Study of Blinatumomab in Japanese Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02412306
• Collaborator: Amgen Astellas Biopharma K.K. (Industry)
• Enrollment: 66
• Locations: 17
• Arms: 5
• Actual Duration (Months): 49
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is an open-label, combined 2-part multicenter study to evaluate the efficacy, safety, and tolerability of blinatumomab in adult and pediatric Japanese patients with relapsed/refractory B-precursor ALL.

Condition or Disease	Intervention/Treatment	Phase
Relapsed Refractory B Precursor Acute Lymphoblastic Leukemia	Drug: Blinatumomab	Phase 1/Phase 2

Detailed Description

The Phase 1b part will investigate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of blinatumomab to determine the maximum tolerated dose (MTD) in both adult and pediatric Japanese patients with relapsed/refractory B-precursor ALL. The Phase 2 part will assess the safety and efficacy of the recommended dose level of blinatumomab identified in the Phase 1b portion of the study in the adult study population.

In June 2017 protocol amendment 4 extended the study to include an expansion cohort of approximately 65 participants to investigate the safety of blinatumomab in participants who did not participate in Phase 1b or Phase 2 of the study. Adult and pediatric patients in the expansion cohort may receive up to 5 cycles of investigational blinatomumab and may receive commercial blinatomumab after a minimum of 2 cycles of the investigational drug.

Study Design

• Study Type: Interventional
• Actual Enrollment: 66 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b/2 Study of Blinatumomab in Japanese Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (Horai Study)
• Actual Study Start Date: Jun 4, 2015
• Actual Primary Completion Date: Feb 6, 2019
• Actual Study Completion Date: Jul 4, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Blinatumomab 9-28 µg/day Phase 1b Adult Population Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter.	Drug: Blinatumomab; Continuous intravenous infusion over four weeks per treatment cycle; Other Names: Blincyto®
Experimental: Blinatumomab 5-15 µg/m^2/day Phase 1b Pediatric Population Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. For pediatric participants the initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Drug: Blinatumomab; Continuous intravenous infusion over four weeks per treatment cycle; Other Names: Blincyto®
Experimental: Blinatumomab 9-28 µg/day Phase 2 Adult Population Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter.	Drug: Blinatumomab; Continuous intravenous infusion over four weeks per treatment cycle; Other Names: Blincyto®
Experimental: Blinatumomab 9-28 µg/day Adult Expansion Population Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter.	Drug: Blinatumomab; Continuous intravenous infusion over four weeks per treatment cycle; Other Names: Blincyto®
Experimental: Blinatumomab 5-15 µg/m^2/day Pediatric Expansion Population Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. For pediatric participants the initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Drug: Blinatumomab; Continuous intravenous infusion over four weeks per treatment cycle; Other Names: Blincyto®

Outcome Measures

Primary Outcome Measures

1. Phase 1b: Number of Participants With Dose-limiting Toxicities [Days 1 to 14]

   Dose-limiting toxicities (DLTs) were defined as any Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade ≥ 3 adverse event related to blinatumomab, excluding specific CTCAE grade ≥ 3 adverse events considered consistent with the current known safety profile of blinatumomab, CTCAE grade ≥ 3 fever or infection, and laboratory parameters of CTCAE grade ≥ 3 not considered clinically relevant and/or responding to routine medical management.

2. Phase 2: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment [Within the first 2 cycles of treatment, 12 weeks]

   Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl and absolute neutrophil count (ANC) > 1,000/µl. Complete Remission With Partial Hematological Recovery (CRh*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets > 50,000/µl and ANC > 500/µl.

3. Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs [From the start of the first infusion to 30 days after the end of the last infusion; median (min, max) treatment duration was 55.6 (25, 140) and 28.0 (8, 56) days in the adult and pediatric expansion cohorts, respectively.]

   TEAEs are defined as those that start between the start of the first infusion of blinatumomab and 30 days after the end of the last infusion during the treatment period. The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; 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.

Secondary Outcome Measures

1. Phase 1b Adults: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment [Within the first 2 cycles of treatment, 12 weeks]

   Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl and absolute neutrophil count (ANC) > 1,000/µl. Complete Remission With Partial Hematological Recovery (CRh*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets > 50,000/µl and ANC > 500/µl

2. Phase 1b Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment [The first 2 cycles of treatment, 12 weeks]

   M1 remission for pediatric participants was defined as ≤ 5% blasts (M1 bone marrow) in the bone marrow and no evidence of disease.

3. Phase 1b and Phase 2: Duration of Response [Median (minimum [min], maximum [max]) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.]

   Duration of response was calculated from the date of bone marrow aspiration when response (CR/CRh*) was detected for the first time during the first 2 cycles of treatment until the earlier of the following events: the date of bone marrow aspiration at which hematological relapse or progressive disease (PD) was first detected, the date of diagnosis on which the hematological or extra medullary relapse was documented, the date of death if patient died due to PD the date of end of induction phase if primary reason for treatment termination was hematological or extramedullary relapse. For a responder who did not report an event and was alive during the study, the end date of duration (censoring) was based on the date of the last available bone marrow aspiration prior to the data cutoff date for the analysis. Participants with response who did not report an event and who died due to reasons other than PD, were censored on the date of death, with death treated as a competing risk.

4. Phase 1b and Phase 2: Relapse-free Survival [Median (min, max) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.]

   Relapse-free survival (RFS) was defined for participants who achieved a response (CR/CRh*) during the first 2 cycles of treatment. RFS was calculated from the date of bone marrow aspiration when response was detected for the first time to the date of bone marrow aspiration at which hematological relapse was first detected or the date of diagnosis on which the hematological or extra medullary relapse was documented or the date of death due to any cause, whichever was earlier. Participants who did not experience hematological relapse and did not die were censored on the date of the last available bone marrow aspiration prior to the data cutoff date for the analysis.

5. Phase 1b and Phase 2: Overall Survival [Median (min, max) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.]

   Overall survival (OS) was calculated from the start date of blinatumomab infusion in the first treatment cycle. All deaths were counted as events on the date of death. Participants still alive were censored on the last documented visit date or the date of the last phone contact when the participant was last known to have been alive. For participants who withdrew their informed consent, only information until the date of withdrawal was used in the analysis.

6. Phase 2: Best Overall Response Within 2 Cycles of Treatment [Within the first 2 cycles of treatment, 12 weeks]

   Best response was defined as one of the following: CR: ≤ 5% blasts in the bone marrow (BM); No evidence of disease; Full recovery of peripheral blood counts: Platelets > 100,000/µl, and absolute neutrophil count (ANC) > 1,000/µl CRh*: ≤ 5% blasts in BM; No evidence of disease; Partial recovery of peripheral blood counts: Platelets > 50,000/µl, and ANC > 500/µl CRi: CR with incomplete count recovery without CRh* Blast free hypoplastic or aplastic BM: ≤ 5 % blasts in BM; No evidence of disease; Insufficient recovery of peripheral blood counts: platelets ≤ 50,000/µl and/or ANC ≤ 500/µl Partial Remission: BM blasts > 5 to < 25% with at least a 50% reduction from baseline Hematological Relapse: > 5% blasts in BM or blasts in peripheral blood after documented CR/CRh* during the study PD: An increase from baseline of ≥ 25% of BM blasts or an absolute increase of ≥ 5,000 cells/µL in the number of circulating leukemia cells.

7. Phase 2: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission [Median (min, max) follow-up time was 26.7 (3.0, 28.5) months.]

   Participants who were eligible for allogeneic HSCT were those who achieved remission (complete response or complete response with partial recovery of peripheral blood counts) after 2 cycles of blinatumomab treatment, and no further anti-leukemic medication was given before HSCT.

8. Phase 2: 100-Day Mortality After Allogeneic HSCT [100 days, from the date of allogeneic HSCT; median (min, max) follow-up time was 26.7 (3.0, 28.5)]

   The analysis of 100-day mortality after allogeneic HSCT was assessed for all participants who received an allogeneic HSCT while in any CR following treatment with blinatumomab. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT. Participants still alive alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive. The 100-day mortality rate after allogeneic HSCT was defined as the percentage of participants having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods.

9. Phase 1b and Phase 2: Number of Participants With TEAEs [From the start of the first infusion to 30 days after the end of the last infusion; median (min, max) treatment duration was 108 (56, 140), 56.0 (5, 84), and 56.0 (11, 115) days in adult phase 1b, adult phase 2 and pediatric phase 1b cohort respectively.]

   TEAEs are defined as those that start between the start of the first infusion of blinatumomab and 30 days after the end of the last infusion during the treatment period. The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; 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.

10. Phase 1b and Phase 2: Serum Blinatumomab Concentration at Steady State [After 24 hours from the start of infusion: Cycle 1 (before dose step) day 2; Cycle 1 (after dose step) days 15 and 29; Cycle 2 onwards day 8 (pediatric and adult), days 15 and 29 (adult).]

    The steady-state concentration (Css) of serum blinatumomab was summarized as the average of the observed concentrations collected after 5 half-lives or after 24 hours from the start of continuous IV infusion. Cycle 1, day 2 values represent steady-state concentration after CIV with the initial dose of blinatumomab (9 µg/day for adults and 5 µg/m²/day for pediatric patients). All other time points were measured after the dose step to 28 µg/day (adults) / 15 µg/m²/day (pediatric participants).

11. Phase 1b and Phase 2: Systemic Clearance of Blinatumomab [After 24 hours from the start of infusion: Cycle 1 (before dose step) day 2; Cycle 1 (after dose step) days 15 and 29; Cycle 2 onwards day 8 (pediatric and adult), days 15 and 29 (adult).]

    Systemic clearance (CL) was calculated as CL = R0/Css, where R0 is the infusion rate (µg/hour or µg/m²/hour).

12. Phase 1b and Phase 2: Terminal Half-life of Blinatumomab [Cycle 1 day 1 predose, 2, 6 (adults), 10, 24 hours; day 8 (prior to dose step) 0 hour (adults); day 15 any time during infusion; day 29 prior to end of infusion, 1 (adults), 2, 4 (adults), 6 hours after end of infusion]

13. Phase 1b and Phase 2: Volume of Distribution of Blinatumomab [Cycle 1 day 1 predose, 2, 6 (adults), 10, 24 hours; day 8 (prior to dose step) 0 hour (adults); day 15 any time during infusion; day 29 prior to end of infusion, 1 (adults), 2, 4 (adults), 6 hours after end of infusion]

14. Phase 1b and Phase 2: Number of Participants Who Developed Anti-Blinatumomab Antibodies [Day 1 before first dose; cycles 1 and 2 day 29, 6 hours after end of infusion; 30 days after last dose.]

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

15. Phase 1b and Phase 2: Interleukin-2 Concentration [Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start]

    The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL).

16. Phase 1b and Phase 2: Interleukin-6 Concentration [Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start]

    The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL).

17. Phase 1b and Phase 2: Interleukin-10 Concentration [Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start]

    The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL).

18. Phase 1b and Phase 2: Tumor Necrosis Factor-Alpha (TNFα) Concentration [Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start]

    The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL).

19. Phase 1b and Phase 2: Interferon Gamma (IFN-γ) Concentration [Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start]

    The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL).

20. Expansion Cohort Adult: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment [Within the first 2 cycles of treatment, 12 weeks]

    Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl and absolute neutrophil count (ANC) > 1,000/µl. Complete Remission With Partial Hematological Recovery (CRh*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets > 50,000/µl and ANC > 500/µl.

21. Expansion Cohort Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment [Within the first 2 cycles of treatment, 12 weeks]

    M1 remission for pediatric participants was defined as ≤ 5% blasts (M1 bone marrow) in the bone marrow and no evidence of disease.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Adult Subjects Key Inclusion Criteria:

• Age ≥ 18 years old at enrollment

• Subjects with Philadelphia-negative B-precursor ALL, with any of the following:

• Relapsed or refractory after first line therapy with first remission duration ≤ 12 months; or

• Relapsed or refractory after first salvage therapy; or

• Relapsed or refractory within 12 months of allogeneic hematopoietic stem cell transplant (alloHSCT)

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.

• Greater than 5% blasts in bone marrow

Pediatric Subjects Key Inclusion Criteria:

• Age < 18 years old at enrollment

• Relapsed/refractory disease, defined as one of the following:

• second or later bone marrow relapse;

• any marrow relapse after alloHSCT; or

• Refractory to other treatments:

• For subjects in first relapse: failure to achieve a complete response (CR) following a full standard reinduction chemotherapy regimen

• For subjects who have not achieved a first remission: failure to achieve remission following a full standard induction regimen

• Greater than 5% blasts in bone marrow

• Karnofsky performance status ≥ 50% for subjects ≥ 16 years

• Lansky performance status ≥ 50% for subjects < 16 years

Key Exclusion Criteria

• Subjects with Burkitt´s Leukemia according to World Health Organization (WHO) classification

• History or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis; with the exception of well-controlled CNS leukemia

• Active ALL in the CNS or testes

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

• Autologous HSCT within 6 weeks prior to start of blinatumomab treatment

• AlloHSCT within 12 weeks prior to start of blinatumomab treatment

• Any active acute Graft-versus-Host Disease (GvHD) grade 2-4 according to Glucksberg criteria or active chronic GvHD requiring systemic treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Nagoya-shi	Aichi	Japan	460-0001
2	Research Site	Nagoya-shi	Aichi	Japan	466-8560
3	Research Site	Fukuoka-shi	Fukuoka	Japan	812-8582
4	Gunmaken Saiseikai Maebashi Hospital	Maebashi-shi	Gunma	Japan	371-0821
5	Research Site	Maebashi-shi	Gunma	Japan	371-0821
6	Research Site	Sapporo-shi	Hokkaido	Japan	003-0006
7	Research Site	Kobe-shi	Hyogo	Japan	650-0017
8	Research Site	Yokohama-shi	Kanagawa	Japan	232-8555
9	Research Site	Nagasaki-shi	Nagasaki	Japan	852-8501
10	Research Site	Niigata-shi	Niigata	Japan	951-8566
11	Research Site	Okayama-shi	Okayama	Japan	700-8558
12	Research Site	Osaka-shi	Osaka	Japan	534-0021
13	Research Site	Osaka-shi	Osaka	Japan	545-8586
14	Research Site	Saitama-shi	Saitama	Japan	330-8777
15	Research Site	Shimotsuke-shi	Tochigi	Japan	329-0498
16	Research Site	Chuo-ku	Tokyo	Japan	104-0045
17	Research Site	Setagaya-ku	Tokyo	Japan	157-8535

Sponsors and Collaborators

• Amgen
• Amgen Astellas Biopharma K.K.

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Study Protocol - Mar 20, 2019
• Statistical Analysis Plan - Apr 12, 2019

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT02412306
• Other Study ID Numbers: 20130265
• First Posted: Apr 9, 2015
• Last Update Posted: Jan 10, 2020
• Last Verified: Dec 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Amgen: Amgen
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Blinatumomab

Study Results

Participant Flow

Recruitment Details	Study was conducted at 16 centers in Japan. Cohort enrollment periods were: adult phase 1b, from 04 Jun 2015 to 13 Jan 2016; pediatric phase 1b, from 17 Feb 2016 to 20 Jun 2016; adult phase 2, from 11 Apr 2016 to 12 Jun 2017; adult expansion cohort, from 04 Dec 2017 to 13 Nov 2018; pediatric expansion cohort, from 05 Nov 2017 to 05 Sep 2018.
Pre-assignment Detail	After a 2-week screening and pre-phase period, participants were treated in an open-label phase 1b part (adult or pediatric), a phase 2 part (adult), or in an expansion cohort (adult or pediatric).

Arm/Group Title	Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/Day (Adults)	Expansion Cohort: Blinatumomab 9/28 μg/Day (Adults)	Expansion Cohort: Blinatumomab 5/15 µg/m²/Day (Pediatric)
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Period Title: Overall Study
STARTED	5	9	21	14	17
COMPLETED	0	1	5	14	15
NOT COMPLETED	5	8	16	0	2

Baseline Characteristics

Arm/Group Title	Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/Day (Adults)	Expansion Cohort: Blinatumomab 9/28 μg/Day (Adults)	Expansion Cohort: Blinatumomab 5/15 µg/m²/Day (Pediatric)	Total
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Total of all reporting groups
Overall Participants	5	9	21	14	17	66
Age, Customized (Count of Participants)
< 2 years	0 0%	0 0%	0 0%	0 0%	1 5.9%	1 1.5%
2 to 6 years	0 0%	0 0%	0 0%	0 0%	5 29.4%	5 7.6%
7 to 17 years	0 0%	9 100%	0 0%	0 0%	11 64.7%	20 30.3%
18 to 34 years	1 20%	0 0%	6 28.6%	5 35.7%	0 0%	12 18.2%
35 to 54 years	1 20%	0 0%	14 66.7%	6 42.9%	0 0%	21 31.8%
55 to 64 years	2 40%	0 0%	1 4.8%	1 7.1%	0 0%	4 6.1%
≥ 65 years	1 20%	0 0%	0 0%	2 14.3%	0 0%	3 4.5%
Sex: Female, Male (Count of Participants)
Female	4 80%	5 55.6%	12 57.1%	9 64.3%	8 47.1%	38 57.6%
Male	1 20%	4 44.4%	9 42.9%	5 35.7%	9 52.9%	28 42.4%
Race/Ethnicity, Customized (Count of Participants)
Japanese	5 100%	9 100%	21 100%	14 100%	17 100%	66 100%

Outcome Measures

1. Primary Outcome

Title	Phase 1b: Number of Participants With Dose-limiting Toxicities
Description	Dose-limiting toxicities (DLTs) were defined as any Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade ≥ 3 adverse event related to blinatumomab, excluding specific CTCAE grade ≥ 3 adverse events considered consistent with the current known safety profile of blinatumomab, CTCAE grade ≥ 3 fever or infection, and laboratory parameters of CTCAE grade ≥ 3 not considered clinically relevant and/or responding to routine medical management.
Time Frame	Days 1 to 14

Outcome Measure Data

Analysis Population Description

Phase 1b participants in who received any infusion of blinatumomab.

Arm/Group Title	Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Measure Participants	5	9
Count of Participants [Participants]	0 0%	0 0%

2. Primary Outcome

Title	Phase 2: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
Description	Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl and absolute neutrophil count (ANC) > 1,000/µl. Complete Remission With Partial Hematological Recovery (CRh*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets > 50,000/µl and ANC > 500/µl.
Time Frame	Within the first 2 cycles of treatment, 12 weeks

Outcome Measure Data

Analysis Population Description

Phase 2 participants who received any infusion of blinatumomab.

Arm/Group Title	Phase 2: Blinatumomab 9/28 μg/Day (Adults)
Arm/Group Description	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.
Measure Participants	21
Number (95% Confidence Interval) [percentage of participants]	38.1 762%

3. Secondary Outcome

Title	Phase 1b Adults: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
Description	Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl and absolute neutrophil count (ANC) > 1,000/µl. Complete Remission With Partial Hematological Recovery (CRh*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets > 50,000/µl and ANC > 500/µl
Time Frame	Within the first 2 cycles of treatment, 12 weeks

Outcome Measure Data

Analysis Population Description

Phase 1b adult participants who received any infusion of blinatumomab.

Arm/Group Title	Phase 1b: Blinatumomab 9/28 μg/Day (Adults)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.
Measure Participants	5
Number (95% Confidence Interval) [percentage of participants]	80.0 1600%

4. Secondary Outcome

Title	Phase 1b Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment
Description	M1 remission for pediatric participants was defined as ≤ 5% blasts (M1 bone marrow) in the bone marrow and no evidence of disease.
Time Frame	The first 2 cycles of treatment, 12 weeks

Outcome Measure Data

Analysis Population Description

Phase 1b pediatric participants who received any infusion of blinatumomab.

Arm/Group Title	Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)
Arm/Group Description	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Measure Participants	9
Number (95% Confidence Interval) [percentage of participants]	55.6 1112%

5. Secondary Outcome

Title	Phase 1b and Phase 2: Duration of Response
Description	Duration of response was calculated from the date of bone marrow aspiration when response (CR/CRh*) was detected for the first time during the first 2 cycles of treatment until the earlier of the following events: the date of bone marrow aspiration at which hematological relapse or progressive disease (PD) was first detected, the date of diagnosis on which the hematological or extra medullary relapse was documented, the date of death if patient died due to PD the date of end of induction phase if primary reason for treatment termination was hematological or extramedullary relapse. For a responder who did not report an event and was alive during the study, the end date of duration (censoring) was based on the date of the last available bone marrow aspiration prior to the data cutoff date for the analysis. Participants with response who did not report an event and who died due to reasons other than PD, were censored on the date of death, with death treated as a competing risk.
Time Frame	Median (minimum [min], maximum [max]) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.

Outcome Measure Data

Analysis Population Description

Phase 1b and Phase 2 participants who received any infusion of blinatumomab and achieved CR/CRh* during the first 2 cycles of treatment.

Arm/Group Title	Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/Day (Adults)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.
Measure Participants	4	5	8
Median (95% Confidence Interval) [months]	13.0	2.3	13.1

6. Secondary Outcome

Title	Phase 1b and Phase 2: Relapse-free Survival
Description	Relapse-free survival (RFS) was defined for participants who achieved a response (CR/CRh*) during the first 2 cycles of treatment. RFS was calculated from the date of bone marrow aspiration when response was detected for the first time to the date of bone marrow aspiration at which hematological relapse was first detected or the date of diagnosis on which the hematological or extra medullary relapse was documented or the date of death due to any cause, whichever was earlier. Participants who did not experience hematological relapse and did not die were censored on the date of the last available bone marrow aspiration prior to the data cutoff date for the analysis.
Time Frame	Median (min, max) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.

Outcome Measure Data

Analysis Population Description

Phase 1b and Phase 2 participants who received any infusion of blinatumomab and achieved CR/CRh* during the first 2 cycles of treatment.

Arm/Group Title	Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/Day (Adults)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.
Measure Participants	4	5	8
Median (95% Confidence Interval) [months]	11.4	2.3	13.1

7. Secondary Outcome

Title	Phase 1b and Phase 2: Overall Survival
Description	Overall survival (OS) was calculated from the start date of blinatumomab infusion in the first treatment cycle. All deaths were counted as events on the date of death. Participants still alive were censored on the last documented visit date or the date of the last phone contact when the participant was last known to have been alive. For participants who withdrew their informed consent, only information until the date of withdrawal was used in the analysis.
Time Frame	Median (min, max) follow-up time was 6.3 (2.4, 13.6) months for Phase 1b and 26.7 (3.0, 28.5) months for Phase 2.

Outcome Measure Data

Analysis Population Description

Phase 1b and Phase 2 participants who received any infusion of blinatumomab.

Arm/Group Title	Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/Day (Adults)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.
Measure Participants	5	9	21
Median (95% Confidence Interval) [months]	11.0	10.6	14.8

8. Secondary Outcome

Title	Phase 2: Best Overall Response Within 2 Cycles of Treatment
Description	Best response was defined as one of the following: CR: ≤ 5% blasts in the bone marrow (BM); No evidence of disease; Full recovery of peripheral blood counts: Platelets > 100,000/µl, and absolute neutrophil count (ANC) > 1,000/µl CRh*: ≤ 5% blasts in BM; No evidence of disease; Partial recovery of peripheral blood counts: Platelets > 50,000/µl, and ANC > 500/µl CRi: CR with incomplete count recovery without CRh* Blast free hypoplastic or aplastic BM: ≤ 5 % blasts in BM; No evidence of disease; Insufficient recovery of peripheral blood counts: platelets ≤ 50,000/µl and/or ANC ≤ 500/µl Partial Remission: BM blasts > 5 to < 25% with at least a 50% reduction from baseline Hematological Relapse: > 5% blasts in BM or blasts in peripheral blood after documented CR/CRh* during the study PD: An increase from baseline of ≥ 25% of BM blasts or an absolute increase of ≥ 5,000 cells/µL in the number of circulating leukemia cells.
Time Frame	Within the first 2 cycles of treatment, 12 weeks

Outcome Measure Data

Analysis Population Description

Phase 2 participants who received any infusion of blinatumomab.

Arm/Group Title	Phase 2: Blinatumomab 9/28 μg/Day (Adults)
Arm/Group Description	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.
Measure Participants	21
CR	5 100%
CRh*	3 60%
CRi	0 0%
Blast-free hypoplastic or aplastic bone marrow	6 120%
Partial remission	0 0%
Hematological relapse	0 0%
PD	2 40%
No response (none of the above)	5 100%

9. Secondary Outcome

Title	Phase 2: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission
Description	Participants who were eligible for allogeneic HSCT were those who achieved remission (complete response or complete response with partial recovery of peripheral blood counts) after 2 cycles of blinatumomab treatment, and no further anti-leukemic medication was given before HSCT.
Time Frame	Median (min, max) follow-up time was 26.7 (3.0, 28.5) months.

Outcome Measure Data

Analysis Population Description

Phase 2 participants who received any infusion of blinatumomab.

Arm/Group Title	Phase 2: Blinatumomab 9/28 μg/Day (Adults)
Arm/Group Description	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.
Measure Participants	21
Number [percentage of participants]	81.0 1620%

10. Secondary Outcome

Title	Phase 2: 100-Day Mortality After Allogeneic HSCT
Description	The analysis of 100-day mortality after allogeneic HSCT was assessed for all participants who received an allogeneic HSCT while in any CR following treatment with blinatumomab. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT. Participants still alive alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive. The 100-day mortality rate after allogeneic HSCT was defined as the percentage of participants having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods.
Time Frame	100 days, from the date of allogeneic HSCT; median (min, max) follow-up time was 26.7 (3.0, 28.5)

Outcome Measure Data

Analysis Population Description

Phase 2 participants who received an allogeneic HSCT.

Arm/Group Title	Phase 2: Blinatumomab 9/28 μg/Day (Adults)
Arm/Group Description	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.
Measure Participants	17
Number [percentage of participants]	11.8 236%

11. Secondary Outcome

Title	Phase 1b and Phase 2: Number of Participants With TEAEs
Description	TEAEs are defined as those that start between the start of the first infusion of blinatumomab and 30 days after the end of the last infusion during the treatment period. The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; 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; median (min, max) treatment duration was 108 (56, 140), 56.0 (5, 84), and 56.0 (11, 115) days in adult phase 1b, adult phase 2 and pediatric phase 1b cohort respectively.

Outcome Measure Data

Analysis Population Description

Phase 1b and Phase 2 participants who received any infusion of blinatumomab.

Arm/Group Title	Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/Day (Adults)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.
Measure Participants	5	9	21
All TEAEs	5 100%	9 100%	21 100%
TEAEs ≥ Grade 3	4 80%	9 100%	21 100%
TEAEs ≥ Grade 4	2 40%	7 77.8%	14 66.7%
Serious TEAEs (STEAEs)	0 0%	1 11.1%	7 33.3%
TEAEs Leading to Blinatumomab Interruption	1 20%	6 66.7%	3 14.3%
STEAEs Leading to Blinatumomab Interruption	0 0%	0 0%	0 0%
TEAEs Leading to Blinatumomab Discontinuation	0 0%	1 11.1%	1 4.8%
STEAEs Leading to Blinatumomab Discontinuation	0 0%	0 0%	1 4.8%
Fatal TEAEs	0 0%	1 11.1%	1 4.8%
All Treatment-Related (TR) TEAEs	5 100%	8 88.9%	21 100%
TR TEAEs ≥ Grade 3	2 40%	8 88.9%	18 85.7%
TR TEAEs ≥ Grade 4	1 20%	5 55.6%	11 52.4%
TR STEAEs	0 0%	0 0%	4 19%
TR TEAEs Leading to Blinatumomab Interruption	1 20%	6 66.7%	1 4.8%
TR STEAEs Leading to Blinatumomab Interruption	0 0%	0 0%	0 0%
TR TEAEs Leading to Blinatumomab Discontinuation	0 0%	1 11.1%	1 4.8%
TR STEAEs Leading to Blinatumomab Discontinuation	0 0%	0 0%	1 4.8%
TR Fatal TEAEs	0 0%	0 0%	0 0%

12. Secondary Outcome

Title	Phase 1b and Phase 2: Serum Blinatumomab Concentration at Steady State
Description	The steady-state concentration (Css) of serum blinatumomab was summarized as the average of the observed concentrations collected after 5 half-lives or after 24 hours from the start of continuous IV infusion. Cycle 1, day 2 values represent steady-state concentration after CIV with the initial dose of blinatumomab (9 µg/day for adults and 5 µg/m²/day for pediatric patients). All other time points were measured after the dose step to 28 µg/day (adults) / 15 µg/m²/day (pediatric participants).
Time Frame	After 24 hours from the start of infusion: Cycle 1 (before dose step) day 2; Cycle 1 (after dose step) days 15 and 29; Cycle 2 onwards day 8 (pediatric and adult), days 15 and 29 (adult).

Outcome Measure Data

Analysis Population Description

Phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacokinetic sample collected, with available data at each time point.

Arm/Group Title	Blinatumomab 9/28 μg/Day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/Day (Phase 1b and Phase 2 Pediatric)	Blinatumomab 9/28 μg/Day (Phase 1b Only Adults)	Blinatumomab 5/15 µg/m²/Day (Phase 1b Only Pediatric)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Measure Participants	25	7	5	7
Cycle 1 before dose step	191 (90.8)	113 (65.0)	135 (41.7)	107 (42.7)
Cycle 1 after dose step	948 (488)	361 (137)	907 (403)	361 (137)
Cycle 2	1150 (575)	427 (66.0)	1040 (493)	427 (66.0)
Cycle 3+	1420 (685)	780 (NA)	1280 (396)

13. Secondary Outcome

Title	Phase 1b and Phase 2: Systemic Clearance of Blinatumomab
Description	Systemic clearance (CL) was calculated as CL = R0/Css, where R0 is the infusion rate (µg/hour or µg/m²/hour).
Time Frame	After 24 hours from the start of infusion: Cycle 1 (before dose step) day 2; Cycle 1 (after dose step) days 15 and 29; Cycle 2 onwards day 8 (pediatric and adult), days 15 and 29 (adult).

Outcome Measure Data

Analysis Population Description

Phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacokinetic sample collected.

Arm/Group Title	Blinatumomab 9/28 μg/Day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/Day (Phase 1b and Phase 2 Pediatric)	Blinatumomab 9/28 μg/Day (Phase 1b Only Adults)	Blinatumomab 5/15 µg/m²/Day (Phase 1b Only Pediatric)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Measure Participants	26	9	5	9
Mean (Standard Deviation) [liters/hour]	1.59 (0.812)	1.88 (0.789)	1.59 (0.998)	1.83 (0.801)

14. Secondary Outcome

Title	Phase 1b and Phase 2: Terminal Half-life of Blinatumomab
Time Frame	Cycle 1 day 1 predose, 2, 6 (adults), 10, 24 hours; day 8 (prior to dose step) 0 hour (adults); day 15 any time during infusion; day 29 prior to end of infusion, 1 (adults), 2, 4 (adults), 6 hours after end of infusion

Outcome Measure Data

Analysis Population Description

Phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacokinetic sample collected with available data.

Arm/Group Title	Blinatumomab 9/28 μg/Day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/Day (Phase 1b and Phase 2 Pediatric)	Blinatumomab 9/28 μg/Day (Phase 1b Only Adults)	Blinatumomab 5/15 µg/m²/Day (Phase 1b Only Pediatric)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Measure Participants	24	5	5	5
Mean (Standard Deviation) [hours]	2.38 (1.36)	1.92 (1.12)	2.60 (2.03)	2.62 (1.67)

15. Secondary Outcome

Title	Phase 1b and Phase 2: Volume of Distribution of Blinatumomab
Time Frame	Cycle 1 day 1 predose, 2, 6 (adults), 10, 24 hours; day 8 (prior to dose step) 0 hour (adults); day 15 any time during infusion; day 29 prior to end of infusion, 1 (adults), 2, 4 (adults), 6 hours after end of infusion

Outcome Measure Data

Analysis Population Description

Phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacokinetic sample collected with available data.

Arm/Group Title	Blinatumomab 9/28 μg/Day (Phase 1b and Phase 2 Adults)	Blinatumomab 5/15 µg/m²/Day (Phase 1b and Phase 2 Pediatric)	Blinatumomab 9/28 μg/Day (Phase 1b Only Adults)	Blinatumomab 5/15 µg/m²/Day (Phase 1b Only Pediatric)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Measure Participants	24	5	5	5
Mean (Standard Deviation) [liters]	6.02 (6.09)	5.05 (3.35)	8.22 (11.7)	6.38 (3.95)

16. Secondary Outcome

Title	Phase 1b and Phase 2: Number of Participants Who Developed Anti-Blinatumomab Antibodies
Description	Antibodies to blinatumomab were detected using an electrochemiluminescence (ECL)-based assay.
Time Frame	Day 1 before first dose; cycles 1 and 2 day 29, 6 hours after end of infusion; 30 days after last dose.

Outcome Measure Data

Analysis Population Description

Phase 1b and Phase 2 participants who received any infusion of blinatumomab.

Arm/Group Title	Phase 1b: Blinatumomab 9/28 μg/Day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)	Phase 2: Blinatumomab 9/28 μg/Day (Adults)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.
Measure Participants	5	9	21
Count of Participants [Participants]	0 0%	0 0%	0 0%

17. Secondary Outcome

Title	Phase 1b and Phase 2: Interleukin-2 Concentration
Description	The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL).
Time Frame	Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start

Outcome Measure Data

Analysis Population Description

Phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacodynamic sample collected, with available data at each time point.

Arm/Group Title	Phase 1b and Phase 2: Blinatumomab 9/28 μg/Day (Adults)	Phase 1b and Phase 2: Blinatumomab 5/15 µg/m²/Day (Pediatric)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Measure Participants	26	9
Cycle 1, day 1, 2 hours after start of infusion	16.1 (17.1)
Cycle 1, day 1, 6 hours after start of infusion	30.2 (72.8)	10.0 (0.0)
Cycle 1, day 1, 10 hours after start of infusion	32.6 (85.0)	10.0 (0.0)
Cycle 1, day 1, 24 hours after start of infusion	17.2 (36.7)	29.8 (55.9)
Cycle 1, day 8, 2 hours after start of infusion	10.0 (0.0)
Cycle 1, day 8, 6 hours after start of infusion	10.0 (0.0)
Cycle 1, day 8, 10 hours after start of infusion	10.0 (0.0)
Cycle 2, day 1, 6 hours after start of infusion	12.6 (11.7)	10.0 (0.0)
Cycle 3, day 1, 6 hours after start of infusion	10.0 (0.0)	10.0 (0.0)
Cycle 4, day 1, 6 hours after start of infusion	10.0 (0.0)	10.0 (NA)
Cycle 5, day 1, 6 hours after start of infusion	10.0 (0.0)	10.0 (NA)

18. Secondary Outcome

Title	Phase 1b and Phase 2: Interleukin-6 Concentration
Description	The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL).
Time Frame	Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start

Outcome Measure Data

Analysis Population Description

Phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacodynamic sample collected, with available data at each time point.

Arm/Group Title	Phase 1b and Phase 2: Blinatumomab 9/28 μg/Day (Adults)	Phase 1b and Phase 2: Blinatumomab 5/15 µg/m²/Day (Pediatric)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Measure Participants	26	9
Cycle 1, day 1, 2 hours after start of infusion	29.1 (40.1)
Cycle 1, day 1, 6 hours after start of infusion	173 (198.1)	275 (371)
Cycle 1, day 1, 10 hours after start of infusion	186 (301.5)	317 (358)
Cycle 1, day 1, 24 hours after start of infusion	246 (907.6)	3714 (10740)
Cycle 1, day 8, 2 hours after start of infusion	14.2 (14.5)
Cycle 1, day 8, 6 hours after start of infusion	10.0 (0.0)
Cycle 1, day 8, 10 hours after start of infusion	10.0 (0.0)
Cycle 2, day 1, 6 hours after start of infusion	20.3 (35.6)	17.5 (19.8)
Cycle 3, day 1, 6 hours after start of infusion	16.6 (18.6)	36.3 (37.1)
Cycle 4, day 1, 6 hours after start of infusion	10.0 (0.0)	62.5 (NA)
Cycle 5, day 1, 6 hours after start of infusion	10.0 (0.0)	62.5 (NA)

19. Secondary Outcome

Title	Phase 1b and Phase 2: Interleukin-10 Concentration
Description	The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL).
Time Frame	Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start

Outcome Measure Data

Analysis Population Description

Phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacodynamic sample collected, with available data at each time point.

Arm/Group Title	Phase 1b and Phase 2: Blinatumomab 9/28 μg/Day (Adults)	Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Measure Participants	26	9
Cycle 1, day 1, 2 hours after start of infusion	101 (81.1)
Cycle 1, day 1, 6 hours after start of infusion	597 (637)	153 (94.7)
Cycle 1, day 1, 10 hours after start of infusion	423 (373)	230 (178)
Cycle 1, day 1, 24 hours after start of infusion	400 (699)	641 (1168)
Cycle 1, day 8, 2 hours after start of infusion	28.9 (25.7)
Cycle 1, day 8, 6 hours after start of infusion	33.1 (26.6)
Cycle 1, day 8, 10 hours after start of infusion	33.1 (26.6)
Cycle 2, day 1, 6 hours after start of infusion	220 (357)	142 (173)
Cycle 3, day 1, 6 hours after start of infusion	121 (146)	62.5 (0.0)
Cycle 4, day 1, 6 hours after start of infusion	88.2 (93.7)	62.5 (NA)
Cycle 5, day 1, 6 hours after start of infusion	36.3 (37.1)	62.5 (NA)

20. Secondary Outcome

Title	Phase 1b and Phase 2: Tumor Necrosis Factor-Alpha (TNFα) Concentration
Description	The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL).
Time Frame	Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start

Outcome Measure Data

Analysis Population Description

Phase 1b and phase 2 participants who received any infusion of blinatumomab and had at least one pharmacodynamic sample collected, with available data at each time point.

Arm/Group Title	Phase 1b and Phase 2: Blinatumomab 9/28 μg/Day (Adults)	Phase 1b and Phase 2: Blinatumomab 5/15 µg/m²/Day (Pediatric)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Measure Participants	26	9
Cycle 1, day 1, 2 hours after start of infusion	37.3 (61.8)
Cycle 1, day 1, 6 hours after start of infusion	24.1 (23.7)	15.8 (17.5)
Cycle 1, day 1, 10 hours after start of infusion	20.1 (21.1)	15.8 (17.5)
Cycle 1, day 1, 24 hours after start of infusion	10.0 (0.0)	15.8 (17.5)
Cycle 1, day 8, 2 hours after start of infusion	16.6 (32.8)
Cycle 1, day 8, 6 hours after start of infusion	10.0 (0.0)
Cycle 1, day 8, 10 hours after start of infusion	10.0 (0.0)
Cycle 2, day 1, 6 hours after start of infusion	12.6 (11.7)	17.5 (19.8)
Cycle 3, day 1, 6 hours after start of infusion	16.6 (18.6)	10.0 (0.0)
Cycle 4, day 1, 6 hours after start of infusion	10.0 (0.0)	10.0 (NA)
Cycle 5, day 1, 6 hours after start of infusion	10.0 (0.0)	10.0 (NA)

21. Secondary Outcome

Title	Phase 1b and Phase 2: Interferon Gamma (IFN-γ) Concentration
Description	The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN-γ) using multiplex cytometric bead assays. The lower limit of quantification (LLOQ) was 125 pg/mL and the limit of detection (LOD) was 20 pg/mL. For calculations of mean cytokine concentrations at every time point across all participants, samples with concentrations below LLOQ were included in the calculation as ½ LLOQ (= 62.5 pg/mL); samples with values below LOD were included as ½ LOD (= 10 pg/mL).
Time Frame	Adults: cycle 1, day 1: 2, 6, 10, 24 hrs after infusion start; day 8: 2, 6, 10 hrs after dose step. Cycles 2-5, day 1: 6 hrs after infusion start. Pediatric: cycle 1, day 1: 6, 10, 24 hrs after infusion start; Cycles 2-5, day 1: 6 hrs after infusion start

Outcome Measure Data

Analysis Population Description

Phase 1b participants who received any infusion of blinatumomab and had at least one pharmacodynamic sample collected, with available data at each time point.

Arm/Group Title	Phase 1b and Phase 2: Blinatumomab 9/28 μg/Day (Adults)	Phase 1b and Phase 2: Blinatumomab 5/15 µg/m²/Day (Pediatric)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Measure Participants	26	9
Cycle 1, day 1, 2 hours after start of infusion	26.2 (24.7)
Cycle 1, day 1, 6 hours after start of infusion	52.3 (56.2)	41.2 (42.8)
Cycle 1, day 1, 10 hours after start of infusion	65.8 (71.6)	64.5 (107)
Cycle 1, day 1, 24 hours after start of infusion	42.1 (51.8)	129 (176)
Cycle 1, day 8, 2 hours after start of infusion	16.3 (17.4)
Cycle 1, day 8, 6 hours after start of infusion	14.2 (14.5)
Cycle 1, day 8, 10 hours after start of infusion	14.2 (14.5)
Cycle 2, day 1, 6 hours after start of infusion	17.9 (19.2)	40.0 (28.1)
Cycle 3, day 1, 6 hours after start of infusion	35.8 (55.0)	10.0 (0.0)
Cycle 4, day 1, 6 hours after start of infusion	10.0 (0.0)	10.0 (NA)
Cycle 5, day 1, 6 hours after start of infusion	10.0 (0.0)	10.0 (NA)

22. Primary Outcome

Title	Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs
Description	TEAEs are defined as those that start between the start of the first infusion of blinatumomab and 30 days after the end of the last infusion during the treatment period. The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; 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; median (min, max) treatment duration was 55.6 (25, 140) and 28.0 (8, 56) days in the adult and pediatric expansion cohorts, respectively.

Outcome Measure Data

Analysis Population Description

Expansion Cohort participants in the who received any infusion of blinatumomab.

Arm/Group Title	Expansion Cohort: Blinatumomab 9/28 μg/Day (Adults)	Expansion Cohort: Blinatumomab 5/15 µg/m²/Day (Pediatric)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Measure Participants	14	17
All TEAEs	14 280%	17 188.9%
TEAEs ≥ Grade 3	11 220%	15 166.7%
TEAEs ≥ Grade 4	7 140%	7 77.8%
Serious TEAEs (STEAEs)	2 40%	3 33.3%
TEAEs Leading to Interruption of Blinatumomab	2 40%	2 22.2%
STEAEs Leading to Interruption of Blinatumomab	0 0%	0 0%
TEAEs Leading to Blinatumomab Discontinuation	0 0%	1 11.1%
STEAEs Leading to Blinatumomab Discontinuation	0 0%	0 0%
Fatal TEAEs	0 0%	2 22.2%
All Treatment-Related (TR) TEAEs	14 280%	14 155.6%
TR TEAEs ≥ Grade 3	9 180%	9 100%
TR TEAEs ≥ Grade 4	5 100%	5 55.6%
TR STEAEs	0 0%	0 0%
TR TEAEs Leading to Blinatumomab Interruption	2 40%	1 11.1%
TR STEAEs Leading to Blinatumomab Interruption	0 0%	0 0%
TR TEAEs Leading to Blinatumomab Discontinuation	0 0%	1 11.1%
TR STEAEs Leading to Blinatumomab Discontinuation	0 0%	0 0%
TR Fatal TEAEs	0 0%	0 0%

23. Secondary Outcome

Title	Expansion Cohort Adult: Percentage of Participants With a Best Response of Complete Remission or Complete Remission With Only Partial Hematological Recovery Within 2 Cycles of Treatment
Description	Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Remission (CR) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts: platelets > 100,000/µl and absolute neutrophil count (ANC) > 1,000/µl. Complete Remission With Partial Hematological Recovery (CRh*) is defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts: platelets > 50,000/µl and ANC > 500/µl.
Time Frame	Within the first 2 cycles of treatment, 12 weeks

Outcome Measure Data

Analysis Population Description

Expansion Cohort adult participants who received any infusion of blinatumomab.

Arm/Group Title	Expansion Cohort: Blinatumomab 9/28 μg/Day (Adults)
Arm/Group Description	Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.
Measure Participants	14
Number (95% Confidence Interval) [percentage of participants]	78.6 1572%

24. Secondary Outcome

Title	Expansion Cohort Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment
Description	M1 remission for pediatric participants was defined as ≤ 5% blasts (M1 bone marrow) in the bone marrow and no evidence of disease.
Time Frame	Within the first 2 cycles of treatment, 12 weeks

Outcome Measure Data

Analysis Population Description

Expansion Cohort pediatric participants who received any infusion of blinatumomab.

Arm/Group Title	Expansion Cohort: Blinatumomab 5/15 µg/m²/Day (Pediatric)
Arm/Group Description	Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
Measure Participants	17
Number (95% Confidence Interval) [percentage of participants]	29.4 588%

Adverse Events

Time Frame	The median treatment duration for blinatumomab was 108 days for Adult Phase 1b Cohort, 56 days for Pediatric Phase 1b Cohort, 56 days for Adult Phase 2 Cohort, 55.6 days for Adult Expansion Cohort and 28 days for Pediatric Expansion Cohort
Adverse Event Reporting Description	All-cause mortality is reported for all participants enrolled/randomized in the study. Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.
Arm/Group Title	Phase 1b: Blinatumomab 9/28 μg/Day (Adults)		Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)		Phase 2: Blinatumomab 9/28 μg/Day (Adults)		Expansion Cohort: Blinatumomab 9/28 μg/Day (Adults)		Expansion Cohort: Blinatumomab 5/15 µg/m²/Day (Pediatric)
Arm/Group Description	Participants received blinatumomab by continuous intravenous (CIV) infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from week 2 and all cycles thereafter.		Participants received blinatumomab by CIV over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.		Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.		Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 9 μg/day for the first week of cycle 1, escalated to 28 μg/day starting from Week 2 and all cycles thereafter.		Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter.
All Cause Mortality
	Phase 1b: Blinatumomab 9/28 μg/Day (Adults)		Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)		Phase 2: Blinatumomab 9/28 μg/Day (Adults)		Expansion Cohort: Blinatumomab 9/28 μg/Day (Adults)		Expansion Cohort: Blinatumomab 5/15 µg/m²/Day (Pediatric)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		7/9 (77.8%)		15/21 (71.4%)		0/14 (0%)		2/17 (11.8%)
Serious Adverse Events
	Phase 1b: Blinatumomab 9/28 μg/Day (Adults)		Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)		Phase 2: Blinatumomab 9/28 μg/Day (Adults)		Expansion Cohort: Blinatumomab 9/28 μg/Day (Adults)		Expansion Cohort: Blinatumomab 5/15 µg/m²/Day (Pediatric)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		1/9 (11.1%)		7/21 (33.3%)		2/14 (14.3%)		3/17 (17.6%)
Gastrointestinal disorders
Colitis	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		0/14 (0%)		0/17 (0%)
Stomatitis	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
General disorders
Disease progression	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Multiple organ dysfunction syndrome	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Immune system disorders
Cytokine release syndrome	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		0/14 (0%)		0/17 (0%)
Infections and infestations
Bacteraemia	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		1/14 (7.1%)		0/17 (0%)
Device related sepsis	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		0/14 (0%)		0/17 (0%)
Sepsis	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		2/17 (11.8%)
Injury, poisoning and procedural complications
Overdose	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Investigations
Neutrophil count decreased	0/5 (0%)		0/9 (0%)		2/21 (9.5%)		0/14 (0%)		0/17 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		0/14 (0%)		0/17 (0%)
Tumour lysis syndrome	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		0/14 (0%)		0/17 (0%)
Vascular disorders
Shock haemorrhagic	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Other (Not Including Serious) Adverse Events
	Phase 1b: Blinatumomab 9/28 μg/Day (Adults)		Phase 1b: Blinatumomab 5/15 µg/m²/Day (Pediatric)		Phase 2: Blinatumomab 9/28 μg/Day (Adults)		Expansion Cohort: Blinatumomab 9/28 μg/Day (Adults)		Expansion Cohort: Blinatumomab 5/15 µg/m²/Day (Pediatric)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		9/9 (100%)		21/21 (100%)		14/14 (100%)		16/17 (94.1%)
Blood and lymphatic system disorders
Anaemia	1/5 (20%)		4/9 (44.4%)		7/21 (33.3%)		4/14 (28.6%)		6/17 (35.3%)
Bone marrow failure	0/5 (0%)		0/9 (0%)		2/21 (9.5%)		0/14 (0%)		0/17 (0%)
Disseminated intravascular coagulation	0/5 (0%)		0/9 (0%)		7/21 (33.3%)		2/14 (14.3%)		3/17 (17.6%)
Febrile neutropenia	2/5 (40%)		5/9 (55.6%)		10/21 (47.6%)		7/14 (50%)		4/17 (23.5%)
Leukopenia	0/5 (0%)		4/9 (44.4%)		3/21 (14.3%)		2/14 (14.3%)		0/17 (0%)
Lymphopenia	0/5 (0%)		4/9 (44.4%)		2/21 (9.5%)		0/14 (0%)		0/17 (0%)
Neutropenia	2/5 (40%)		5/9 (55.6%)		5/21 (23.8%)		6/14 (42.9%)		0/17 (0%)
Thrombocytopenia	0/5 (0%)		3/9 (33.3%)		5/21 (23.8%)		3/14 (21.4%)		0/17 (0%)
Hypoglobulinaemia	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		1/14 (7.1%)		0/17 (0%)
Pancytopenia	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Thrombotic microangiopathy	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Cardiac disorders
Cardiac failure	0/5 (0%)		1/9 (11.1%)		1/21 (4.8%)		0/14 (0%)		0/17 (0%)
Sinus bradycardia	0/5 (0%)		0/9 (0%)		2/21 (9.5%)		0/14 (0%)		0/17 (0%)
Arrhythmia	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Ventricular tachycardia	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Endocrine disorders
Steroid withdrawal syndrome	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Eye disorders
Conjunctival haemorrhage	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Dry eye	0/5 (0%)		1/9 (11.1%)		1/21 (4.8%)		1/14 (7.1%)		0/17 (0%)
Photophobia	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Vitreous floaters	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Glaucoma	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Gastrointestinal disorders
Abdominal distension	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Abdominal pain	0/5 (0%)		3/9 (33.3%)		0/21 (0%)		0/14 (0%)		2/17 (11.8%)
Abdominal pain upper	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Aphthous ulcer	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Constipation	1/5 (20%)		3/9 (33.3%)		0/21 (0%)		0/14 (0%)		2/17 (11.8%)
Diarrhoea	0/5 (0%)		3/9 (33.3%)		8/21 (38.1%)		4/14 (28.6%)		2/17 (11.8%)
Dyspepsia	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Gastritis	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Gingival swelling	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Nausea	2/5 (40%)		2/9 (22.2%)		9/21 (42.9%)		8/14 (57.1%)		2/17 (11.8%)
Oral pain	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Pancreatitis	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Proctitis	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Stomatitis	1/5 (20%)		2/9 (22.2%)		7/21 (33.3%)		5/14 (35.7%)		2/17 (11.8%)
Vomiting	2/5 (40%)		5/9 (55.6%)		3/21 (14.3%)		4/14 (28.6%)		6/17 (35.3%)
Dental caries	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Gastrointestinal disorder	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		1/14 (7.1%)		0/17 (0%)
Haemorrhoids	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		1/14 (7.1%)		0/17 (0%)
Lip pain	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Oral disorder	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Proctalgia	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Salivary gland pain	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
General disorders
Chest pain	0/5 (0%)		0/9 (0%)		2/21 (9.5%)		0/14 (0%)		0/17 (0%)
Fatigue	2/5 (40%)		2/9 (22.2%)		0/21 (0%)		0/14 (0%)		3/17 (17.6%)
Localised oedema	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Malaise	1/5 (20%)		1/9 (11.1%)		6/21 (28.6%)		3/14 (21.4%)		0/17 (0%)
Oedema	1/5 (20%)		1/9 (11.1%)		0/21 (0%)		3/14 (21.4%)		0/17 (0%)
Pain	0/5 (0%)		2/9 (22.2%)		0/21 (0%)		1/14 (7.1%)		3/17 (17.6%)
Pyrexia	1/5 (20%)		7/9 (77.8%)		15/21 (71.4%)		4/14 (28.6%)		15/17 (88.2%)
Catheter site pain	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		1/14 (7.1%)		1/17 (5.9%)
Chills	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		1/17 (5.9%)
Disease progression	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Face oedema	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		1/17 (5.9%)
Infusion site extravasation	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Non-cardiac chest pain	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Oedema peripheral	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		0/14 (0%)		1/17 (5.9%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Liver disorder	1/5 (20%)		1/9 (11.1%)		4/21 (19%)		0/14 (0%)		0/17 (0%)
Liver injury	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Cholecystitis	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Drug-induced liver injury	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Hepatic function abnormal	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Hepatic pain	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Immune system disorders
Acute graft versus host disease	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Cytokine release syndrome	4/5 (80%)		5/9 (55.6%)		8/21 (38.1%)		5/14 (35.7%)		6/17 (35.3%)
Hypogammaglobulinaemia	2/5 (40%)		2/9 (22.2%)		2/21 (9.5%)		6/14 (42.9%)		0/17 (0%)
Engraftment syndrome	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Graft versus host disease	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Hypersensitivity	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Infections and infestations
Bronchopulmonary aspergillosis	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Conjunctivitis	1/5 (20%)		0/9 (0%)		2/21 (9.5%)		0/14 (0%)		0/17 (0%)
Cystitis	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Cytomegalovirus infection	0/5 (0%)		0/9 (0%)		2/21 (9.5%)		0/14 (0%)		0/17 (0%)
Device related infection	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Gingivitis	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Hepatitis B	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Herpes zoster	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Infection	0/5 (0%)		0/9 (0%)		2/21 (9.5%)		1/14 (7.1%)		0/17 (0%)
Nasopharyngitis	0/5 (0%)		1/9 (11.1%)		2/21 (9.5%)		0/14 (0%)		0/17 (0%)
Otitis media	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Pneumonia	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Sepsis	1/5 (20%)		0/9 (0%)		1/21 (4.8%)		0/14 (0%)		0/17 (0%)
Staphylococcal sepsis	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Upper respiratory tract infection	0/5 (0%)		0/9 (0%)		2/21 (9.5%)		0/14 (0%)		0/17 (0%)
Bacteraemia	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		1/17 (5.9%)
Folliculitis	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Fungal infection	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Gastroenteritis norovirus	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		2/17 (11.8%)
Paronychia	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		1/14 (7.1%)		0/17 (0%)
Pharyngitis	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		1/14 (7.1%)		0/17 (0%)
Sialoadenitis	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Skin candida	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Injury, poisoning and procedural complications
Contusion	1/5 (20%)		1/9 (11.1%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Infusion related reaction	1/5 (20%)		1/9 (11.1%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Wrist fracture	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Arthropod bite	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Investigations
Activated partial thromboplastin time prolonged	0/5 (0%)		3/9 (33.3%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Alanine aminotransferase increased	1/5 (20%)		5/9 (55.6%)		4/21 (19%)		2/14 (14.3%)		6/17 (35.3%)
Amylase increased	0/5 (0%)		2/9 (22.2%)		1/21 (4.8%)		1/14 (7.1%)		0/17 (0%)
Aspartate aminotransferase increased	1/5 (20%)		4/9 (44.4%)		3/21 (14.3%)		0/14 (0%)		6/17 (35.3%)
Blood alkaline phosphatase increased	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Blood bilirubin increased	0/5 (0%)		3/9 (33.3%)		1/21 (4.8%)		0/14 (0%)		0/17 (0%)
Blood glucose decreased	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Blood uric acid increased	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Gamma-glutamyltransferase increased	0/5 (0%)		4/9 (44.4%)		1/21 (4.8%)		1/14 (7.1%)		3/17 (17.6%)
Glucose urine present	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Hepatic enzyme increased	0/5 (0%)		2/9 (22.2%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Immunoglobulins decreased	0/5 (0%)		0/9 (0%)		3/21 (14.3%)		1/14 (7.1%)		0/17 (0%)
International normalised ratio increased	0/5 (0%)		2/9 (22.2%)		1/21 (4.8%)		1/14 (7.1%)		2/17 (11.8%)
Lipase increased	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Lymphocyte count decreased	1/5 (20%)		0/9 (0%)		3/21 (14.3%)		1/14 (7.1%)		2/17 (11.8%)
Neutrophil count decreased	0/5 (0%)		1/9 (11.1%)		5/21 (23.8%)		1/14 (7.1%)		3/17 (17.6%)
Oxygen saturation decreased	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Platelet count decreased	1/5 (20%)		1/9 (11.1%)		5/21 (23.8%)		1/14 (7.1%)		5/17 (29.4%)
Prothrombin time prolonged	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Serum ferritin increased	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Weight decreased	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Weight increased	1/5 (20%)		2/9 (22.2%)		1/21 (4.8%)		2/14 (14.3%)		2/17 (11.8%)
White blood cell count decreased	1/5 (20%)		1/9 (11.1%)		4/21 (19%)		2/14 (14.3%)		4/17 (23.5%)
Antithrombin III decreased	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		3/17 (17.6%)
Bilirubin conjugated increased	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Blast cell count increased	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Blood cholesterol increased	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Blood creatinine increased	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Blood fibrinogen decreased	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		0/14 (0%)		2/17 (11.8%)
Metabolism and nutrition disorders
Decreased appetite	1/5 (20%)		3/9 (33.3%)		3/21 (14.3%)		3/14 (21.4%)		5/17 (29.4%)
Fluid retention	0/5 (0%)		0/9 (0%)		3/21 (14.3%)		1/14 (7.1%)		0/17 (0%)
Hypercalcaemia	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Hyperglycaemia	0/5 (0%)		1/9 (11.1%)		1/21 (4.8%)		2/14 (14.3%)		1/17 (5.9%)
Hyperkalaemia	1/5 (20%)		1/9 (11.1%)		0/21 (0%)		1/14 (7.1%)		2/17 (11.8%)
Hyperlipidaemia	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Hyperuricaemia	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Hypoalbuminaemia	1/5 (20%)		5/9 (55.6%)		2/21 (9.5%)		0/14 (0%)		4/17 (23.5%)
Hypocalcaemia	0/5 (0%)		2/9 (22.2%)		0/21 (0%)		1/14 (7.1%)		3/17 (17.6%)
Hypokalaemia	0/5 (0%)		2/9 (22.2%)		6/21 (28.6%)		4/14 (28.6%)		1/17 (5.9%)
Hypomagnesaemia	0/5 (0%)		2/9 (22.2%)		3/21 (14.3%)		2/14 (14.3%)		0/17 (0%)
Hyponatraemia	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		1/14 (7.1%)		4/17 (23.5%)
Hypophosphataemia	1/5 (20%)		0/9 (0%)		0/21 (0%)		2/14 (14.3%)		1/17 (5.9%)
Hypernatraemia	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		1/17 (5.9%)
Hypertriglyceridaemia	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		1/17 (5.9%)
Hypoglycaemia	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/5 (0%)		1/9 (11.1%)		1/21 (4.8%)		1/14 (7.1%)		2/17 (11.8%)
Arthritis	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Musculoskeletal pain	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Myalgia	0/5 (0%)		1/9 (11.1%)		1/21 (4.8%)		0/14 (0%)		0/17 (0%)
Myopathy	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Neck pain	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Pain in extremity	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		1/14 (7.1%)		3/17 (17.6%)
Pain in jaw	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Spinal osteoarthritis	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Spinal pain	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Back pain	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		2/14 (14.3%)		0/17 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Central nervous system leukaemia	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Leukaemic infiltration extramedullary	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Nervous system disorders
Altered state of consciousness	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Aphasia	0/5 (0%)		1/9 (11.1%)		1/21 (4.8%)		0/14 (0%)		0/17 (0%)
Facial paralysis	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Headache	3/5 (60%)		4/9 (44.4%)		6/21 (28.6%)		3/14 (21.4%)		4/17 (23.5%)
Hypoaesthesia	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Intention tremor	0/5 (0%)		1/9 (11.1%)		1/21 (4.8%)		0/14 (0%)		0/17 (0%)
Lethargy	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Peripheral sensory neuropathy	1/5 (20%)		0/9 (0%)		1/21 (4.8%)		1/14 (7.1%)		0/17 (0%)
Seizure	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Somnolence	2/5 (40%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Tremor	0/5 (0%)		1/9 (11.1%)		2/21 (9.5%)		1/14 (7.1%)		3/17 (17.6%)
Haemorrhage intracranial	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Movement disorder	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Posterior reversible encephalopathy syndrome	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Wernicke's encephalopathy	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Psychiatric disorders
Agitation	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Delirium	0/5 (0%)		2/9 (22.2%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Insomnia	0/5 (0%)		2/9 (22.2%)		3/21 (14.3%)		3/14 (21.4%)		1/17 (5.9%)
Sleep disorder	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Disorientation	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		1/14 (7.1%)		0/17 (0%)
Hallucination	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Renal and urinary disorders
Cystitis haemorrhagic	0/5 (0%)		1/9 (11.1%)		2/21 (9.5%)		1/14 (7.1%)		0/17 (0%)
Renal disorder	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Cystitis noninfective	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Pollakiuria	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Urinary retention	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Reproductive system and breast disorders
Balanoposthitis	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Metrorrhagia	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Pelvic pain	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/5 (20%)		0/9 (0%)		1/21 (4.8%)		1/14 (7.1%)		2/17 (11.8%)
Epistaxis	0/5 (0%)		2/9 (22.2%)		1/21 (4.8%)		0/14 (0%)		1/17 (5.9%)
Hiccups	1/5 (20%)		0/9 (0%)		1/21 (4.8%)		0/14 (0%)		0/17 (0%)
Rhinorrhoea	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Dyspnoea	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		1/17 (5.9%)
Hypoxia	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		1/17 (5.9%)
Laryngeal pain	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Oropharyngeal pain	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Skin and subcutaneous tissue disorders
Acne	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Alopecia	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Asteatosis	1/5 (20%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Dermatitis contact	0/5 (0%)		0/9 (0%)		2/21 (9.5%)		0/14 (0%)		0/17 (0%)
Dry skin	0/5 (0%)		0/9 (0%)		3/21 (14.3%)		2/14 (14.3%)		1/17 (5.9%)
Erythema	0/5 (0%)		0/9 (0%)		3/21 (14.3%)		3/14 (21.4%)		0/17 (0%)
Ingrowing nail	1/5 (20%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Palmar-plantar erythrodysaesthesia syndrome	0/5 (0%)		1/9 (11.1%)		0/21 (0%)		0/14 (0%)		0/17 (0%)
Rash	0/5 (0%)		2/9 (22.2%)		3/21 (14.3%)		2/14 (14.3%)		1/17 (5.9%)
Rash maculo-papular	2/5 (40%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Urticaria	0/5 (0%)		2/9 (22.2%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Dermatitis acneiform	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		1/14 (7.1%)		0/17 (0%)
Dermatitis diaper	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		1/17 (5.9%)
Dermatitis exfoliative generalised	0/5 (0%)		0/9 (0%)		0/21 (0%)		1/14 (7.1%)		0/17 (0%)
Eczema	0/5 (0%)		0/9 (0%)		0/21 (0%)		0/14 (0%)		2/17 (11.8%)
Pruritus	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		1/14 (7.1%)		0/17 (0%)
Vascular disorders
Hypertension	0/5 (0%)		4/9 (44.4%)		0/21 (0%)		1/14 (7.1%)		2/17 (11.8%)
Hypotension	1/5 (20%)		1/9 (11.1%)		1/21 (4.8%)		0/14 (0%)		0/17 (0%)
Hot flush	0/5 (0%)		0/9 (0%)		1/21 (4.8%)		1/14 (7.1%)		0/17 (0%)

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.