and 16.  Serum concentrations will be measured with a 
validated assay.  Steady state serum concentrations will be summarized by dose levels 
and time points with descriptive statistics.  The following PK parameters will be 
estimated if data supports: 
• Steady state concentration 
• Systemic clearance 
• Half life 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample ICF is provided for the investigator to prepare the informed consent 
document to be used at his or her site.  Updates to the template are to be communicated 
formally in writing from the Amgen Clinical Study Manager to the investigator.  The 
written ICF is to be prepared in the language(s) of the potential patient population. 
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Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol-specific screening procedures or any IP(s) 
is/are administered.  A legally acceptable representative is an individual or other body 
authorized under applicable law to consent, on behalf of a prospective subject, to the 
subject’s participation in the clinical study.  
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.  
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the ICF is to be signed and personally dated by the subject or a legally 
acceptable representative and by the person who conducted the informed consent 
discussion.  The original signed ICF is to be retained in accordance with institutional 
policy, and a copy of the signed consent form is to be provided to the subject or legally 
acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
ICF to the subject and must allow for questions.  Thereafter, both the subject and the 
witness must sign the ICF to attest that informed consent was freely given and 
understood. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed ICF, other written subject information, and any 
proposed advertising material must be submitted to the IRB/IEC for written approval.  A 
copy of the written approval of the protocol and ICF must be received by Amgen before 
recruitment of subjects into the study and shipment of Amgen IP. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
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document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.  
• 
Subjects are to be identified by a unique subject identification number.  
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.  
• 
On the eCRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.  
• 
For Serious Adverse Events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with 
local laws and regulations), and date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in 
confidence by the investigator, except as described below. 
In compliance with governmental/ICH GCP Guidelines, it is required that the investigator 
and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IRB/IEC direct access to review the subject’s original medical records 
for verification of study-related procedures and data.  Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the 
evaluation of the study.  The investigator is obligated to inform and obtain the consent of 
the subject to permit such individuals to have access to his/her study-related records, 
including personal information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
• 
a recognized expert in the therapeutic area 
• 
an Investigator who provided significant contributions to either the design or 
interpretation of the study 
• 
an Investigator contributing a high number of eligible subjects 
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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, 
Investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB/IEC must be 
informed of all amendments and give approval.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
Investigator reserve the right to terminate the Investigator’s participation in the study 
according to the Clinical Trial Agreement.  The investigator is to notify the IRB/IEC in 
writing of the study’s completion or early termination and send a copy of the notification 
to Amgen.  
Subjects may be eligible for continued treatment with Amgen IP(s) by an extension 
protocol or as provided for by the local country’s regulatory mechanism.  However, 
Amgen reserves the unilateral right, at its sole discretion, to determine whether to supply 
Amgen IP(s) and by what mechanism, after termination of the study and before the 
product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRF s will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
eCRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
In this study, the IVRS captures the following data points and these are considered 
source data: subject identification; phase 3 randomization and stratification factors. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  
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Elements to include: 
• 
Subject files containing completed eCRFs, ICFs, and subject identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
• 
IP-related correspondence including Proof of Receipts, IP Accountability Record(s), 
Return of IP for Destruction Form(s), Final IP Reconciliation Statement, as 
applicable. 
• 
Non-IP(s) and or medical device(s) documentation 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Clinical Monitor is responsible for verifying the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The Clinical Monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the eCRFs. 
The investigator agrees to cooperate with the Clinical Monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing eCRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research & Development Compliance 
and Audit function (or designees).  Inspection of site facilities (eg, pharmacy, 
protocol-required therapy storage areas, laboratories) and review of study-related 
records will occur to evaluate the study conduct and compliance with the protocol, ICH 
GCP, and applicable regulatory requirements. 
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Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the eCRFs must be maintained and 
readily available. 
• 
Updates to eCRFs will be automatically documented through the software’s “audit 
trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.In addition, the data are reviewed for adherence to the protocol and 
GCP. To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
• 
The investigator signs only the Investigator Verification Form for this EDC study or 
the investigator applies an electronic signature in the EDC system if the study is set 
up to accept an electronic signature. This signature indicates that investigator 
inspected or reviewed the data on the eCRF, the data queries, and agrees with the 
content. 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 5 to Table 9), the investigator can search publically 
available records [where permitted]) to ascertain survival status.  This ensures that the 
data set(s) produced as an outcome of the study is/are as comprehensive as possible.  
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
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Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors) Recommendations for the 
Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical Journals, 
which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published and (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part of the 
work are appropriately investigated and resolved. Authors should meet conditions 
1, 2, 3, and 4. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript. These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
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13. 
REFERENCES 
Ardeshna KM, et al. Conventional second-line salvage chemotherapy regimens are not 
warranted in patients with malignant lymphomas who have progressive disease after 
first-line salvage therapy regimens. Br J Haematol. 2005;130(3):363-372. 
Armand P, et al. Prognostic factors for patients with diffuse large B cell lymphoma and 
transformed indolent lymphoma undergoing autologous stem cell transplantation in the 
positron emission tomography era. Br J Haematol. 2013;160(5):608-617. 
Blinatumomab Investigator’s Brochure. Thousand Oaks, CA. Amgen Inc. 
Brookmeyer R and Crowley J. A Confidence Interval for the Median Survival Time. 
Biometrics. 1982;38:29-41. 
Clopper CJ and Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika. 1934;26(4):404-413. 
Crump M, et al. Gemcitabine, dexamethasone, and cisplatin in patients with recurrent or 
refractory aggressive histology B-cell non-Hodgkin lymphoma: a Phase II study by the 
National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). Cancer. 
2004;101(8):1835-1842. 
Crump M, et al. Randomized comparison of gemcitabine, dexamethasone, and cisplatin 
versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous 
stem-cell transplantation for relapsed and refractory aggressive lymphomas: 
NCIC-CTG LY.12. J Clin Oncol. 2014;32(31):3490-3496. 
Derenzini E, et al. Pretransplantation positron emission tomography scan is the main 
predictor of autologous stem cell transplantation outcome in aggressive B-cell 
non-Hodgkin lymphoma. Cancer. 2008;113(9):2496-2503. 
DeVita VT Jr, et al. Advanced diffuse histiocytic lymphoma, a potentially curable 
disease. Lancet. 1975;1(7901):248-50. 
Dickinson M, et al. Improved survival for relapsed diffuse large B-cell lymphoma is 
predicted by a negative pre-transplant FDG-PET scan following salvage chemotherapy. 
Br J Haematol. 2010;150(1):39-45. 
Dreier T, Lorenczewski G, Brandl C, et al. Extremely potent, rapid and 
costimulation-independent cytotoxic T-cell response against lymphoma cells catalyzed 
by a single-chain bispecific antibody. Int J Cancer. 2002;100(6):690-697. 
Elstrom RL, et al. Response to second-line therapy defines the potential for cure in 
patients with recurrent diffuse large B-cell lymphoma: implications for the development of 
novel therapeutic strategies. Clin Lymphoma Myeloma Leuk. 2010;10(3):192-196. 
Fisher SG and Fisher RI. The Epidemiology of Non-Hodgkin's Lymphoma. Oncogene. 
2004;23(38):6524-534.  
Gao P, Ware JH, Mehta, C. Sample Size Re-estimation for Adaptive Sequential Design 
in Clinical Trials. Journal of Biopharmaceutical Statistics. 2008;1184-1196. 
Gisselbrecht C, et al. Salvage regimens with autologous transplantation for relapsed 
large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184-4190. 
Goebeler ME, et al. Bispecific T-Cell Engager (BiTE) Antibody Construct Blinatumomab 
for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma: Final 
Results From a Phase I Study. J Clin Oncol. 2016. 
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Gutierrez M, et al. Role of a doxorubicin-containing regimen in relapsed and resistant 
lymphomas: an 8-year follow-up study of EPOCH. J Clin Oncol. 2000;18(21):3633-3642. 
Hamlin PA, et al. Age-adjusted International Prognostic Index predicts autologous stem 
cell transplantation outcome for patients with relapsed or primary refractory diffuse large 
B-cell lymphoma. Blood. 2003;102(6):1989-1996. 
Haematological Malignancy Research Network. 
https://www.hmrn.org/statistics/incidence  
Kalbfleisch JD and Prentice R L. The Statistical Analysis of Failure Time Data. New 
York: John Wiley & Sons;1980. 
Kewalramani T, et al. Rituximab and ICE as second-line therapy before autologous stem 
cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. 
Blood. 2004;103(10):3684-3688. 
Martin A, et al. R-ESHAP as salvage therapy for patients with relapsed or refractory 
diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. 
A GEL/TAMO study. Haematologica. 2008;93(12):1829-1836. 
Mey UJ, et al. Dexamethasone, high-dose cytarabine, and cisplatin in combination with 
rituximab as salvage treatment for patients with relapsed or refractory aggressive 
non-Hodgkin's lymphoma. Cancer Invest. 2006;24(6):593-600. 
Moskowitz CH, et al. Ifosfamide, carboplatin, and etoposide: a highly effective 
cytoreduction and peripheral-blood progenitor-cell mobilization regimen for 
transplant-eligible patients with non-Hodgkin's lymphoma. J Clin Oncol. 
1999;17(12):3776-3785. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
Philip T, et al. High-dose therapy and autologous bone marrow transplantation after 
failure of conventional chemotherapy in adults with intermediate-grade or high-grade 
non-Hodgkin's lymphoma. N Engl J Med. 1987;316(24):1493-1498. 
Robinson SP, et al. Autologous stem cell transplantation for relapsed/refractory diffuse 
large B-cell lymphoma: efficacy in the rituximab era and comparison to first allogeneic 
transplants. A report from the EBMT Lymphoma Working Party. Bone Marrow 
Transplant. 2016;51(3):365-371. 
Roland V, et al. Impact of high-dose chemotherapy followed by auto-SCT for positive 
interim [18F] FDG-PET diffuse large B-cell lymphoma patients. Bone Marrow Transplant. 
2011;46 (3):393-399. 
Sauter CS, et al. Prognostic value of FDG-PET prior to autologous stem cell 
transplantation for relapsed and refractory diffuse large B-cell lymphoma. Blood. 
2015;125(16):2579-2581. 
Schlereth B, Kleindienst P, Fichtner I, et al. Potent inhibition of local and disseminated 
tumor growth in immunocompetent mouse models by a bispecific antibody construct 
specific for Murine CD3. Cancer Immunol Immunother. 2006;55(7):785-796. 
Sehn LH and Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the 
context of clinical and biologic heterogeneity. Blood. 2015;125(1):22-32. 
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Simpson L, et al. Effectiveness of second line salvage chemotherapy with ifosfamide, 
carboplatin, and etoposide in patients with relapsed diffuse large B-cell lymphoma not 
responding to cis-platinum, cytosine arabinoside, and dexamethasone. Leuk Lymphoma. 
2007;48(7):1332-1337. 
Swerdlow SH, et al. The 2016 revision of the World Health Organization (WHO) 
classification of lymphoid neoplasms. Blood. 2016 
Tilly H, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines 
for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):116-125. 
Van Den Neste E, et al. Outcome of patients with relapsed diffuse large B-cell lymphoma 
who fail second-line salvage regimens in the International CORAL study. Bone Marrow 
Transplant. 2016;51(1):51-57. 
van Imhoff GW, et al. Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in 
Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The Orcharrd Study 
(OMB110928). 56th Annual Meeting of the American Society of Hematology. 
2014;124:630. 
Velasquez WS, et al. ESHAP-an effective chemotherapy regimen in refractory and 
relapsing lymphoma: a 4-year follow-up study. J Clin Oncol. 1994;12(6):1169-1176. 
Velasquez, WS., et al. Effective salvage therapy for lymphoma with cisplatin in 
combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 
1988;71(1):117-122. 
Viardot A, et al. Phase 2 study of bispecific T-cell engager (BiTE(R)) antibody 
blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016. 
Witzig TE, et al. Salvage chemotherapy with rituximab DHAP for relapsed non-Hodgkin 
lymphoma: a phase II trial in the North Central Cancer Treatment Group. Leuk 
Lymphoma. 2008;49(6):1074-1080. 
Zelenetz AD, et al. Non-Hodgkin’s Lymphomas, Version I.2016', National 
Comprehensive Cancer Network Guidelines. 
Ziepert M, et al. Standard International prognostic index remains a valid predictor of 
outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J Clin 
Oncol. 2010;28(14):2373-2380. 
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14. 
APPENDICES 
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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The CTCAE is available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.5 require 
the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate eCRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed 
and sent to Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.2.2. 
Additional Clinical Assessments and Observation 
All subjects in whom IP(s) or protocol-required therapies is/are withheld (either 
permanently or conditionally) due to potential DILI as specified in Table 4 or who 
experience AST or ALT elevations > 3 x ULN or 2-fold increases above baseline values 
for subjects with elevated values before drug are to undergo a period of “close 
observation” until abnormalities return to normal or to the subject’s baseline levels.  
Local laboratory assessments that are to be performed during this period include:  
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
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Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the IP(s) or protocol-required therapies has/have been discontinued AND the 
subject is asymptomatic. 
• 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL. The following are to be considered depending on the clinical situation: 
− 
Complete blood count (CBC) with differential to assess for eosinophilia 
− 
Serum total IgG, Anti-nuclear antibody (ANA), Anti Smooth Muscle Antibody, and 
Liver Kidney Microsomal antibody 1 (LKM1) to assess for autoimmune hepatitis 
− 
Serum acetaminophen (paracetamol) levels 
− 
A more detailed history of:  
• 
Prior and/or concurrent diseases or illness 
• 
Exposure to environmental and/or industrial chemical agents  
• 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
• 
Prior and/or concurrent use of alcohol, recreational drugs and special diets 
• 
Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
− 
Viral serologies 
− 
CPK, haptoglobin, LDH, and peripheral blood smear 
− 
Appropriate liver imaging if clinically indicated 
• 
Appropriate blood sampling for PK analysis if this has not already been collected  
• 
Hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator. 
The “close observation period” is to continue for a minimum of 4 weeks after 
discontinuation of all IP(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding eCRFs. 
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Appendix B.  Sample eSerious Event Contingency Form 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
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Appendix D.  Response Assessment per the Lugano Classification 
5- point scale (Deauville) 
1. no uptake above background;  
2. uptake ≤ mediastinum;  
3. uptake > mediastinum but ≤ liver;  
4. uptake moderately > liver;  
5. uptake markedly higher than liver and/or new lesions;  
X. new areas of uptake unlikely to be related to lymphoma. 
 
Response 
Compete 
Response  
Partial Response 
Stable Disease 
Progressive 
Disease 
PET/CT 
Response 
Complete 
Metabolic 
Response 
Partial Metabolic 
Response 
No Metabolic 
Response 
Progressive 
Metabolic Disease 
Target 
Masses 
Score 1, 2, or 3 
with or without a 
residual mass 
Score 4 or 5  
reduced uptake 
compared with 
baseline  
residual mass(es) 
of any size 
Score 4 or 5  
no significant 
change in FDG 
uptake from 
baseline  
Score 4 or 5 with an 
increase in intensity 
of uptake from 
baseline and/or 
new FDG-avid foci 
consistent with 
lymphoma  
New 
Lesions 
None 
None 
None 
New FDG-avid foci 
consistent with 
lymphoma rather 
than another 
etiology  
Bone 
Marrow 
No FDG avid focal 
lesions 
Residual uptake 
higher than 
uptake in normal 
marrow but 
reduced 
compared with 
baseline  
No change from 
baseline 
New or recurrent 
FDG-avid foci 
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Appendix E.  ECOG Performance Status Scale 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (eg, light housework, office work). 
2 
Ambulatory and capable of all selfcare, but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
Source: Oken MM, Creech RH, Tormey DC et al. Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982; 5: 649-655 
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Appendix F.  EQ-5D 
 
EQ-5D-5L Tablet version 
English (USA) 
Health Questionnaire 
English version for the USA 
  
Please tap the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems walking 
I have slight problems walking  
I have moderate problems walking 
I have severe problems walking 
I am unable to walk 
SELF-CARE 
I have no problems washing or dressing myself  
I have slight problems washing or dressing myself  
I have moderate problems washing or dressing myself  
I have severe problems washing or dressing myself  
I am unable to wash or dress myself  
USUAL ACTIVITIES (eg, work, study, housework, family or leisure activities) 
I have no problems doing my usual activities  
I have slight problems doing my usual activities  
I have moderate problems doing my usual activities  
I have severe problems doing my usual activities  
I am unable to do my usual activities  
PAIN / DISCOMFORT 
I have no pain or discomfort  
I have slight pain or discomfort  
I have moderate pain or discomfort  
I have severe pain or discomfort  
I have extreme pain or discomfort  
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ANXIETY / DEPRESSION 
I am not anxious or depressed  
I am slightly anxious or depressed  
I am moderately anxious or depressed  
I am severely anxious or depressed  
I am extremely anxious or depressed  
We would like to know how good or bad your health is TODAY. 
This scale is numbered from 0 to 100. 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
Please tap on the scale to indicate how your health is TODAY. 
The best health 
you can imagine 
The worst health  
you can imagine 
YOUR  HEALTH TODAY 
Next 
Previous 
 EuroQol Research Foundation. EQ-5D is a trade mark of the EuroQol Research Foundation 
Disclaimer: This is a preview of the EQ-5D instrument. It demonstrates the text, questions and 
response options included in this version. This preview does not represent the final product and 
should not be used as an official EQ-5D instrument. 
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Appendix G.  FACT-Lymphoma 
 
 
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Amendment 2 
Protocol Title:  A Phase 2/3 Multi-center Study to Evaluate the Safety and Efficacy 
of Blinatumomab in Subjects With Relapsed/Refractory Aggressive B-Cell 
Non Hodgkin Lymphoma 
 
Amgen Protocol Number Blinatumomab 20150292 
 
Amendment Date: 
07 May 2019 
Rationale: 
This protocol is being amended to: 
• 
Provide post facto option of not proceeding to Phase 3 
• 
Provide 2 years of long term follow up for Phase 2 cohort 
• 
Clarify End of Study and End of Follow Up for Phase 2 
• 
Redefine primary and final analyses endpoints 
• 
Make administrative and editorial changes 
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Description of Changes: 
Section:  Global 
Change:  Administrative and editorial changes throughout. 
Section:  Global 
Change:  Changed date from 27 April 2017 to 07 May 2019. 
Section:  Title Page 
Replace: 
Key Sponsor Contact(s): 
MD 
Clinical Research Medical Director 
 
Email: 
 
 
Global Clinical Trial Manager 
Phone:
Email: 
 
With: 
Key Sponsor Contact(s): 
, MD 
Clinical Research Medical Director 
Email: 
 
 
 
Global Clinical Trial Manager 
Phone:
Email: 
 
Section:  Protocol Synopsis, Secondary Objectives 
Replace: 
Phase 3: 
• 
To compare the efficacy of blinatumomab to IC chemotherapy with respect to:  
− 
Overall survival (OS) 
− 
DOR 
− 
The rate of successful HSC mobilization 
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− 
Ability to proceed to hematopoietic stem cell transplant (HSCT) (both autologous 
and allogeneic) rates among responding subjects (CMR) or those in sustained 
partial metabolic response (PMR) 
− 
Objective response rate (ORR; CMR + PMR)  
− 
PFS 
• 
To compare the safety profile of blinatumomab to that of IC chemotherapy 
• 
To compare the quality of life reported by subjects treated with blinatumomab or IC 
chemotherapy 
With:  
Phase 3: 
• 
To compare the efficacy of blinatumomab to IC chemotherapy with respect to:  
- 
Overall survival (OS) 
- 
DOR 
- 
The rate of successful HSC mobilization 
- 
Ability to proceed to hematopoietic stem cell transplant (HSCT) (both autologous 
and allogeneic) rates among responding subjects (CMR) or those in sustained 
partial metabolic response (PMR) 
- 
Objective response rate (ORR; CMR + PMR)  
- 
PFS 
• 
To compare the safety profile of blinatumomab to that of IC chemotherapy 
• 
To compare the quality of life reported by subjects treated with blinatumomab and 
those treated with IC chemotherapy 
Section:  Protocol Synopsis, Other Secondary Endpoints 
Replace: 
Phase 2: 
• 
Objective response rate (ORR; CMR + PMR)  
• 
PFS 
• 
DOR 
• 
Successful mobilization rate (defined as CD34+ cell 2x106/kg) 
• 
HSCT (both autologous and allogeneic) rates among subjects with 
post-blinatumomab complete response (CMR) + partial response (PMR) 
• 
100-day non-relapse mortality (NRM) after autologous HSCT 
• 
Blinatumomab concentration steady state, clearance, and half life 
• 
Incidence and severity of adverse events 
Approved 
 
 


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Phase 3: 
• 
ORR (CMR+PMR)  
• 
PFS 
• 
DOR 
• 
Successful mobilization rate (defined as CD34+ cell 2x106/kg) following protocol 
assigned therapy 
• 
HSCT (both autologous and allogeneic) rates among responding subjects (CMR or 
PMR) 
• 
100-day NRM after autologous HSCT rate 
• 
Patient-reported clinical outcome assessments quality of life (QOLCOA) using the 
EQ-5D and FACT-Lymphoma tools 
• 
Blinatumomab steady state concentration and clearance 
• 
Overall incidence and severity of treatment-emergent adverse events 
With: 
Phase 2: 
• 
Objective response rate (ORR; including CMR and PMR)  
• 
PFS 
• 
DOR 
• 
Successful mobilization rate (defined as CD34+ cell 2x106/kg) 
• 
HSCT (both autologous and allogeneic) rates among subjects with 
post-blinatumomab complete response (CMR) + partial response (PMR) 
• 
100-day non-relapse mortality (NRM) after autologous HSCT 
• 
Blinatumomab concentration steady state, clearance, and half life 
• 
Incidence and severity of adverse events 
Phase 3: 
• 
ORR (including CMR and PMR)  
• 
PFS 
• 
DOR 
• 
Successful mobilization rate (defined as CD34+ cell 2x106/kg) following protocol 
assigned therapy 
• 
HSCT (both autologous and allogeneic) rates among responding subjects (CMR or 
PMR) 
• 
100-day NRM after HSCT rate 
• 
Patient-reported clinical outcome assessments quality of life (QOLCOA) using the 
EQ-5D and FACT-Lymphoma tools 
• 
Blinatumomab steady state concentration and clearance 
• 
Overall incidence and severity of treatment-emergent adverse events 
Approved 
 
 


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Section:  Protocol Synopsis, Study Design, paragraph 2 
Add:  
The phase 2 component of the study will consist of up to a 28-day screening period, 
approximately 70 to 112 days of study treatment, a 30-day (± 3days) safety follow up, 
and long-term follow up that will conclude with the final analysis of the phase 3 
component, estimated at 30 months after initiation of the phase 3 component.  In the 
event that phase 3 is not initiated, LTFU for phase 2 subjects will proceed as 
detailed in Section 7.2.7. 
Section:  Protocol Synopsis, Study Design, paragraph 6 
Add: 
Following the response assessment, subjects may undergo hematopoietic stem and 
progenitor cell (HSC) mobilization and autologous hematopoietic stem cell transplant or 
allogeneic HSCT. 
 
Approved 
 
 


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Section:  Figure 2, Phase 3 Study Schema 
Replace: 
 
 
Approved 
 
 


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With: 
 
 
Approved 
 
 


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Section:  Study Glossary 
Replace:   
End of Follow-up 
defined as concluding with FA of phase 2 component, which will be 
triggered by the date when the 236th death of a phase 3 subject is 
reported in the clinical trial database, or when the study duration 
reaches 12 months from the last subject randomized 
With: 
End of Follow-up 
defined as concluding with FA of phase 3 component, which will be 
triggered by the date when the 236th death of a phase 3 subject is 
reported in the clinical trial database, or when the study duration 
reaches 12 months from the last subject randomized, or in the 
event that the trial does not proceed to phase 3, defined as the 
date when the last phase 2 subject has had the opportunity to 
complete their 2 year follow-up after treatment. 
Section:  Study Glossary 
Replace:   
End of Study (primary 
completion) 
the time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary 
analysis; the primary analysis will be triggered when 296 subjects 
have had the opportunity to complete at least 1 tumor response 
assessment. 
With:   
End of Study (primary 
completion) 
the time when the last subject enrolled in phase 2 finishes their 
2 year follow-up.   
Section:  Study Glossary 
Add:   
End of Study (end of trial) the time when the last subject is assessed or receives an 
intervention for evaluation in the study; the final analysis will be 
triggered by the date when the 236th death for a phase 3 subject is 
reported in the clinical trial database, or the study duration reaches 
12 months from the last subject randomized.  In case that the 
phase 3 portion of the study is not initiated, the final analysis 
will occur when all subjects in phase 2 complete long term 
follow-up. 
Section:  Study Glossary 
Add:   
OR 
objective response 
TDAS 
Target Dose Analysis set 
Approved 
 
 


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Section:  Study Glossary 
Delete: 
SEC 
self-evident corrections 
Section:  1 Objectives, Secondary 
Replace: 
1.2.2  Phase 3 
• 
To compare the efficacy of blinatumomab to IC chemotherapy with respect to:  
− 
Overall survival (OS) 
− 
DOR 
− 
The rate of successful HSC mobilization 
− 
Ability to proceed to hematopoietic stem cell transplant (HSCT) (both autologous 
and allogeneic) rates among responding subjects (CMR) or those in sustained 
partial metabolic response (PMR) 
− 
Objective response rate (ORR; CMR+PMR)  
− 
PFS 
• 
To compare the safety profile of blinatumomab to that of IC chemotherapy 
• 
To compare the quality of life reported by subjects treated with blinatumomab or IC 
chemotherapy 
With: 
1.2.2  Phase 3 
• 
To compare the efficacy of blinatumomab to IC chemotherapy with respect to:  
− 
Overall survival (OS) 
− 
DOR 
− 
The rate of successful HSC mobilization 
− 
Ability to proceed to hematopoietic stem cell transplant (HSCT) (both autologous 
and allogeneic) rates among responding subjects (CMR) or those in sustained 
partial metabolic response (PMR) 
− 
Objective response rate (ORR; including CMR and PMR)  
− 
PFS 
• 
To compare the safety profile of blinatumomab to that of IC chemotherapy 
• 
To compare the quality of life reported by subjects treated with blinatumomab or IC 
chemotherapy 
Approved 
 
 


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Section:  2.1.1 Primary Refractory or Relapsed Disease 
Replace: 
Patients with DLBCL who do not respond to frontline therapy, or who experience 
relapse after a remission, are generally considered incurable unless able to receive 
either high dose chemotherapy (HDT) with autologous HSCT or allogeneic HSCT 
(Robinson et al, 2016).  HSCT is preceded by a course of salvage chemotherapy.  
“Chemoresponsivess”, indicating a partial response (PR) or complete response (CR) to 
salvage chemotherapy, has been as used as 1 criterion to define HSCT eligibility, since 
early trials demonstrated the extremely poor outcomes of patients without an objective 
response to salvage chemotherapy (Philip et al, 1987).  It is not known if responsiveness 
to newer classes of therapies, such as those that are immune-based, may also be 
sufficient to permit the successful use of HDT. 
With: 
Patients with DLBCL who do not respond to frontline therapy, or who experience 
relapse after a remission, are generally considered incurable unless able to receive high 
dose chemotherapy (HDT) plus either autologous HSCT or allogeneic HSCT 
(Robinson et al, 2016).  HSCT is preceded by a course of salvage chemotherapy.  
“Chemoresponsivess”, indicating a partial response (PR) or complete response (CR) to 
salvage chemotherapy, has been as used as 1 criterion to define HSCT eligibility, since 
early trials demonstrated the extremely poor outcomes of patients without an objective 
response to salvage chemotherapy (Philip et al, 1987).  It is not known if responsiveness 
to newer classes of therapies, such as those that are immune-based, may also be 
sufficient to permit the successful use of HDT/HSCT. 
Section:  2.1.2 First Salvage Chemotherapy, paragraph 1 
Add:   
The most commonly used regimens in the S1 treatment of transplant-eligible patients 
contain rituximab and a platinum-based agent such as cisplatin (eg, R-DHAP, R-GDP, 
R-ESHAP) or carboplatin (eg R-ICE) (Crump et al, 2014; Martin et al, 2008; 
Witzig et al, 2008; Kewalramani et al, 2004).  Each regimen is administered over 
4-5 days every 2-4 weeks.  Two to three cycles of therapy are given before response 
assessment.  Those with PR or CR typically undergo HSC mobilization and an additional 
1-2 cycles may be given before HDT/HSCT.  Non-responders, if offered additional 
chemotherapy, typically receive an alternative regimen. 
Approved 
 
 


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Section:  2.2 Amgen Investigational Product Background: Blinatumomab, paragraph 5 
Replace:  
The single agent clinical response seen in R/R DLBCL subjects suggests blinatumomab 
may be a novel agent to add to frontline therapy to improve the low PFS/OS that occurs 
in relapse/refractory subjects with present day therapies.  
With:   
The single agent clinical response seen in R/R DLBCL subjects suggests blinatumomab 
may be an effective therapy to improve the low PFS/OS that occurs in 
relapse/refractory subjects with present day therapies.  
Section:  3.1 Study Design, paragraph 1 
Replace:   
This is a phase 2/3 open label, multicenter trial testing blinatumomab monotherapy for 
the treatment of subjects with R/R aggressive B-NHL not achieving CMR after standard 
platinum-based chemotherapy regimens administered as S1.  In the phase 3 part of the 
study, blinatumomab will be compared to IC chemotherapy.  This study incorporates 
multiple interim analyses for futility, efficacy, and unblinded sample-size re-estimation, 
described further in Section 10.4.1.  The primary endpoint for both the phase 2 and 
3 components of this trial is CMR rate, determined after 1 cycle of blinatumomab or 
1 block (up to 3 cycles) of IC chemotherapy. 
With:   
This is a phase 2/3 open label, multicenter trial testing blinatumomab monotherapy for 
the treatment of subjects with R/R aggressive B-NHL not achieving CMR after standard 
platinum-based chemotherapy regimens administered as S1.  In the phase 3 part of the 
study, blinatumomab will be compared to IC chemotherapy.  This study incorporates 
multiple interim analyses for futility, efficacy, and unblinded sample-size re-estimation, 
described further in Section 10.4.1.  The primary endpoint for both the phase 2 and 
3 components of this trial is CMR rate, determined during the first 12 weeks after 
initiation of blinatumomab or after initiation of IC chemotherapy for phase 3. 
Approved 
 
 


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Section:  3.1 Study Design, paragraph 8 
Replace:   
Subjects in the phase 2 and subjects randomized to blinatumomab in phase 3 will 
receive a single 70-day cycle, with a total of 56 days of blinatumomab continuous 
infusion of 7 days at 9 µg/day, 7 days at 28 µg/day, and 42 days at 112 µg/days, 
followed by a treatment-free period of 14 days.  Response will be assessed by central 
review of a PET/CT after this single cycle. 
With:   
Subjects in the phase 2 and subjects randomized to blinatumomab in phase 3 will 
receive a single 70-day cycle, with a total of 56 days of blinatumomab continuous 
infusion of 7 days at 9 µg/day, 7 days at 28 µg/day, and 42 days at 112 µg/days, 
followed by a treatment-free period of 14 days.  Response will be assessed by central 
review of a PET/CT within 12 weeks of initiation of blinatumomab. 
Section:  3.5.2 End of Study, paragraph 2 
Replace:   
End of Trial: the time when the last subject is assessed or receives an intervention for 
evaluation in the study; the final analysis will be triggered by the date when the 
236th death of a phase 3 subject is reported in the clinical trial database, or the study 
duration reaches 12 months from the last subject randomized. 
This study is event-driven and will conclude when approximately 236 death events in 
phase 3 have occurred. 
It is anticipated that the enrollment period will be approximately 33 months, and the 
study duration will be approximately 52 months from the date that the first subject is 
enrolled, randomized (approximately 12 months from the completion of randomization in 
phase 3). 
With:   
End of Trial: triggered by the date when the 236th death of a phase 3 subject is reported 
in the clinical trial database, or the study duration reaches 12 months from the last 
subject randomized. 
This study is event-driven and will conclude when approximately 236 death events in 
phase 3 have occurred.It is anticipated that the enrollment period will be approximately 
Approved 
 
 


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33 months, and the study duration will be approximately 52 months from the date that 
the first subject is enrolled, randomized (approximately 12 months from the completion 
of randomization in phase 3). 
At the end of phase 2, when all phase 2 subjects have had an opportunity to have 
a tumor assessment by week 12, a data analysis will be done to facilitate the 
decision whether to proceed to phase 3.  If the study will not continue for the 
phase 3 portion, the study will conclude when phase 2 subjects have had an 
opportunity to complete long term follow-up. 
If the study only includes the phase 2 portion, the enrollment period is 
approximately 12 months, and the study duration will be approximately 24 months 
from the date the last subject completes treatment. 
Section 6.9 Excluded Treatments, Medical Devices, and/or Procedures During 
Screening and Treatment Periods, bullet 2 
Replace:   
• 
Radiation therapy. Note that radiotherapy to previously bulky sites of disease that 
upon response assessment is metabolically inactive (Deauville ≤ 4) will not be 
counted as an event. Intrathecal chemotherapy may be administered if the 
investigator deems the subject to be at high risk of CNS relapse. Evidence of CNS 
disease will be reported as relapse or progression. 
With: 
• 
Radiation therapy. Note that radiotherapy to previously bulky sites of disease that 
upon response assessment, remains metabolically inactive (Deauville ≤ 4) will not 
be counted as an event. Intrathecal chemotherapy may be administered if the 
investigator deems the subject to be at high risk of CNS relapse. Evidence of CNS 
disease will be reported as relapse or progression. 
Section:  7.2.4 Safety Follow-up Visit(s), paragraph 1 
Add: 
For phase 2 and phase 3, all subjects, including subjects who withdraw from treatment 
early, will complete a safety follow-up visit approximately 30 (± 3) days after their last 
dose of blinatumomab or 30 (± 3) days or after the last day of the last cycle of IC 
chemotherapy.  In the event that a planned cycle of therapy is delayed beyond 30 days, 
then the safety follow-up may be delayed without a protocol deviation.  However, in the 
event that therapy is not resumed, the subject should be seen for safety follow-up as 
Approved 
 
 


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soon as possible.  For subjects proceeding to HSCT, the safety follow-up visit must be 
conducted before the initiation of the transplant conditioning regimen. 
Section 7.2.5 Mobilization, paragraph 1 
Replace: 
Mobilization should be with colony stimulating factors (ie G-CSF or GM-CSF alone) and 
should not be preceded by chemotherapy (chemomobilization) or used in planned 
conjunction with another mobilizing agent, such as plerixafor. 
With: 
Mobilization should be with colony stimulating factors (ie G-CSF or GM-CSF alone) and 
should not be preceded by chemotherapy (chemomobilization) or done in planned 
conjunction with another mobilizing agent, such as plerixafor. 
Section 7.2.7 Long-term Follow-up, paragraph 2 
Add:   
For both phase 2 and phase 3, follow-up visits for assessment of relapse, transplant 
status, and survival will take place every 3 months (calculated from the safety follow up 
visit) until completion of a 2-year period after treatment, and then may be completed in 
person or by telephone call every 6 months (± 28 days) until study completion.  Study 
completion will occur once 236 death events for phase 3 subjects have occurred or 
12 months since last subject in phase 3 is randomized if 236th death in phase 3 subjects 
is not observed.  If the study will not continue for the phase 3 portion, study 
completion will occur when the last phase 2 subject has had the opportunity to 
complete their 2 year follow-up visit after treatment. 
Should a subject fail to return to the clinic for a scheduled protocol visit or neglect 
to participate in a scheduled follow up telephone call, sites will need to make 
3 attempts to contact subjects by a combination of telephone and mail.  Sites 
must document all 3 attempts to contact the subject.  If a subject does not 
respond within 1 month after the third contact, the subject will be considered lost 
to follow-up. 
Approved 
 
 


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Section 7.2.8 End of Study, paragraph 2 
Add:  
Study completion will occur once 236 death events for phase 3 subjects have occurred 
or 12 months after the last subject in phase 3 is randomized if 236th death in 
phase 3 subjects is not observed. 
If the study will not continue for the phase 3 portion, the study will conclude when 
all phase 2 subjects have had the opportunity to complete long term follow-up as 
described above 
Section 7.3.7 Vital Signs 
Add: 
The anatomic temperature assessment location selected for a subject should be the 
same throughout the study and documented on the vital signs eCRF.   
Section 9.1.3 Serious Adverse Events, paragraph 5 
Replace: 
The criteria for grade 4 in the CTCAE grading scale laboratory event differs from the 
regulatory criteria for serious adverse events.  It is left to the investigators judgement to 
report these grade 4 abnormalities as serious adverse events. 
With: 
If the criteria for grade 4 in the CTCAE grading scale for laboratory event differs from 
the regulatory criteria for serious adverse events, it is left to the investigator’s judgement 
whether to report these grade 4 abnormalities as serious adverse events. 
Section:  10.1.1.2 Secondary Endpoint(s), Other Secondary Endpoints 
Replace: 
Phase 2: 
• 
Objective response rates (ORR; CMR + PMR 
• 
PFS: calculated as the time from start of blinatumomab until the date of diagnosis of 
progression of lymphoma, or date of death, whichever is earliest.  Subjects who are 
alive and did not have progression will be censored at the last date of tumor 
assessment. 
Approved 
 
 


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• 
DOR: calculated only for subjects who achieve an ORR.  The duration will be 
calculated from the date a response, CMR or PMR, is first achieved until the earliest 
date of a disease assessment indicating a relapse event or death, whichever occurs 
first.  Subjects who do not have a relapse event will be censored on their last disease 
assessment date.  If the last disease assessment date is after the date that triggers 
the analysis, the subject will be censored at the analysis trigger date.  A sensitivity 
analysis will censor subjects who receive a HSCT at the time of HSCT unless there 
is no assessment after the HSCT, in which case the last assessment prior to the 
HSCT will be used as the censoring time. 
• 
Successful mobilization rate (defined as CD34+ cell 2x106/kg) 
• 
HSCT (both autologous and allogeneic) rates among subjects with 
post-blinatumomab CMR+PMR 
• 
100-day non-relapse mortality (NRM) after autologous HSCT 
• 
Blinatumomab steady state concentration and clearance 
• 
Incidence and severity of treatment-emergent adverse events 
Phase 3: 
• 
ORR (CMR+PMR) 
• 
PFS: calculated as the time from the date of randomization until the date of diagnosis 
of progression of lymphoma, or date of death, whichever is earliest.  Subjects who 
are alive and did not have progression will be censored at the last date of tumor 
assessment. 
• 
DOR 
• 
Successful mobilization rate (defined as CD34+ cell 2x106/kg) following protocol 
assigned therapy 
• 
HSCT (both autologous and allogeneic) rates among responding subjects (CMR or 
PMR) 
• 
100-day NRM after autologous HSCT rate 
• 
Patient-reported clinical outcome assessments quality of life (QOLCOA) using the 
EQ-5D and FACT-Lymphoma tools 
• 
Blinatumomab concentration steady state, clearance, and half life 
With:   
Phase 2: 
• 
Objective response rate (ORR including CMR and PMR) 
• 
PFS: calculated as the time from start of blinatumomab until the date of diagnosis of 
progression of lymphoma, or date of death, whichever is earliest.  Subjects who are 
alive and did not have progression will be censored at the last date of tumor 
assessment. 
Approved 
 
 


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• 
DOR: calculated only for subjects who achieve an OR.  The duration will be 
calculated from the date a response, CMR or PMR, is first achieved per central 
review during the first 12 weeks after starting blinatumomab until the earliest 
date of a disease assessment indicating a relapse event or death, whichever occurs 
first.  Subjects who do not have a relapse event will be censored on their last disease 
assessment date.  If the last disease assessment date is after the date that triggers 
the analysis, the subject will be censored at the analysis trigger date.  A sensitivity 
analysis will censor subjects who receive a HSCT at the time of HSCT unless there 
is no assessment after the HSCT, in which case the last assessment prior to the 
HSCT will be used as the censoring time.  Disease assessment during LTFU will 
be reviewed by investigators only per central review agreement. 
• 
Successful mobilization rate (defined as CD34+ cell 2x106/kg) 
• 
HSCT (both autologous and allogeneic) rates among subjects with 
post-blinatumomab CMR+PMR 
• 
100-day non-relapse mortality (NRM) after HSCT 
• 
Blinatumomab steady state concentration and clearance 
• 
Incidence and severity of treatment-emergent adverse events 
Phase 3: 
• 
OR (including CMR and PMR) 
• 
PFS: calculated as the time from the date of randomization until the date of diagnosis 
of progression of lymphoma, or date of death, whichever is earliest.  Subjects who 
are alive and did not have progression will be censored at the last date of tumor 
assessment. 
• 
DOR 
• 
Successful mobilization rate (defined as CD34+ cell 2x106/kg) following protocol 
assigned therapy 
• 
HSCT (both autologous and allogeneic) rates among responding subjects (CMR or 
PMR) 
• 
100-day NRM after autologous HSCT rate 
• 
Patient-reported clinical outcome assessments quality of life (QOLCOA) using the 
EQ-5D and FACT-Lymphoma tools 
• 
Blinatumomab concentration steady state, clearance, and half life 
Section 10.1.2 Analysis Sets 
Replace:   
The primary analysis of efficacy from the phase 3 part of the study will be performed on 
all randomized subjects analyzed according to their randomized treatment assignment 
(the Full Analysis Set [FAS]).  Sensitivity analyses of efficacy will be performed on the 
Safety Analysis Set.  
Approved 
 
 


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The primary analysis of safety will be performed on the Safety Analysis Set which will 
include all subjects who received protocol-specified therapy analyzed according to the 
treatment they received. 
10.1.2.1 
Full Analysis Set (FAS) 
For the phase 2 part of the study, the FAS includes all subjects who are treated with 
blinatumomab. 
For the phase 3 part of the study, the FAS Includes all subjects who are randomized.  
Analysis will be performed according to the randomized treatment, regardless of the 
treatment actually received. 
10.1.2.2 
AutoHSCT Analysis Set 
Includes all subjects who achieve a response and undergo autoHSCT.  
10.1.2.3 
Responder Analysis Set  
Includes all subjects who had CMR or PMR after first cycle of blinatumomab or IC 
chemotherapy. 
10.1.2.4 
Safety Analysis Set 
Includes all subjects from both phases of the study who received protocol-specified 
therapy.  Analysis will be performed according to the treatment received. 
With:   
The primary analysis of efficacy from the phase 2 part of the study will be performed 
on all subjects who received blinatumomab.  The primary analysis of efficacy from 
the phase 3 part of the study will be performed on all randomized subjects analyzed 
according to their randomized treatment assignment (the Full Analysis Set [FAS]).  
Sensitivity analyses of efficacy will be performed on the Safety Analysis Set.  
The primary analysis of safety will be performed on the Safety Analysis Set which will 
include all subjects who received protocol-specified therapy analyzed according to the 
treatment they received. 
10.1.2.1 
AutoHSCT Analysis Set 
Includes all subjects who achieve a response and undergo autoHSCT while in 
remission and without any other anti-cancer treatment.  
Approved 
 
 


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10.1.2.2 
Full Analysis Set (FAS) 
For the phase 2 part of the study, the FAS includes all subjects who are treated with 
blinatumomab. 
For the phase 3 part of the study, the FAS Includes all subjects who are randomized.  
Analysis will be performed according to the randomized treatment, regardless of the 
treatment actually received. 
10.1.2.3 
Target Dose Analysis Set (TDAS) 
All subjects of the FAS who completed at least 7 days of infusion on the highest 
intended dose level will consistute Target Dose Analysis set (TDAS).  In addition, 
all subjects who discontinue the treatment due to progression of disease during 
the first cycle of treatment will be included.  The primary efficacy endpoint will be 
analyzed using TDAS. 
10.1.2.4 
Responder Analysis Set  
Includes all subjects who had CMR or PMR during the first 12 weeks after initiation of 
blinatumomab or IC chemotherapy (for phase 3). 
10.1.2.5 
Safety Analysis Set 
Includes all subjects from both phases of the study who received protocol-specified 
therapy.  Analysis will be performed according to the treatment received. 
Section 10.1.3 Covariates and Subgroups 
Add: 
The analysis to determine if blinatumomab is superior to IC arm with respect to the 
primary endpoint and key secondary endpoint for phase 3 will be stratified by the 
stratification factors at randomization:  
• 
Response to S1: PMR vs NMR/PMD 
• 
Cytarabine administered in S1 (eg, R-DHAP and R-ESHAP vs R-ICE and R-GDP): 
yes vs no 
• 
PMBCL and B-cell lymphoma, unclassifiable, with features intermediate between 
DLBCL and classical Hodgkin lymphoma vs all other histologies of aggressive B-cell 
lymphoma 
Approved 
 
 


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Section:  10.2 Sample Size Considerations 
Replace:  
10.2.1 Phase 2 
The sample size for the phase 2 part of the study is determined by a 1-sample test of the 
rate of CMR after 1 cycle of blinatumomab.  With the 1-sided type I error rate (α) set at 
0.025, a null hypothesis response probability (π0) of 15%, and an alternative response 
probability (π1) of 40%, a sample size of 36 subjects will provide 90% power to reject the 
null hypothesis that the response probability is no more than 15%.  Being able to make 
this determination will represent evidence of clinical activity and warrant advancement 
into the phase 3 part of the study. 
With:   
The sample size for the phase 2 part of the study is determined by a 1-sample test of the 
rate of CMR during the first 12 weeks after initiation of blinatumomab.  With the 
1-sided type I error rate (α) set at 0.025, a null hypothesis response probability (π0) of 
15%, and an alternative response probability (π1) of 40%, a sample size of 36 subjects 
will provide 90% power to reject the null hypothesis that the response probability is no 
more than 15%.  Being able to make this determination will represent evidence of clinical 
activity and warrant advancement into the phase 3 part of the study. 
Section:  10.4.4 Final Analysis, paragraph 2 
Add: 
The final analysis will test whether OS is superior in the group randomized to 
blinatumomab compared to the group randomized to IC.  The final analysis will be 
triggered by the date when the 236th death in phase 3 subjects is reported in the clinical 
trial database, or the study duration reaches 12 months from the last subject 
randomized.  The estimated time is 26 months to reach the OS event goal.  Barring a 
sample-size increase, since the enrollment period is expected to last 21 months, the 
estimated maximum follow up time is 33 months. 
In case that the phase 3 portion of the study is not initiated, the final analysis will 
occur when all subjects in phase 2 complete long term follow-up defined in 
Section 7.2.7. 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20150292 
Date:  07 May 2019 
Page 21 of 25 
CONFIDENTIAL 
 
 
Section:  10.5.2 Primary Efficacy Endpoint, paragraph 1 
Replace:   
Phase 2: 
The percentage of subjects with a CMR after the first cycle of blinatumomab will be 
summarized with an exact binomial 95% confidence interval.  Summary of CMR during 
the treatment will also be provided.  
With: 
Phase 2: 
The percentage of subjects with a CMR during the first 12 weeks after initiation of 
blinatumomab will be summarized with an exact binomial 95% confidence interval.  
Summary of CMR during the treatment will also be provided.  
Section:  10.5.3 Secondary Efficacy Endpoint(s), phase 2 
Replace: 
Phase 2: 
Other secondary efficacy endpoints include ORR after the first cycle of blinatumomab or 
IC chemotherapy and during the treatment, PFS, duration of CMR, DOR, successful 
mobilization rate, alloHSCT rate, autoHSCT rate and 100-day NRM after autoHSCT.  
ORR afterthe first cycle starting blinatumomab during the treatment will be summarized 
with an exact binomial 95% confidence interval.  
PFS will be summarized with the KM summaries.  
Duration of CMR and duration of response will be summarized with the KM summaries 
in Responders Analysis Set. 
Successful mobilization rate, autoHSCT rate and alloHSCT rate will be summarized with 
an exact binomial 95% confidence interval. AutoHSCT rate will be analyzed using 
autoHSCT Analysis Set.  
The 100-day NRM after autoHSCT rate will be summarized with the cumulative 
incidence function with non-relapse deaths treated as competing risks.  For this 
endpoint, time to non-relapse deaths will be measured starting from the date of 
autologous HSCT. 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20150292 
Date:  07 May 2019 
Page 22 of 25 
CONFIDENTIAL 
 
 
With: 
Phase 2: 
Other secondary efficacy endpoints include OR after initiation of blinatumomab and 
during the treatment, PFS, duration of CMR, DOR, successful mobilization rate, 
alloHSCT rate, autoHSCT rate and 100-day NRM after autoHSCT.  
OR during the first 12 weeks after initiation of blinatumomab during the treatment will 
be summarized with an exact binomial 95% confidence interval.  
PFS will be summarized with the KM summaries.  
Duration of CMR and duration of response will be summarized with the KM summaries 
in Responders Analysis Set. 
Successful mobilization rate, autoHSCT rate and alloHSCT rate will be summarized with 
an exact binomial 95% confidence interval. AutoHSCT rate will be analyzed using 
autoHSCT Analysis Set.  
The 100-day NRM after autoHSCT rate will be summarized with the cumulative 
incidence function with relapse or deaths due to relapse treated as competing risks.  
For this endpoint, time to non-relapse deaths will be measured starting from the date of 
autologous HSCT. 
Section:  10.5.3 Secondary Efficacy Endpoint(s), phase 3, paragraph 2 
Delete:  
Other secondary efficacy endpoints include ORR, PFS, duration of CMR and ORR, 
successful mobilization rate, HSCT rate, 100-day NRM after HSCT rate.  Overall 
response rate will be summarized by treatment group with an exact binomial 
95% confidence interval. 
Section:  10.5.4.1 Adverse Events, paragraph 4 
Replace: 
A summary of treatment-emergent AEs with at least a 5% higher subject incidence in 
1 treatment arm compared to the other will be presented by preferred term. 
With: 
For phase 3, a summary of treatment-emergent AEs with at least a 5% higher subject 
incidence in 1 treatment arm compared to the other will be presented by preferred term. 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20150292 
Date:  07 May 2019 
Page 23 of 25 
CONFIDENTIAL 
 
 
Section:  10.5.4.1 Adverse Events, paragraph 6 
Delete: 
All races (if appropriate) with less than 5% of the total randomized subjects will be 
pooled together for summary purposes. 
Section:  10.5.4.2 Laboratory Test Results, paragraph 1 
Replace: 
Shift tables between the worst post-baseline and baseline grades for selected laboratory 
parameters will be provided. Plots or other summaries overtime will be presented for 
selected laboratory parameters including immunoglobulins, platelets, and liver 
parameters by treatment group for subjects in the Safety Analysis Set.   
With: 
Shift tables between the worst post-baseline and baseline grades for selected laboratory 
parameters will be provided. Plots or other summaries overtime will be presented for 
selected laboratory parameters including immunoglobulins, platelets, and liver 
parameters for subjects in the Safety Analysis Set.  The summary will be done by 
treatment group for phase 3. 
Section:  10.5.4.3 Vital Signs, paragraph 1 
Replace: 
The number and percentage of subjects with abnormal changes in systolic blood 
pressure, diastolic blood pressure and heart rate will be summarized by treatment group 
for subjects in the Safety Analysis Set.   
With: 
The number and percentage of subjects with abnormal changes in systolic blood 
pressure, diastolic blood pressure and heart rate will be summarized for subjects in the 
Safety Analysis Set.  The summary will be done by treatment group for phase 3. 
Section:  10.5.4.6 Exposure to Investigational Product, paragraph 1 
Replace: 
Descriptive statistics will be produced to describe the exposure to IP by treatment group 
for subjects in the Safety Analysis Set. For both treatment groups, the number of cycles 
of protocol-specified therapy administered will be summarized with an additional 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20150292 
Date:  07 May 2019 
Page 24 of 25 
CONFIDENTIAL 
 
 
breakdown of the number of cycles completed, discontinued, and re-started. In addition, 
the duration of therapy, the relative treatment duration, the cumulative dose, and the 
percent of intended dose will be summarized by cycle and overall for the treatment 
group and, if calculable, for the IC arm. The number and percent of subjects with dose 
modifications (eg, dose changes, dose interruptions) and reason for modification will be 
summarized for both treatment groups.  For subjects receiving IC chemotherapy, the 
chemotherapy will be summarized. 
With: 
Descriptive statistics will be produced to describe the exposure to IP for subjects in the 
Safety Analysis Set. The number of cycles of protocol-specified therapy administered will 
be summarized with an additional breakdown of the number of cycles completed, 
discontinued, and re-started. In addition, the duration of therapy, the relative treatment 
duration, the cumulative dose, and the percent of intended dose will be summarized by 
cycle and overall. The number and percent of subjects with dose modifications (eg, dose 
changes, dose interruptions) and reason for modification will be summarized. The 
summary will be done by treatment group for phase 3. 
Section:  10.5.4.7 Exposure to Concomitant Medication, paragraph 1 
Replace: 
The number and proportion of subjects receiving concomitant medications from study 
day 1 through safety follow-up will be summarized by preferred term as coded by the 
World Health Organization Drug (WHODRUG) dictionary by treatment group in the 
Safety Analysis Set. In addition, the number and proportion of subjects receiving 
anticancer therapies (including HSCT conditioning regimens) during long term follow-up 
will be summarized by WHODRUG preferred term for each treatment group in the FAS. 
With: 
The number and proportion of subjects receiving concomitant medications from study 
day 1 through safety follow-up will be summarized by preferred term as coded by the 
World Health Organization Drug (WHODRUG) dictionary in the Safety Analysis Set. In 
addition, the number and proportion of subjects receiving anticancer therapies (including 
HSCT conditioning regimens) during long term follow-up will be summarized by 
WHODRUG preferred term in the FAS. The summary will be done by treatment 
group for phase 3. 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20150292 
Date:  07 May 2019 
Page 25 of 25 
CONFIDENTIAL 
 
 
Section:  12.4 Investigator Responsibilities for Data Collection, paragraph 1 
Delete: 
Amgen (or designee) will perform Self-Evident Corrections (SEC) to obvious data errors 
in the clinical trial database. SECs will be documented in the eCRF instructions available 
in the EDC system. Examples of obvious data errors that may be corrected by Amgen 
(or designee) include deletion of obvious duplicate data (ie, the same results sent twice 
with the same date with different visit, [eg, week 4 and early termination]) and updating a 
specific response if the confirming datum is provided in the “other, specify” field (eg, for 
race, reason for ending study). 
Approved 
 
 

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