Clinical Study With Blinatumomab in Pediatric and Adolescent Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia

• Sponsor: Amgen Research (Munich) GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01471782
• Collaborator: (none)
• Enrollment: 93
• Locations: 30
• Arm: 1
• Duration (Months): 52
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the dose of the bispecific T cell engager blinatumomab (MT103) in pediatric and adolescent patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and to assess whether this dose of blinatumomab is effective.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia	Biological: Blinatumomab	Phase 1/Phase 2

Detailed Description

Childhood acute lymphoblastic leukemia (ALL) is a type of cancer of the blood and bone marrow in which the bone marrow makes too many abnormal immature lymphocytes.

Blinatumomab is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T cell activation and a cytotoxic T cell response against cluster of differentiation (CD)19 expressing cells.

The purpose of this study is to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of escalating doses of blinatumomab in pediatric and adolescent patients with relapsed/refractory B-precursor ALL, to select a dose and to investigate the efficacy and safety of that dose of blinatumomab in the above-mentioned patient population.

The phase 1 part of the study included the evaluation of four dose levels of blinatumomab with comprehensive PK/PD assessments and was separated in 2 parts:

• Phase 1 dose evaluation/escalation part to define the recommended phase 2 dose of blinatumomab in patients aged 2 to 17 years

• Phase 1 PK expansion part in patients aged < 18 years to further assess PK/PD at the recommended phase 2 dose. In this part additional participants were enrolled to ensure that 6 patients in each of the 2 older age groups (2-6 and 7-17 years) were analyzed for PK before recruitment of infants < 2 years of age began.

In the phase 2 extension cohort (efficacy phase) of the study, eligible participants less than 18 years were enrolled according to a two-stage design and received blinatumomab at the recommended dose level (5/15 μg/m²/day).

The study consisted of a screening period, a treatment period, and an End of Core Study visit 30 days after last dose of study medication. A treatment cycle consisted of a continuous intravenous (cIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks. Participants who achieved complete remission (CR) within 2 cycles of treatment could receive up to 3 additional consolidation cycles of blinatumomab. Instead of consolidation cycles with blinatumomab, participants could be withdrawn from blinatumomab treatment to receive chemotherapy or allogeneic HSCT as early as the first cycle, at the discretion of the investigator.

After the last treatment cycle and End of Core Study visit, all participants were followed for efficacy and survival for up to 24 months after treatment start. Participants who suffered a hematological relapse of B-precursor ALL during their follow-up period (at least 3 months after completion of treatment) had the possibility for retreatment with blinatumomab.

Study Design

• Study Type: Interventional
• Actual Enrollment: 93 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single-Arm Multicenter Phase II Study Preceded by Dose Evaluation to Investigate the Efficacy, Safety, and Tolerability of the BiTE® Antibody Blinatumomab (MT103) in Pediatric and Adolescent Patients With Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: May 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Blinatumomab Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate over 4 weeks followed by a treatment-free interval of 2 weeks. Doses ranged between 5 and 30 µg/m²/day. Each participant received up to five cycles of treatment.	Biological: Blinatumomab; Administered by continuous intravenous infusion; Other Names: MT103 AMG103 BLINCYTO®

Outcome Measures

Primary Outcome Measures

1. Phase I: Number of Participants With Dose-limiting Toxicities (DLTs) [Cycle 1, 28 days]

   The maximum tolerated dose (MTD) was defined as one or fewer out of 6 participants experiencing a dose limiting toxicity (DLT) or the maximum administered dose (MAD). A dose limiting toxicity is any Grade ≥ 3 adverse event related to study drug, Grade 3 fatigue, headache, insomnia, fever, hypotension or infection were not considered dose limiting toxicities. Laboratory parameters of Grade ≥ 3 but not considered as clinically relevant and/or responding to routine medical management, thrombocytopenia, leukopenia (including neutropenia and lymphopenia), and anemia were not considered dose limiting toxicities.

2. Percentage of Participants With Complete Remission in the First Two Cycles [Cycles 1 and 2 (12 weeks)]

   Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central laboratory. Complete remission (CR) was defined as M1 bone marrow (bone marrow blasts < 5%) No evidence of circulating blasts or extra-medullary disease Complete remission includes participants with incomplete recovery of peripheral blood counts.

Secondary Outcome Measures

1. Number of Participants With Adverse Events [From the start of the first infusion to 30 days after the end of the last infusion in the core study or from the start of the first retreatment cycle infusion to 30 days after the end of the last retreatment cycle, median treatment duration was 28 days]

   The severity (or intensity) of adverse events (AEs) was assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v4.03 and according to the following: Grade 1 - Mild adverse event; Grade 2 - Moderate adverse event; Grade 3 - Severe and undesirable adverse event; Grade 4 - Life-threatening or disabling adverse event; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab.

2. Steady State Concentration of Blinatumomab [Cycles 1 and 2 during the IV infusion on day 3 (at least 48 hours after start of infusion) and days 8, 15 and 22 (steady state) and day 29 at End of Infusion (EoI) and 2, 4, and 8 hours after EoI for ages ≥ 2 years.]

   Blinatumomab serum concentrations were quantified in all patients during the first 2 treatment cycles in the phase 1 part of the study only. Blinatumomab concentrations were quantified using a validated bioassay, the lower limit of quantification was 50 pg/mL. Steady state serum concentration (Css) was presumed on day 1, approximately 5 half-lives after the start of the IV infusion. The steady state serum concentration reported is the mean of the observed concentrations collected after during cycles 1 and 2.

3. Time to Hematological Relapse (Duration of Response) [Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.5 months for phase 2.]

   Time to hematological relapse was measured only for participants in remission and was measured from the time the participant first achieved remission until first documented relapse or death due to disease progression. Participants without a documented relapse (hematological or extramedullary) and who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Participants who died without having reported hematological relapse or without showing any clinical sign of disease progression were censored on their date of death. Hematological relapse is defined as the proportion of blasts in bone marrow > 25% following documented remission, or extramedullary relapse. Time to hematological relapse was analyzed by Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method.

4. Overall Survival [Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.6 months for phase 2.]

   Overall survival (OS) was measured for all participants from the first treatment of blinatumomab until death due to any cause or the date of the last follow-up. Participants who did not die were censored on the last documented visit date or the date of the last contact when the patient was last known to have been alive. For patients who withdrew their informed consent only information until the date of withdrawal was analyzed. Overall survival was estimated using Kaplan-Meier methods. The median follow-up time with respect to overall survival was calculated by the reverse Kaplan-Meier method.

5. Relapse-free Survival [Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.5 months for phase 2.]

   Relapse-free survival (RFS) was assessed for participants who achieved a complete remission during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to any cause. Participants without a documented relapse (hematological or extramedullary) or who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Relapse free survival was estimated using Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan-Meier method.

6. Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant During Blinatumomab Induced Remission [Up to the data cut-off date of 12 January 2015; Maximum duration on study was 24 months in phase 1 and 15 months for phase 2.]

   The percentage of participants who received allogeneic hematopoietic stem cell transplantation (HSCT) while in remission due to treatment with blinatumomab during the first two cycles, and received no further anti-leukemic medication before HSCT.

7. Number of Participants Who Developed Anti-blinatumomab Antibodies [Predose up until 30 days after last dose of study medication; median treatment duration was 28 days.]

   Antibodies to blinatumomab were detected using an electrochemiluminescence (ECL)-based assay.

8. Serum Cytokine Peak Levels [Cycle 1 and 2 day 1 (prior to infusion, 2 and 6 hours after infusion start), day 2 and day 3.]

   The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-ɣ) using cytometric bead assays. The limit of detection of the assay (LOD) was 20 pg/mL and the lower limit of quantification (LLOQ) was 125 pg/mL. Data below LOD were set to 10 pg/mL while data < LOQ and > LOD were reported as measured.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Morphologic evidence of B-precursor ALL with > 25% blasts in bone marrow (M3) at study enrolment

• Age less than 18 years at enrollment

• Relapsed/refractory disease:

• Second or later bone marrow relapse,

• Any marrow relapse after allogeneic hematopoietic stem cell transplantation (HSCT), or

• Refractory to other treatments: Patients in first relapse must have failed to achieve a CR following full standard reinduction chemotherapy regimen of at least 4 weeks duration. Patients who have not achieved a first remission must have failed a full standard induction regimen

• Karnofsky performance status more than or equal to 50% for patients more than or equal to 16 years and Lansky Performance Status (LPS) of more than or equal to 50% for patients less than 16 years

• Organ function requirements: All patients must have adequate renal and liver functions

Exclusion Criteria:

• Active acute or extensive chronic graft-versus-host disease (GvHD)

• Immunosuppressive agents to prevent or treat GvHD within 2 weeks prior to blinatumomab treatment

• Evidence for current central nervous system (CNS) involvement by ALL (CNS 2, CNS 3) or testicular involvement by ALL

• History of relevant CNS pathology or current relevant CNS pathology

• History of autoimmune disease with potential CNS involvement or current autoimmune disease

• Any HSCT within 3 months prior to blinatumomab treatment

• Cancer chemotherapy within 2 weeks prior to blinatumomab treatment (except for intrathecal chemotherapy and/or low dose maintenance therapy such as vinca alkaloids, mercaptopurine, methotrexate, glucocorticoids)

• Chemotherapy related toxicities that haven't resolved to less than or equal to Grade 2

• Radiotherapy within 2 weeks prior to blinatumomab treatment

• Immunotherapy (e.g. rituximab, alemtuzumab) within 6 weeks prior to blinatumomab treatment

• Any investigational product within 4 weeks prior to study entry

• Previous treatment with blinatumomab

• Active severe infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol

• Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HbsAg positive) or hepatitis C virus (anti-HCV positive)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital Denver	Aurora	Colorado	United States	80045
2	Children's Healthcare of Atlanta at Egleston	Atlanta	Georgia	United States	30322
3	Washington University	ST. Louis	Missouri	United States
4	Memorial Sloan Kettering	New York	New York	United States	10065
5	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
6	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
7	St Jude Children's Research Hospital	Memphis	Tennessee	United States	38105-3678
8	UT Southwestern Medical Center	Dallas	Texas	United States	75390-9063
9	Texas Children's Cancer Center/ Baylor	Houston	Texas	United States	77030-2399
10	Primary Children's Medical Center	Salt Lake City	Utah	United States
11	Seattle Children's Hospital	Seattle	Washington	United States	98105
12	St. Anna Kinderspital	Vienna		Austria	1090
13	Hospital for Sick Children	Toronto	Ontario	Canada	M5G1X8
14	(CHU Besancon) Hopital Saint-Jaques	Besancon		France	25030
15	Hôpital de la Timone (Enfants)	Marseille		France
16	Hopital Robert Debré (AP-HP)	Paris Cedex 19		France	75935
17	Charité Campus Virchow Klinikum, Otto-Heubner-Centrum (OHC) für Kinder- und Jugendmedizin	Berlin		Germany	13353
18	Universitätsklinikum Düsseldorf	Düsseldorf		Germany	40225
19	Universitätsklinikum Essen	Essen		Germany
20	Klinikum der Johann Wolfgang Goethe-Universität Frankfurt/Main	Frankfurt am Main		Germany	60590
21	Universitätsklinikum Hamburg-Eppendorf	Hamburg		Germany
22	Medizinische Hochschule Hannover	Hannover		Germany
23	Universitätsklinikum Schleswig-Holstein Campus Kiel	Kiel		Germany
24	Klinikum der Universität München, Dr. von Haunersches Kinderspital	München		Germany	80337
25	Universitätsklinik für Kinder- und Jugendmedizin Tübingen	Tübingen		Germany	72076
26	Universitätsklinikum Würzburg	Würzburg		Germany
27	University of Milano-Bicocca, Hospital San Gerardo	Monza		Italy	20052
28	Dipartimento della Donna e del Bambino	Padova		Italy
29	The Bambino Gesù Children's Hospital	Rome		Italy	00165
30	Erasmus MC, Sophia Children's Hospital	Rotterdam		Netherlands	3015 GJ

Sponsors and Collaborators

• Amgen Research (Munich) GmbH

Investigators

• Study Chair: Arend von Stackelberg, MD, Charite University, Berlin, Germany
• Study Chair: Lia Gore, MD, Children's Hospital Denver, USA

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Amgen Research (Munich) GmbH
• ClinicalTrials.gov Identifier: NCT01471782
• Other Study ID Numbers: MT103-205; 2010-024264-18
• First Posted: Nov 16, 2011
• Last Update Posted: Feb 8, 2017
• Last Verified: Dec 1, 2016

• Keywords provided by Amgen Research (Munich) GmbH: ALL; relapsed, refractory B-precursor ALL; Leukemia; Leukemia, Lymphoid; Precursor Cell Lymphoblastic Leukemia; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Antibodies, Bispecific
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Blinatumomab

Study Results

Participant Flow

Recruitment Details	The study was conducted in 26 centers in Germany, France, Italy, the Netherlands, the United Kingdom, and the United States of America. Results are reported for the primary analysis with a data cut-off date of 12 January 2015.
Pre-assignment Detail	The Phase 1 part of the study comprised 2 parts: a dose evaluation/escalation part in patients aged 2 to 17 years to define the recommended phase 2 dose of blinatumomab (4 arms), a pharmacokinetic (PK) expansion part in patients less than 18 years. The Phase 2 efficacy part enrolled patients at the recommended dose determined in phase 1.

Arm/Group Title	Phase 1: Blinatumomab 5 µg/m²/Day	Phase 1: Blinatumomab 15 µg/m²/Day	Phase 1: Blinatumomab 30 µg/m²/Day	Phase 1: Blinatumomab 15/30 µg/m²/Day	Phase 1: Blinatumomab 5/15 µg/m²/Day	Phase 2: Blinatumomab 5/15 µg/m²/Day
Arm/Group Description	Dose Evaluation/Escalation: Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate of 5 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Dose Evaluation/Escalation: Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Dose Evaluation/Escalation: Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Dose Evaluation/Escalation: Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day for the first week of cycle 1 and then at 30 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 30 µg/m²/day for up to five cycles of treatment.	PK Expansion: Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.
Period Title: Overall Study
STARTED	5	7	5	6	26	44
COMPLETED	0	1	0	1	0	3
NOT COMPLETED	5	6	5	5	26	41

Baseline Characteristics

Arm/Group Title	Phase 1: Blinatumomab 5 µg/m²/Day	Phase 1: Blinatumomab 15 µg/m²/Day	Phase 1: Blinatumomab 30 µg/m²/Day	Phase 1: Blinatumomab 15/30 µg/m²/Day	Phase 1: Blinatumomab 5/15 µg/m²/Day	Phase 2: Blinatumomab 5/15 µg/m²/Day	Total
Arm/Group Description	Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate of 5 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day for the first week of cycle 1 and then at 30 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 30 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.	Total of all reporting groups
Overall Participants	5	7	5	6	26	44	93
Age, Customized (participants) [Number]
< 2 years	0 0%	0 0%	0 0%	0 0%	8 30.8%	2 4.5%	10 10.8%
2 - 6 years	3 60%	5 71.4%	2 40%	4 66.7%	9 34.6%	11 25%	34 36.6%
7 - 17 years	2 40%	2 28.6%	3 60%	2 33.3%	9 34.6%	31 70.5%	49 52.7%
Gender (Count of Participants)
Female	3 60%	4 57.1%	2 40%	1 16.7%	11 42.3%	12 27.3%	33 35.5%
Male	2 40%	3 42.9%	3 60%	5 83.3%	15 57.7%	32 72.7%	60 64.5%
Race/Ethnicity, Customized (participants) [Number]
White	5 100%	7 100%	5 100%	5 83.3%	22 84.6%	33 75%	77 82.8%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
American Indian or Alaska native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or other Pacific islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Other	0 0%	0 0%	0 0%	1 16.7%	3 11.5%	5 11.4%	9 9.7%
Unknown	0 0%	0 0%	0 0%	0 0%	1 3.8%	6 13.6%	7 7.5%
Prior Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) (participants) [Number]
Yes	3 60%	6 85.7%	2 40%	4 66.7%	15 57.7%	25 56.8%	55 59.1%
No	2 40%	1 14.3%	3 60%	2 33.3%	11 42.3%	19 43.2%	38 40.9%

Outcome Measures

1. Primary Outcome

Title	Phase I: Number of Participants With Dose-limiting Toxicities (DLTs)
Description	The maximum tolerated dose (MTD) was defined as one or fewer out of 6 participants experiencing a dose limiting toxicity (DLT) or the maximum administered dose (MAD). A dose limiting toxicity is any Grade ≥ 3 adverse event related to study drug, Grade 3 fatigue, headache, insomnia, fever, hypotension or infection were not considered dose limiting toxicities. Laboratory parameters of Grade ≥ 3 but not considered as clinically relevant and/or responding to routine medical management, thrombocytopenia, leukopenia (including neutropenia and lymphopenia), and anemia were not considered dose limiting toxicities.
Time Frame	Cycle 1, 28 days

Outcome Measure Data

Analysis Population Description

Participants in the Phase 1 dose evaluation/escalation part of the study

Arm/Group Title	Phase 1: Blinatumomab 5 µg/m²/Day	Phase 1: Blinatumomab 15 µg/m²/Day	Phase 1: Blinatumomab 30 µg/m²/Day	Phase 1: Blinatumomab 15/30 µg/m²/Day
Arm/Group Description	Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate of 5 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day for the first week of cycle 1 and then at 30 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 30 µg/m²/day for up to five cycles of treatment.
Measure Participants	5	7	5	6
Number [participants]	0 0%	1 14.3%	2 40%	1 16.7%

2. Primary Outcome

Title	Percentage of Participants With Complete Remission in the First Two Cycles
Description	Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central laboratory. Complete remission (CR) was defined as M1 bone marrow (bone marrow blasts < 5%) No evidence of circulating blasts or extra-medullary disease Complete remission includes participants with incomplete recovery of peripheral blood counts.
Time Frame	Cycles 1 and 2 (12 weeks)

Outcome Measure Data

Analysis Population Description

The full analysis set includes all participants who received any infusion of blinatumomab.

Arm/Group Title	Phase 1: Blinatumomab 5 µg/m²/Day	Phase 1: Blinatumomab 15 µg/m²/Day	Phase 1: Blinatumomab 30 µg/m²/Day	Phase 1: Blinatumomab 15/30 µg/m²/Day	Phase 1: Blinatumomab 5/15 µg/m²/Day	Phase 2: Blinatumomab 5/15 µg/m²/Day	Phase 1+2: Blinatumomab 5/15 µg/m²/Day
Arm/Group Description	Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate of 5 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day for the first week of cycle 1 and then at 30 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 30 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/ day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.
Measure Participants	5	7	5	6	26	44	70
Number (95% Confidence Interval) [percentage of participants]	20.0 400%	42.9 612.9%	20.0 400%	33.3 555%	50.0 192.3%	31.8 72.3%	38.6 41.5%

3. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	The severity (or intensity) of adverse events (AEs) was assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), v4.03 and according to the following: Grade 1 - Mild adverse event; Grade 2 - Moderate adverse event; Grade 3 - Severe and undesirable adverse event; Grade 4 - Life-threatening or disabling adverse event; Grade 5 - Death. The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab.
Time Frame	From the start of the first infusion to 30 days after the end of the last infusion in the core study or from the start of the first retreatment cycle infusion to 30 days after the end of the last retreatment cycle, median treatment duration was 28 days

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Phase 1: Blinatumomab 5 µg/m²/Day	Phase 1: Blinatumomab 15 µg/m²/Day	Phase 1+2: Blinatumomab 5/15 µg/m²/Day	Phase 1: Blinatumomab 15/30 µg/m²/Day	Phase 1: Blinatumomab 30 µg/m²/Day
Arm/Group Description	Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate of 5 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day for the first week of cycle 1 and then at 30 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 30 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.
Measure Participants	5	7	70	6	5
Any adverse event (AE)	5 100%	7 100%	70 1400%	6 100%	5 19.2%
Adverse event of at least CTC grade 3	4 80%	7 100%	61 1220%	6 100%	5 19.2%
Serious adverse event (SAEs)	4 80%	4 57.1%	39 780%	4 66.7%	3 11.5%
SAE of at least grade 3	4 80%	3 42.9%	28 560%	4 66.7%	3 11.5%
AE leading to interruption of study drug	0 0%	0 0%	10 200%	2 33.3%	2 7.7%
AE leading to discontinuation of study drug	1 20%	1 14.3%	4 80%	2 33.3%	2 7.7%
Adverse event leading to death	0 0%	1 14.3%	8 160%	3 50%	1 3.8%
Treatment-related adverse event (TRAE)	5 100%	6 85.7%	59 1180%	5 83.3%	5 19.2%
TRAE of at least CTC grade 3	4 80%	5 71.4%	38 760%	4 66.7%	5 19.2%
Treatment-related serious adverse event	3 60%	2 28.6%	15 300%	1 16.7%	2 7.7%
TRAE leading to discontinuation of study drug	1 20%	1 14.3%	2 40%	1 16.7%	2 7.7%
TRAE leading to death	0 0%	0 0%	0 0%	1 16.7%	0 0%

4. Secondary Outcome

Title	Steady State Concentration of Blinatumomab
Description	Blinatumomab serum concentrations were quantified in all patients during the first 2 treatment cycles in the phase 1 part of the study only. Blinatumomab concentrations were quantified using a validated bioassay, the lower limit of quantification was 50 pg/mL. Steady state serum concentration (Css) was presumed on day 1, approximately 5 half-lives after the start of the IV infusion. The steady state serum concentration reported is the mean of the observed concentrations collected after during cycles 1 and 2.
Time Frame	Cycles 1 and 2 during the IV infusion on day 3 (at least 48 hours after start of infusion) and days 8, 15 and 22 (steady state) and day 29 at End of Infusion (EoI) and 2, 4, and 8 hours after EoI for ages ≥ 2 years.

Outcome Measure Data

Analysis Population Description

Phase 1 participants with available blinatumomab concentration data

Arm/Group Title	Phase 1: Blinatumomab 5 µg/m²/Day	Phase 1: Blinatumomab 15 µg/m²/Day	Phase 1: Blinatumomab 30 µg/m²/Day
Arm/Group Description	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day.
Measure Participants	27	34	7
Cycle 1 (N = 27, 34, 7)	162 (179)	533 (392)	1520 (1020)
Cycle 2 (N = 3, 13, 5)	456 (288)	866 (655)	1150 (701)

5. Secondary Outcome

Title	Time to Hematological Relapse (Duration of Response)
Description	Time to hematological relapse was measured only for participants in remission and was measured from the time the participant first achieved remission until first documented relapse or death due to disease progression. Participants without a documented relapse (hematological or extramedullary) and who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Participants who died without having reported hematological relapse or without showing any clinical sign of disease progression were censored on their date of death. Hematological relapse is defined as the proportion of blasts in bone marrow > 25% following documented remission, or extramedullary relapse. Time to hematological relapse was analyzed by Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method.
Time Frame	Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.5 months for phase 2.

Outcome Measure Data

Analysis Population Description

Full analysis set with complete remission

Arm/Group Title	Phase 1: Blinatumomab	Phase 2: Blinatumomab 5/15 µg/m²/Day	Phase 1+2: Blinatumomab 5/15 µg/m²/Day
Arm/Group Description	Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate ranging from 5 to 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/ day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.
Measure Participants	21	14	27
Median (95% Confidence Interval) [months]	10.3	3.4	5.2

6. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) was measured for all participants from the first treatment of blinatumomab until death due to any cause or the date of the last follow-up. Participants who did not die were censored on the last documented visit date or the date of the last contact when the patient was last known to have been alive. For patients who withdrew their informed consent only information until the date of withdrawal was analyzed. Overall survival was estimated using Kaplan-Meier methods. The median follow-up time with respect to overall survival was calculated by the reverse Kaplan-Meier method.
Time Frame	Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.6 months for phase 2.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Phase 1: Blinatumomab	Phase 2: Blinatumomab 5/15 µg/m²/Day	Phase 1+2: Blinatumomab 5/15 µg/m²/Day
Arm/Group Description	Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate ranging from 5 to 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/ day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.
Measure Participants	49	44	70
Median (95% Confidence Interval) [months]	6.5	8.2	7.5

7. Secondary Outcome

Title	Relapse-free Survival
Description	Relapse-free survival (RFS) was assessed for participants who achieved a complete remission during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to any cause. Participants without a documented relapse (hematological or extramedullary) or who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Relapse free survival was estimated using Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan-Meier method.
Time Frame	Up to the data cut-off date of 12 January 2015; median observation time was 23.5 months for phase 1 and 11.5 months for phase 2.

Outcome Measure Data

Analysis Population Description

Full analysis set with complete remission

Arm/Group Title	Phase 1: Blinatumomab	Phase 2: Blinatumomab 5/15 µg/m²/Day	Phase 1+2: Blinatumomab 5/15 µg/m²/Day
Arm/Group Description	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate ranging from 5 to 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/ day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.
Measure Participants	21	14	27
Median (95% Confidence Interval) [months]	7.9	3.4	4.4

8. Secondary Outcome

Title	Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant During Blinatumomab Induced Remission
Description	The percentage of participants who received allogeneic hematopoietic stem cell transplantation (HSCT) while in remission due to treatment with blinatumomab during the first two cycles, and received no further anti-leukemic medication before HSCT.
Time Frame	Up to the data cut-off date of 12 January 2015; Maximum duration on study was 24 months in phase 1 and 15 months for phase 2.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Phase 1: Blinatumomab 5 µg/m²/Day	Phase 1: Blinatumomab 15 µg/m²/Day	Phase 1: Blinatumomab 30 µg/m²/Day	Phase 1: Blinatumomab 15/30 µg/m²/Day	Phase 1: Blinatumomab 5/15 µg/m²/Day	Phase 2: Blinatumomab 5/15 µg/m²/Day	Phase 1+2: Blinatumomab 5/15 µg/m²/Day
Arm/Group Description	Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate of 5 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day for the first week of cycle 1 and then at 30 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 30 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/ day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.
Measure Participants	5	7	5	6	26	44	70
Number (95% Confidence Interval) [percentage of participants]	20.0 400%	28.6 408.6%	20.0 400%	16.7 278.3%	30.8 118.5%	11.4 25.9%	18.6 20%

9. Secondary Outcome

Title	Number of Participants Who Developed Anti-blinatumomab Antibodies
Description	Antibodies to blinatumomab were detected using an electrochemiluminescence (ECL)-based assay.
Time Frame	Predose up until 30 days after last dose of study medication; median treatment duration was 28 days.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Phase 1: Blinatumomab 5 µg/m²/Day	Phase 1: Blinatumomab 15 µg/m²/Day	Phase 1: Blinatumomab 30 µg/m²/Day	Phase 1: Blinatumomab 15/30 µg/m²/Day	Phase 1: Blinatumomab 5/15 µg/m²/Day	Phase 2: Blinatumomab 5/15 µg/m²/Day
Arm/Group Description	Blinatumomab was administered as a continuous intravenous (cIV) infusion at a constant daily flow rate of 5 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day for the first week of cycle 1 and then at 30 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 30 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.
Measure Participants	5	7	5	6	26	44
Number [participants]	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

10. Secondary Outcome

Title	Serum Cytokine Peak Levels
Description	The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-alpha (TNF-α) and interferon gamma (IFN-ɣ) using cytometric bead assays. The limit of detection of the assay (LOD) was 20 pg/mL and the lower limit of quantification (LLOQ) was 125 pg/mL. Data below LOD were set to 10 pg/mL while data < LOQ and > LOD were reported as measured.
Time Frame	Cycle 1 and 2 day 1 (prior to infusion, 2 and 6 hours after infusion start), day 2 and day 3.

Outcome Measure Data

Analysis Population Description

Phase 1 full analysis set participants with available data

Arm/Group Title	Phase 1: Blinatumomab 5 µg/m²/Day	Phase 1: Blinatumomab 15 µg/m²/Day	Phase 1: Blinatumomab 30 µg/m²/Day
Arm/Group Description	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day..	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day.	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day.
Measure Participants	31	14	5
IL-6: Cycle 1 Week 1 (N=31, 13, 5)	4970 (17000)	1780 (2620)	23400 (24100)
IL-6: Cycle 2 Week 1 (N=4, 14, 5)	526 (844)	892 (2370)	40.4 (68.0)
IL-10: Cycle 1 Week 1 (N=31, 13, 5)	562 (710)	1400 (2030)	3170 (1720)
IL-10: Cycle 2 Week 1 (N=4, 14, 5)	519 (497)	432 (692)	277 (308)
IFN-ɣ: Cycle 1 Week 1 (N=31, 13, 5)	207 (516)	539 (1240)	2260 (1540)
IFN-ɣ: Cycle 2 Week 1 (N=4, 14, 5)	51.8 (65.6)	47.6 (51.5)	22.8 (28.6)
IL-2: Cycle 1 Week 1 (N=31, 13, 5)	22.7 (23)	93.9 (150)	900 (1390)
IL-2: Cycle 2 Week 1 (N=4, 14, 5)	10.0 (0.00)	14.3 (8.84)	10.0 (0.00)
TNF-α: Cycle 1 Week 1 (N=31, 13, 5)	87.3 (241)	60.2 (127)	285 (306)
TNF-α: Cycle 2 Week 1 (N=4, 14, 5)	10.0 (0.00)	10.0 (0.00)	10.0 (0.00)
IL-4: Cycle 1 Week 1 (N=0, 0, 0)	NA (NA)	NA (NA)	NA (NA)
IL-4: Cycle 2 Week 1 (N=0, 0, 0)	NA (NA)	NA (NA)	NA (NA)

Adverse Events

Time Frame	From the start of the first infusion to 30 days after the end of the last infusion in the core study or from the start of the first retreatment cycle infusion to 30 days after the end of the last retreatment cycle, median treatment duration was 28 days.
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Phase 1: Blinatumomab 5 µg/m²/Day		Phase 1: Blinatumomab 15 µg/m²/Day		Phase 1+2: Blinatumomab 5/15 µg/m²/Day		Phase 1: Blinatumomab 15/30 µg/m²/Day		Phase 1: Blinatumomab 30 µg/m²/Day		Total
Arm/Group Description	Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.		Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.		Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 5 µg/m²/day for the first week of cycle 1 and then at 15 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 15 µg/m²/day for up to five cycles of treatment.		Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 15 µg/m²/day for the first week of cycle 1 and then at 30 µg/m²/day for 3 weeks followed by a treatment-free interval of 2 weeks. Participants received subsequent cycles at 30 µg/m²/day for up to five cycles of treatment.		Blinatumomab was administered as a continuous intravenous infusion at a constant daily flow rate of 30 µg/m²/day over 4 weeks followed by a treatment-free interval of 2 weeks for up to five cycles of treatment.		All Participants who received blinatumomab administered as a continuous intravenous infusion at a constant daily flow rate.
All Cause Mortality
	Phase 1: Blinatumomab 5 µg/m²/Day		Phase 1: Blinatumomab 15 µg/m²/Day		Phase 1+2: Blinatumomab 5/15 µg/m²/Day		Phase 1: Blinatumomab 15/30 µg/m²/Day		Phase 1: Blinatumomab 30 µg/m²/Day		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase 1: Blinatumomab 5 µg/m²/Day		Phase 1: Blinatumomab 15 µg/m²/Day		Phase 1+2: Blinatumomab 5/15 µg/m²/Day		Phase 1: Blinatumomab 15/30 µg/m²/Day		Phase 1: Blinatumomab 30 µg/m²/Day		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/5 (80%)		4/7 (57.1%)		39/70 (55.7%)		4/6 (66.7%)		3/5 (60%)		54/93 (58.1%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Febrile neutropenia	0/5 (0%)		0/7 (0%)		8/70 (11.4%)		0/6 (0%)		0/5 (0%)		8/93 (8.6%)
Histiocytosis haematophagic	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		1/5 (20%)		2/93 (2.2%)
Thrombocytopenia	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Cardiac disorders
Cardiac arrest	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Cardiac failure	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Gastrointestinal disorders
Colitis	1/5 (20%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Mouth haemorrhage	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Oesophageal pain	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Vomiting	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
General disorders
Death	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Device malfunction	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Disease progression	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		1/6 (16.7%)		0/5 (0%)		2/93 (2.2%)
Influenza like illness	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Multi-organ failure	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Pyrexia	2/5 (40%)		1/7 (14.3%)		8/70 (11.4%)		0/6 (0%)		0/5 (0%)		11/93 (11.8%)
Hepatobiliary disorders
Hepatic failure	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Immune system disorders
Cytokine release syndrome	0/5 (0%)		1/7 (14.3%)		4/70 (5.7%)		0/6 (0%)		2/5 (40%)		7/93 (7.5%)
Drug hypersensitivity	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Infections and infestations
Appendicitis	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Bacteraemia	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Bronchopneumonia	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Bronchopulmonary aspergillosis	0/5 (0%)		1/7 (14.3%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Cytomegalovirus infection	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Device related infection	0/5 (0%)		0/7 (0%)		3/70 (4.3%)		0/6 (0%)		0/5 (0%)		3/93 (3.2%)
Fungal infection	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Gastroenteritis viral	1/5 (20%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Infection	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		1/6 (16.7%)		0/5 (0%)		2/93 (2.2%)
Periorbital cellulitis	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Pneumonia	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Rectal abscess	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Sepsis	0/5 (0%)		0/7 (0%)		3/70 (4.3%)		1/6 (16.7%)		0/5 (0%)		4/93 (4.3%)
Sinusitis	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Urinary tract infection	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Injury, poisoning and procedural complications
Overdose	1/5 (20%)		0/7 (0%)		3/70 (4.3%)		0/6 (0%)		0/5 (0%)		4/93 (4.3%)
Spinal compression fracture	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Vascular access complication	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Investigations
Enterococcus test positive	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Escherichia test positive	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Staphylococcus test positive	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Stenotrophomonas test positive	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Metabolism and nutrition disorders
Hypertriglyceridaemia	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Tumour lysis syndrome	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Musculoskeletal and connective tissue disorders
Back pain	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Bone pain	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Muscular weakness	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Leukaemia recurrent	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Nervous system disorders
Atonic seizures	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Convulsion	1/5 (20%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		0/5 (0%)		3/93 (3.2%)
Haemorrhage intracranial	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Headache	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Hypotonia	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Neuralgia	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Psychiatric disorders
Confusional state	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Renal and urinary disorders
Renal failure acute	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Reproductive system and breast disorders
Acquired phimosis	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Cough	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Dyspnoea	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Epistaxis	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Hypoxia	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		1/5 (20%)		3/93 (3.2%)
Pleural effusion	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Pneumonitis	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Respiratory failure	0/5 (0%)		2/7 (28.6%)		2/70 (2.9%)		1/6 (16.7%)		1/5 (20%)		6/93 (6.5%)
Surgical and medical procedures
Tooth extraction	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Vascular disorders
Capillary leak syndrome	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		2/93 (2.2%)
Haemorrhage	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Hypertension	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Hypotension	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Other (Not Including Serious) Adverse Events
	Phase 1: Blinatumomab 5 µg/m²/Day		Phase 1: Blinatumomab 15 µg/m²/Day		Phase 1+2: Blinatumomab 5/15 µg/m²/Day		Phase 1: Blinatumomab 15/30 µg/m²/Day		Phase 1: Blinatumomab 30 µg/m²/Day		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		7/7 (100%)		70/70 (100%)		6/6 (100%)		5/5 (100%)		93/93 (100%)
Blood and lymphatic system disorders
Anaemia	3/5 (60%)		2/7 (28.6%)		29/70 (41.4%)		2/6 (33.3%)		4/5 (80%)		40/93 (43%)
Bone marrow failure	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Coagulopathy	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Disseminated intravascular coagulation	1/5 (20%)		2/7 (28.6%)		3/70 (4.3%)		1/6 (16.7%)		1/5 (20%)		8/93 (8.6%)
Febrile neutropenia	0/5 (0%)		0/7 (0%)		8/70 (11.4%)		1/6 (16.7%)		0/5 (0%)		9/93 (9.7%)
Hypoglobulinaemia	1/5 (20%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Leukopenia	0/5 (0%)		2/7 (28.6%)		9/70 (12.9%)		1/6 (16.7%)		2/5 (40%)		14/93 (15.1%)
Lymphopenia	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		1/5 (20%)		2/93 (2.2%)
Neutropenia	0/5 (0%)		1/7 (14.3%)		12/70 (17.1%)		0/6 (0%)		0/5 (0%)		13/93 (14%)
Thrombocytopenia	2/5 (40%)		2/7 (28.6%)		14/70 (20%)		1/6 (16.7%)		2/5 (40%)		21/93 (22.6%)
Cardiac disorders
Pericardial effusion	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Sinus bradycardia	0/5 (0%)		0/7 (0%)		3/70 (4.3%)		1/6 (16.7%)		2/5 (40%)		6/93 (6.5%)
Sinus tachycardia	0/5 (0%)		0/7 (0%)		5/70 (7.1%)		1/6 (16.7%)		1/5 (20%)		7/93 (7.5%)
Tachycardia	0/5 (0%)		0/7 (0%)		3/70 (4.3%)		0/6 (0%)		1/5 (20%)		4/93 (4.3%)
Ear and labyrinth disorders
Ear pain	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		1/5 (20%)		2/93 (2.2%)
Endocrine disorders
Adrenal insufficiency	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Cushingoid	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		1/5 (20%)		3/93 (3.2%)
Eye disorders
Eyelid haematoma	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Eyelid oedema	0/5 (0%)		1/7 (14.3%)		2/70 (2.9%)		0/6 (0%)		0/5 (0%)		3/93 (3.2%)
Ocular icterus	0/5 (0%)		1/7 (14.3%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Photophobia	0/5 (0%)		1/7 (14.3%)		2/70 (2.9%)		0/6 (0%)		1/5 (20%)		4/93 (4.3%)
Vision blurred	1/5 (20%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Gastrointestinal disorders
Abdominal distension	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		1/5 (20%)		3/93 (3.2%)
Abdominal pain	3/5 (60%)		3/7 (42.9%)		13/70 (18.6%)		0/6 (0%)		1/5 (20%)		20/93 (21.5%)
Abdominal pain upper	1/5 (20%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Ascites	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		1/5 (20%)		2/93 (2.2%)
Constipation	0/5 (0%)		0/7 (0%)		6/70 (8.6%)		2/6 (33.3%)		0/5 (0%)		8/93 (8.6%)
Diarrhoea	2/5 (40%)		2/7 (28.6%)		9/70 (12.9%)		0/6 (0%)		1/5 (20%)		14/93 (15.1%)
Dyspepsia	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		1/6 (16.7%)		0/5 (0%)		3/93 (3.2%)
Glossodynia	1/5 (20%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Ileus	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		1/6 (16.7%)		0/5 (0%)		2/93 (2.2%)
Mouth haemorrhage	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		2/5 (40%)		2/93 (2.2%)
Nausea	2/5 (40%)		1/7 (14.3%)		23/70 (32.9%)		1/6 (16.7%)		1/5 (20%)		28/93 (30.1%)
Stomatitis	0/5 (0%)		0/7 (0%)		5/70 (7.1%)		0/6 (0%)		0/5 (0%)		5/93 (5.4%)
Vomiting	2/5 (40%)		2/7 (28.6%)		17/70 (24.3%)		2/6 (33.3%)		2/5 (40%)		25/93 (26.9%)
General disorders
Adverse drug reaction	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Application site scab	1/5 (20%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Catheter site haematoma	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Chest pain	1/5 (20%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		0/5 (0%)		3/93 (3.2%)
Chills	0/5 (0%)		0/7 (0%)		3/70 (4.3%)		0/6 (0%)		1/5 (20%)		4/93 (4.3%)
Face oedema	1/5 (20%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		1/5 (20%)		3/93 (3.2%)
Facial pain	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Fatigue	2/5 (40%)		2/7 (28.6%)		5/70 (7.1%)		0/6 (0%)		2/5 (40%)		11/93 (11.8%)
Injection site erythema	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Injection site haematoma	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Localised oedema	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		1/5 (20%)		2/93 (2.2%)
Non-cardiac chest pain	0/5 (0%)		0/7 (0%)		4/70 (5.7%)		0/6 (0%)		0/5 (0%)		4/93 (4.3%)
Oedema	0/5 (0%)		0/7 (0%)		3/70 (4.3%)		2/6 (33.3%)		0/5 (0%)		5/93 (5.4%)
Oedema peripheral	1/5 (20%)		0/7 (0%)		5/70 (7.1%)		0/6 (0%)		1/5 (20%)		7/93 (7.5%)
Pain	1/5 (20%)		2/7 (28.6%)		6/70 (8.6%)		3/6 (50%)		0/5 (0%)		12/93 (12.9%)
Pyrexia	4/5 (80%)		7/7 (100%)		54/70 (77.1%)		4/6 (66.7%)		5/5 (100%)		74/93 (79.6%)
Hepatobiliary disorders
Cholestasis	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Hepatic failure	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Hepatosplenomegaly	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		1/6 (16.7%)		0/5 (0%)		2/93 (2.2%)
Hepatotoxicity	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		2/93 (2.2%)
Immune system disorders
Cytokine release syndrome	1/5 (20%)		0/7 (0%)		4/70 (5.7%)		2/6 (33.3%)		2/5 (40%)		9/93 (9.7%)
Drug hypersensitivity	0/5 (0%)		1/7 (14.3%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Infections and infestations
Adenovirus infection	1/5 (20%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		2/93 (2.2%)
BK virus infection	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Conjunctivitis	0/5 (0%)		1/7 (14.3%)		2/70 (2.9%)		0/6 (0%)		1/5 (20%)		4/93 (4.3%)
Device related infection	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Enterocolitis infectious	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Legionella infection	1/5 (20%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Lung infection	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Nasopharyngitis	1/5 (20%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		2/93 (2.2%)
Oral herpes	0/5 (0%)		1/7 (14.3%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Polyomavirus-associated nephropathy	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Rhinitis	0/5 (0%)		0/7 (0%)		7/70 (10%)		0/6 (0%)		0/5 (0%)		7/93 (7.5%)
Rhinovirus infection	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		1/6 (16.7%)		0/5 (0%)		2/93 (2.2%)
Staphylococcal infection	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Staphylococcal sepsis	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Viral myositis	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Injury, poisoning and procedural complications
Contusion	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		1/5 (20%)		3/93 (3.2%)
Ear abrasion	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Fall	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		1/5 (20%)		2/93 (2.2%)
Infusion related reaction	0/5 (0%)		1/7 (14.3%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Skin abrasion	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Investigations
Activated partial thromboplastin time prolonged	0/5 (0%)		1/7 (14.3%)		4/70 (5.7%)		0/6 (0%)		0/5 (0%)		5/93 (5.4%)
Alanine aminotransferase increased	1/5 (20%)		0/7 (0%)		13/70 (18.6%)		2/6 (33.3%)		2/5 (40%)		18/93 (19.4%)
Aspartate aminotransferase increased	1/5 (20%)		1/7 (14.3%)		10/70 (14.3%)		2/6 (33.3%)		2/5 (40%)		16/93 (17.2%)
Blood alkaline phosphatase increased	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		1/5 (20%)		2/93 (2.2%)
Blood bilirubin increased	0/5 (0%)		1/7 (14.3%)		4/70 (5.7%)		1/6 (16.7%)		3/5 (60%)		9/93 (9.7%)
Blood creatinine increased	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		2/5 (40%)		4/93 (4.3%)
Blood fibrinogen decreased	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		1/5 (20%)		2/93 (2.2%)
Blood fibrinogen increased	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Blood immunoglobulin A decreased	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Blood immunoglobulin G decreased	0/5 (0%)		4/7 (57.1%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		5/93 (5.4%)
Blood immunoglobulin M decreased	0/5 (0%)		1/7 (14.3%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Blood lactate dehydrogenase increased	0/5 (0%)		1/7 (14.3%)		7/70 (10%)		0/6 (0%)		2/5 (40%)		10/93 (10.8%)
C-reactive protein increased	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Cytomegalovirus test positive	0/5 (0%)		1/7 (14.3%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Electroencephalogram abnormal	1/5 (20%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Fibrin D dimer increased	0/5 (0%)		2/7 (28.6%)		6/70 (8.6%)		1/6 (16.7%)		1/5 (20%)		10/93 (10.8%)
Haemoglobin decreased	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
International normalised ratio increased	1/5 (20%)		2/7 (28.6%)		3/70 (4.3%)		2/6 (33.3%)		0/5 (0%)		8/93 (8.6%)
Lymphocyte count decreased	0/5 (0%)		0/7 (0%)		3/70 (4.3%)		1/6 (16.7%)		1/5 (20%)		5/93 (5.4%)
Neutrophil count decreased	0/5 (0%)		0/7 (0%)		9/70 (12.9%)		3/6 (50%)		2/5 (40%)		14/93 (15.1%)
Platelet count decreased	0/5 (0%)		0/7 (0%)		10/70 (14.3%)		2/6 (33.3%)		1/5 (20%)		13/93 (14%)
Protein total decreased	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		1/6 (16.7%)		0/5 (0%)		3/93 (3.2%)
Roseolovirus test positive	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Urine output decreased	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Weight decreased	0/5 (0%)		0/7 (0%)		4/70 (5.7%)		1/6 (16.7%)		0/5 (0%)		5/93 (5.4%)
Weight increased	0/5 (0%)		1/7 (14.3%)		12/70 (17.1%)		2/6 (33.3%)		1/5 (20%)		16/93 (17.2%)
White blood cell count decreased	0/5 (0%)		0/7 (0%)		8/70 (11.4%)		3/6 (50%)		2/5 (40%)		13/93 (14%)
Metabolism and nutrition disorders
Acidosis	0/5 (0%)		1/7 (14.3%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Decreased appetite	0/5 (0%)		0/7 (0%)		3/70 (4.3%)		0/6 (0%)		1/5 (20%)		4/93 (4.3%)
Dehydration	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		1/5 (20%)		2/93 (2.2%)
Hyperglycaemia	0/5 (0%)		0/7 (0%)		6/70 (8.6%)		1/6 (16.7%)		0/5 (0%)		7/93 (7.5%)
Hyperkalaemia	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Hypernatraemia	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Hyperphosphataemia	0/5 (0%)		2/7 (28.6%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Hyperuricaemia	0/5 (0%)		1/7 (14.3%)		2/70 (2.9%)		0/6 (0%)		0/5 (0%)		3/93 (3.2%)
Hypoalbuminaemia	0/5 (0%)		2/7 (28.6%)		4/70 (5.7%)		2/6 (33.3%)		0/5 (0%)		8/93 (8.6%)
Hypocalcaemia	0/5 (0%)		1/7 (14.3%)		8/70 (11.4%)		1/6 (16.7%)		1/5 (20%)		11/93 (11.8%)
Hypokalaemia	0/5 (0%)		4/7 (57.1%)		15/70 (21.4%)		3/6 (50%)		0/5 (0%)		22/93 (23.7%)
Hypomagnesaemia	0/5 (0%)		0/7 (0%)		6/70 (8.6%)		1/6 (16.7%)		0/5 (0%)		7/93 (7.5%)
Hyponatraemia	0/5 (0%)		0/7 (0%)		5/70 (7.1%)		2/6 (33.3%)		0/5 (0%)		7/93 (7.5%)
Hypophosphataemia	0/5 (0%)		0/7 (0%)		10/70 (14.3%)		2/6 (33.3%)		0/5 (0%)		12/93 (12.9%)
Tumour lysis syndrome	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		2/5 (40%)		3/93 (3.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/5 (0%)		0/7 (0%)		4/70 (5.7%)		0/6 (0%)		1/5 (20%)		5/93 (5.4%)
Back pain	2/5 (40%)		2/7 (28.6%)		14/70 (20%)		0/6 (0%)		2/5 (40%)		20/93 (21.5%)
Bone pain	1/5 (20%)		1/7 (14.3%)		7/70 (10%)		0/6 (0%)		1/5 (20%)		10/93 (10.8%)
Muscular weakness	0/5 (0%)		0/7 (0%)		4/70 (5.7%)		0/6 (0%)		0/5 (0%)		4/93 (4.3%)
Musculoskeletal pain	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		1/5 (20%)		3/93 (3.2%)
Myalgia	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Myopathy	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Neck pain	0/5 (0%)		1/7 (14.3%)		3/70 (4.3%)		0/6 (0%)		1/5 (20%)		5/93 (5.4%)
Pain in extremity	3/5 (60%)		2/7 (28.6%)		8/70 (11.4%)		2/6 (33.3%)		2/5 (40%)		17/93 (18.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	1/5 (20%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Nervous system disorders
Aphasia	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Cognitive disorder	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		1/5 (20%)		2/93 (2.2%)
Dizziness	1/5 (20%)		1/7 (14.3%)		3/70 (4.3%)		0/6 (0%)		0/5 (0%)		5/93 (5.4%)
Dysaesthesia	1/5 (20%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Dyskinesia	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Encephalopathy	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		1/6 (16.7%)		0/5 (0%)		2/93 (2.2%)
Epilepsy	1/5 (20%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Essential tremor	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Headache	5/5 (100%)		4/7 (57.1%)		20/70 (28.6%)		0/6 (0%)		2/5 (40%)		31/93 (33.3%)
Lethargy	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Neuralgia	1/5 (20%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Peripheral sensory neuropathy	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Tremor	0/5 (0%)		1/7 (14.3%)		4/70 (5.7%)		2/6 (33.3%)		0/5 (0%)		7/93 (7.5%)
Psychiatric disorders
Agitation	0/5 (0%)		1/7 (14.3%)		3/70 (4.3%)		0/6 (0%)		1/5 (20%)		5/93 (5.4%)
Anxiety	1/5 (20%)		0/7 (0%)		4/70 (5.7%)		0/6 (0%)		1/5 (20%)		6/93 (6.5%)
Confusional state	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		1/5 (20%)		2/93 (2.2%)
Irritability	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		1/5 (20%)		3/93 (3.2%)
Personality change	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Renal and urinary disorders
Dysuria	1/5 (20%)		1/7 (14.3%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		3/93 (3.2%)
Haematuria	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		1/6 (16.7%)		0/5 (0%)		3/93 (3.2%)
Oliguria	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Proteinuria	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		1/6 (16.7%)		0/5 (0%)		3/93 (3.2%)
Renal failure chronic	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Renal tubular disorder	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Urinary retention	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		1/5 (20%)		2/93 (2.2%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/5 (0%)		0/7 (0%)		3/70 (4.3%)		1/6 (16.7%)		0/5 (0%)		4/93 (4.3%)
Cough	1/5 (20%)		0/7 (0%)		13/70 (18.6%)		0/6 (0%)		2/5 (40%)		16/93 (17.2%)
Dyspnoea	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		1/6 (16.7%)		0/5 (0%)		3/93 (3.2%)
Epistaxis	0/5 (0%)		1/7 (14.3%)		10/70 (14.3%)		1/6 (16.7%)		0/5 (0%)		12/93 (12.9%)
Hypoxia	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		1/5 (20%)		3/93 (3.2%)
Laryngeal oedema	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Lung disorder	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		1/6 (16.7%)		0/5 (0%)		2/93 (2.2%)
Oropharyngeal pain	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		1/6 (16.7%)		0/5 (0%)		2/93 (2.2%)
Pleural effusion	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		1/5 (20%)		3/93 (3.2%)
Pneumonia aspiration	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Productive cough	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		0/6 (0%)		1/5 (20%)		2/93 (2.2%)
Pulmonary oedema	0/5 (0%)		0/7 (0%)		1/70 (1.4%)		1/6 (16.7%)		1/5 (20%)		3/93 (3.2%)
Wheezing	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Skin and subcutaneous tissue disorders
Alopecia	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Dermatitis diaper	0/5 (0%)		1/7 (14.3%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Drug eruption	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Dry skin	0/5 (0%)		1/7 (14.3%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Erythema	2/5 (40%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		0/5 (0%)		4/93 (4.3%)
Erythema nodosum	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Hair growth abnormal	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Petechiae	1/5 (20%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Pruritus	1/5 (20%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		0/5 (0%)		3/93 (3.2%)
Rash	1/5 (20%)		1/7 (14.3%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		3/93 (3.2%)
Rash maculo-papular	0/5 (0%)		2/7 (28.6%)		3/70 (4.3%)		1/6 (16.7%)		1/5 (20%)		7/93 (7.5%)
Skin discolouration	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Trichorrhexis	0/5 (0%)		0/7 (0%)		0/70 (0%)		1/6 (16.7%)		0/5 (0%)		1/93 (1.1%)
Surgical and medical procedures
Infusion	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Oxygen supplementation	0/5 (0%)		1/7 (14.3%)		1/70 (1.4%)		0/6 (0%)		0/5 (0%)		2/93 (2.2%)
Parenteral nutrition	0/5 (0%)		1/7 (14.3%)		0/70 (0%)		0/6 (0%)		0/5 (0%)		1/93 (1.1%)
Vascular disorders
Capillary leak syndrome	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		2/6 (33.3%)		0/5 (0%)		4/93 (4.3%)
Flushing	0/5 (0%)		0/7 (0%)		3/70 (4.3%)		0/6 (0%)		1/5 (20%)		4/93 (4.3%)
Haematoma	0/5 (0%)		0/7 (0%)		2/70 (2.9%)		0/6 (0%)		1/5 (20%)		3/93 (3.2%)
Hyperaemia	0/5 (0%)		0/7 (0%)		0/70 (0%)		0/6 (0%)		1/5 (20%)		1/93 (1.1%)
Hypertension	0/5 (0%)		5/7 (71.4%)		18/70 (25.7%)		2/6 (33.3%)		1/5 (20%)		26/93 (28%)
Hypotension	0/5 (0%)		1/7 (14.3%)		10/70 (14.3%)		2/6 (33.3%)		1/5 (20%)		14/93 (15.1%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

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