Efficacy and Safety of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)

Sponsor
Amgen (Industry)
Overall Status
Completed
CT.gov ID
NCT03476239
Collaborator
(none)
121
23
1
41.7
5.3
0.1

Study Details

Study Description

Brief Summary

This study is being done to evaluate the rate of hematological response (complete remission/complete remission with partial hematological recovery [CR/CRh*]) induced by blinatumomab in Chinese adults with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL).

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

This is an open label, single-arm, multicenter phase 3 study to evaluate efficacy and safety of the BiTE (bispecific T cell engager) antibody blinatumomab in Chinese adults with relapsed/refractory B-precursor ALL. The study will consist of a screening period, a treatment period, and a follow-up period.

Treatment will consist of up to 5 cycles of blinatumomab. Participants who achieve a bone marrow (BM) response (≤ 5% BM blasts) or CR/CRh*/CRi within 2 induction cycles of treatment may continue to receive up to 3 additional consolidation cycles of blinatumomab. Thirty days after end of the last dose of protocol-specified therapy, participants will have a safety follow-up visit.

If subjects are suitable for allogeneic stem cell transplantation (alloHSCT) after treatment with blinatumomab, they may undergo alloHSCT instead of receiving further consolidation cycles with blinatumomab.

Participants will be followed via clinic visit or telephone contact every 3 months after their safety follow-up visit until death has been observed or a maximum of 2 years after start of treatment, whichever occurs first.

A planned interim analysis to assess efficacy and safety of blinatumomab was to be based on the interim analysis set (N = 90). The efficacious benefit assessment based on an O'Brien-Fleming alpha spending function (O'Brien and Fleming, 1979) with the critical boundary 42.2% at the interim analysis and 39.2% at the primary analysis in CR/CRh* rate. If the interim analysis showed statistically efficacious and overall benefit-risk analysis to be promising per the data review team review, then the interim analysis could become the primary analysis of this study. In addition, the study would continue its enrollment until 120 participants had been enrolled and continued their participation in the study to complete protocol-specified procedures.

The data cutoff date of 12 April 2019 allowed for the 90th participant enrolled before 21 February 2019 to have had the opportunity to complete 2 cycles of treatment and the safety follow-up visit (if the participant had discontinued treatment after 2 cycles).

Study Design

Study Type:
Interventional
Actual Enrollment :
121 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
Evaluate the efficacy and safety of blinatumomab in Chinese subjects with relapsed/refractory B-precursor ALL, The study will consist of a screening period, a treatment period, and a follow-up period. Treatment will consist of up to 5 cycles of blinatumomabEvaluate the efficacy and safety of blinatumomab in Chinese subjects with relapsed/refractory B-precursor ALL, The study will consist of a screening period, a treatment period, and a follow-up period. Treatment will consist of up to 5 cycles of blinatumomab
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open-label, Multicenter, Phase 3 Study to Evaluate Efficacy and Safety of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)
Actual Study Start Date :
Oct 18, 2017
Actual Primary Completion Date :
Aug 21, 2019
Actual Study Completion Date :
Apr 8, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Blinatumomab

Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for Days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4). This is followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.

Drug: Blinatumomab
Blinatumomab will be supplied as single-use glass injection vials as a sterile, preservative-free, white to off-white, lyophilized powder for reconstitution and administration by continuous intravenous infusion (CIVI). A single cycle of blinatumomab treatment is 6 weeks in duration, which includes 4 weeks of blinatumomab CIVI followed by a 2 week treatment-free interval. The treatment-free interval may be prolonged by up to 7 days, if deemed necessary by the investigator.
Other Names:
  • BLINCYTO®
  • AMG 103
  • MT103
  • Drug: Dexamthasone
    Premedication with dexamethasone was intended to prevent cytokine release syndrome (CRS) events associated with blinatumomab treatment. Treatment could start pre-study. Dexamethasone 20 mg IV was administered within 3 hours before start of blinatumomab in each treatment cycle, and within 3 hours before dose step increase.

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants With a Hematological Response of Complete Remission (CR) or Complete Remission With Partial Hematological Recovery (CRh*) During the First 2 Treatment Cycles With Blinatumomab [Within 2 cycles of treatment (12 weeks)]

      A CR is defined as having ≤ 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). 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. CR/CRh* rate is defined as the percentage of participants who achieve CR/CRh* within 2 cycles of treatment with blinatumomab. Participants without response assessment were accounted for in the denominator when calculating the response rate, ie, these participants were counted as non-responders. The interim analysis was to become the primary analysis by meeting pre-specified efficacy and safety criteria based on an O'Brien-Fleming alpha spending function with the critical boundary 42.2%. Results for both the interim and final analysis are reported.

    Secondary Outcome Measures

    1. Percentage of Participants With a Hematological Response of Complete Remission (CR) During the First 2 Treatment Cycles With Blinatumomab [Within 2 cycles of treatment (12 weeks)]

      A CR is defined as having ≤ 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). CR rate is defined as the percentage of participants who achieved CR within 2 cycles of treatment with blinatumomab. Participants without response assessment were accounted for in the denominator when calculating the response rate, ie, these participants were counted as non-responders. Results for both the interim and final analysis are reported.

    2. Percentage of Participants With a CR or CRh* or Complete Remission With Incomplete Hematological Recovery Without CRh* (CRi) (CR/CRh*/CRi) During the First 2 Treatment Cycles With Blinatumomab [Within 2 cycles of treatment (12 weeks)]

      CRi is defined as ≤ 5% blasts in the bone marrow, no evidence of disease and incomplete recovery of peripheral blood counts: platelets > 100,000/μl or ANC > 1,000/μl (but not both). CR/CRh*/CRi rate is defined as the percentage of participants who achieve CR/CRh*/CRi within 2 cycles of treatment with blinatumomab. Participants without response assessment were accounted for in the denominator when calculating the response rate, ie, these participants were counted as non-responders. Results for both the interim and final analysis are reported.

    3. Pharmacokinetic (PK) Parameter: Concentration of Blinatumomab at Steady State (Css) [Cycle 1: Days 2, 15, and 29; Cycle 2: Days 2, 15, and 29 (approximately study days 44, 57, and 71)]

      Blinatumomab serum concentration was quantified using a validated enzyme- linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 50 pg/mL. Blinatumomab serum steady-state concentrations (Css) was summarized as the average of the observed concentrations collected after 24 hours from the start of continuous IV infusion for each dose level. Cycle 1 day 2 values represent Css for the initial dose of blinatumomab (9 µg/day). Values collected from other time points were used to calculate Css of 28 µg/day dose in their respective cycles.

    4. Pharmacokinetic (PK) Parameter: Clearance [Cycle 1: Days 2, 15 and 29; Cycle 2: Days 2, 15 and 29 (approximately study days 44, 57 and 71)]

      Systemic clearance (CL) calculated as the average CL value during cycle 1 and cycle 2, where CL = infusion rate (μg/hour) / Css

    5. Pharmacokinetic (PK) Parameter: Terminal Half-Life [Cycle 1 Day 29: prior to end of infusion and after the end of infusion at 3 hours and 6 hours]

      Terminal half-life (t1/2,z) calculated as t1/2,z = ln(2)/lambda-z, where lambda-z was the first-order rate constant estimated via linear regression of the terminal log-linear decay phase from day 29 post-end of infusion collections.

    6. Pharmacokinetic (PK) Parameter: Volume of Distribution [Cycle 1: Days 2, 15 and 29; Cycle 2: Days 2, 15, and 29 (approximately study days 44, 57 and 71)]

      The volume of distribution (Vz) was calculated as Vz = CL/lambda-z, where lambda-z was the first-order rate constant estimated based on cycle 1 day 29 collections via linear regression of the terminal log-linear decay phase as determined from the noncompartmental analysis and where CL was the CL averaged over multiple cycles. Volume of distribution was estimated for participants who have sufficient evaluable PK data.

    7. Kaplan-Meier Estimates for Overall Survival (OS) [Interim analysis: From first dose of blinatumomab to the data cutoff date of 12 April 2019; maximum time on follow-up for OS was 14.7 months. Final analysis: From first dose of blinatumomab to end of study; maximum time on follow-up for OS was 25.7 months]

      Overall survival time was calculated from the time of first infusion of blinatumomab until death due to any cause. Participants still alive were censored at the date last known to be alive up until the data cut-off date (interim analysis) or end of study date (final analysis). Months are calculated as days from the first treatment to death/censor date, divided by 30.5. Results for both the interim and final analysis are reported.

    8. Kaplan-Meier Estimate for Relapse-Free Survival (RFS) [Interim Analysis: From first onset of CR/CRh* to the data cutoff date of 12 April 2019; maximum time on follow-up for RFS was 12.4 months. Final Analysis: From first onset of CR/CRh* to end of study; maximum time on follow-up for RFS was 18.1 months.]

      Relapse-free survival time was calculated from the first onset of CR/CRh* within the first 2 cycles until the documented hematological relapse, extra-medullary disease, or death due to any cause, whichever occurred first. Participants who were still alive and relapse-free were censored at the date of last disease assessment. Months were calculated as days from the first onset of CR/CRh* within the 2 cycles until the documented hematological relapse/extra-medullary disease/death/censor date, divided by 30.5. Results for both the interim and final analysis are reported.

    9. Percentage of Participants With Minimal Residual Disease (MRD) Response During the First Two Treatment Cycles [Within 2 cycles of treatment (12 weeks)]

      The detection of MRD (the presence of a low number of leukemic cells that are not detectable by light microscopy) after induction therapy and/or consolidation therapy is an independent prognostic factor for poor outcome of ALL. Participants highly responsive to chemotherapy with a MRD-level < 1 × 10^-4 leukemic cells detectable by flow cytometry induced by induction treatment, have a favorable prognosis. MRD response is defined as < 1 ×10^-4 leukemic cells detectable as measured by flow cytometry. MRD complete response is defined as having no detectable leukemic cells by flow cytometry. Results for both the interim and final analysis are reported.

    10. Percentage of Participants Who Received an Allogenic Hematopoietic Stem Cell Transplant (alloHSCT) After Achieving CR/CRh* During Treatment [Interim analysis: Up to the data cutoff date of 12 April 2019; maximum time on follow-up was 14.7 months. Final analysis: Up to the end of study; maximum time on follow-up was 25.7 months.]

      Percentage of participants who underwent allogenic HSCT while in remission among those who responded to treatment by achieving CR/CRh* during treatment. Results for both the interim and final analysis are reported.

    11. 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant [100 days after HSCT]

      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. 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.

    12. Kaplan-Meier Estimates for Time to a ≥ Ten-Point Decrease From Baseline in Global Health Status Quality of Life [EORTC QLQ C30 was completed on days 1, 8, 15, and 29 during Cycle 1; days 1, 15, and 29 during cycle 2 and each consolidation cycle, and at the SFU visit (30 days after last dose).]

      The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales, and 9 symptom scales/items. The GHS is reported in this outcome. For the GHS, scores range from 0 to 100 with a high score indicating better global health status/functioning. A ≥ 10-point decrease from baseline indicates a deterioration in quality of life. Months are calculated from start of blinatumomab date to deterioration/censor date, divided by 30.5.

    13. Number of Participants With Treatment-Emergent Adverse Events (TEAE) [From day 1 to 30 days after last infusion of blinatumomab; median (min, max) treatment duration was 30.9 (1, 142) days.]

      Adverse events (AEs) were evaluated for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. An AE was considered "serious" if it resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions, was a congenital anomaly or birth defect or was a medically important condition.

    14. Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (TEAE) [From day 1 to 30 days after last infusion of blinatumomab; median (min, max) treatment duration was 30.9 (1, 142) days.]

      Adverse events (AEs) were evaluated for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, 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. An AE was considered "serious" if it resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions, was a congenital anomaly or birth defect or was a medically important condition.

    15. Participants With Anti-Blinatumomab Antibody Formation [Cycle 2, day 29 (after the completion of Cycle 2) and the SFU visit (30 days after last dose of blinatumomab)]

      Anti-blinatumomab binding antibodies were evaluated with a validated blinatumomab anti-drug antibody assay.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Subjects have provided informed consent/assent prior to initiation of any study-specific activities/procedures or subjects legally acceptable representative has provided informed consent prior to any study-specific activities/procedures being initiated when the subject has any kind of condition that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent.

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

    • Primary refractory after induction therapy or who had relapsed within 12 months of first remission or

    • Relapsed within 12 months of receiving allogeneic hematopoietic stem cell transplantation (alloHSCT) or

    • Relapsed or refractory after first salvage therapy or beyond

    • 5% blasts in bone marrow (by morphology)

    • Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2

    • Age ≥ 18 years at the time of informed consent

    Exclusion Criteria:

    Disease Related

    • Subjects with Ph-positive ALL

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

    • History or presence of clinically relevant CNS pathology as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, and psychosis

    • Active ALL in the central nervous system (CNS) (confirmed by cerebrospinal fluid [CSF] analysis) or testes

    • Isolated extramedullary disease

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

    Other Medical Conditions

    • History of malignancy other than ALL within 5 years prior to start of protocol-specified therapy with the exception of:

    • Malignancy treated with curative intent and with no known active disease present for 5 years before enrollment and felt to be at low risk for recurrence by the treating physician.

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

    • Adequately treated cervical carcinoma in situ without evidence of disease.

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

    • Prostatic intraepithelial neoplasia without evidence of prostate cancer.

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

    Medications or Other Treatments

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

    • AlloHSCT within 3 months prior to start of blinatumomab treatment

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

    • Any systemic therapy against active GvHD within 2 weeks prior to start of blinatumomab treatment

    • Cancer chemotherapy within 2 weeks prior to start of blinatumomab treatment (intrathecal chemotherapy and dexamethasone are allowed until start of blinatumomab treatment). In addition, any subject whose organ toxicity (excluding hematologic) from prior ALL treatment has not resolved to common terminology criteria for adverse events (CTCAE) ≤ grade 1.

    • Radiotherapy within 2 weeks prior to start of blinatumomab treatment

    • Immunotherapy (eg, rituximab) within 4 weeks prior to start of blinatumomab treatment

    • Currently receiving treatment in another investigational device or drug study, or less than 4 weeks prior to start of blinatumomab treatment.

    • Previous treatment with anti-CD19 therapy

    General

    • Known hypersensitivity to immunoglobulins or to any other component of the IMP formulation

    • Pregnant women and women planning to become pregnant should not participate in this study. Subjects who are breast feeding prior to start of blinatumomab treatment may be enrolled if they stop breast feeding with breast milk produced during blinatumomab treatment and for an additional 48 hours after the last dose of blinatumomab.

    • Male participants are not required to use birth control during treatment with blinatumomab. However, you should let your female partner know you are in this study.

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

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

    • Previous treatment with blinatumomab

    • Abnormal screening laboratory values as defined below:

    • Aspartate aminotransferase (AST) and/or alanine aminotransferase ALT and/or alkaline phosphatase (ALP) ≥ 5 * upper limit of normal (ULN)

    • Total bilirubin (TBL) ≥ 1.5 * ULN (unless related to Gilbert´s or Meulengracht disease)

    • Creatinine ≥ 1.5 ULN or creatinine clearance < 60 ml/min (calculated)

    • Woman of childbearing potential and is not willing to use 2 effective methods of contraception during treatment and for an additional 48 hours after the last dose of blinatumomab. Birth control is not required for postmenopausal women, or women with uterus/or both ovaries/ or both fallopian tubes removed.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Peking University Third Hospital Beijing Beijing China 100191
    2 Peking Union Medical College Hospital Beijing Beijing China 100730
    3 Chinese People Liberation Army General Hospital Beijing Beijing China 100853
    4 Fujian Medical University Union Hospital Fuzhou Fujian China 350001
    5 Guangdong Provincial Peoples Hospital Guangzhou Guangdong China 510080
    6 The First Affiliated Hospital of Sun Yat-sen University Guangzhou Guangdong China 510080
    7 Sun Yat-sen Memorial Hospital, Sun Yat-sen University Guangzhou Guangdong China 510120
    8 Nanfang Hospital, Southern Medical University Guangzhou Guangdong China 510515
    9 Henan Cancer Hospital Zhengzhou Henan China 450008
    10 Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei China 430030
    11 Xiangya Hospital Central South University Changsha Hunan China 410008
    12 Jiangsu Province Hospital Nanjing Jiangsu China 210029
    13 The First Affiliated Hospital of Soochow University Suzhou Jiangsu China 215006
    14 The First Hospital of Jilin University Changchun Jilin China 130021
    15 The First Hospital of China Medical University Shenyang Liaoning China 110001
    16 The Second Affiliated Hospital of Xi an Jiaotong University XI An Shaanxi China 71004
    17 West China Hospital, Sichuang University Chengdu Sichuan China 610041
    18 Institute of Hematology and Blood Diseases Hospital Peking Union Medical College Tianjin Tianjin China 300020
    19 The First Affiliated Hospital, College of Medicine, Zhejiang University Hangzhou Zhejiang China 310003
    20 Second Affiliated Hospital Zhejiang University College of Medicine Hangzhou Zhejiang China 310009
    21 Peking University International Hosipital Beijing China 102206
    22 Anhui Provincial Hospital Hefei China 230001
    23 Huashan Hospital Affiliated to Fudan University Shanghai China 200040

    Sponsors and Collaborators

    • Amgen

    Investigators

    • Study Director: MD, Amgen

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT03476239
    Other Study ID Numbers:
    • 20130316
    First Posted:
    Mar 26, 2018
    Last Update Posted:
    May 2, 2022
    Last Verified:
    Mar 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Amgen
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details This study was conducted at 23 centers in China. The study included a treatment period, a safety follow-up (SFU) visit 30 days after last dose and a follow-up period.
    Pre-assignment Detail A pre-specified interim analysis was to occur after the first 90 participants had a chance to complete 2 cycles of treatment and safety follow-up; the data cutoff date for this analysis was 12 April 2019. If the pre-specified efficacious benefit criteria were met, the interim analysis would become the primary analysis. A final analysis was conducted once all enrolled participants completed the study.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Period Title: Overall Study
    STARTED 121
    Received Blinatumomab 120
    Interim Analysis Set 90
    COMPLETED 23
    NOT COMPLETED 98

    Baseline Characteristics

    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Overall Participants 120
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    35.4
    (15.2)
    Age, Customized (Count of Participants)
    < 35 years
    71
    59.2%
    ≥ 35 to < 55 years
    31
    25.8%
    ≥ 55 years
    18
    15%
    Age, Customized (Count of Participants)
    < 65 years
    115
    95.8%
    ≥ 65 to < 75 years
    5
    4.2%
    ≥ 75 years
    0
    0%
    Sex: Female, Male (Count of Participants)
    Female
    64
    53.3%
    Male
    56
    46.7%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    120
    100%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    0
    0%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Age at Diagnosis (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    34.78
    (15.1)
    Eastern Cooperative Oncology Group (ECOG) Performance Scale (Count of Participants)
    Status 0
    43
    35.8%
    Status 1
    53
    44.2%
    Status 2
    24
    20%
    Status > 2
    0
    0%
    Key Entry Criterion (Count of Participants)
    Criteria #1
    70
    58.3%
    Criteria #2
    10
    8.3%
    Criteria #3
    40
    33.3%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants With a Hematological Response of Complete Remission (CR) or Complete Remission With Partial Hematological Recovery (CRh*) During the First 2 Treatment Cycles With Blinatumomab
    Description A CR is defined as having ≤ 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). 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. CR/CRh* rate is defined as the percentage of participants who achieve CR/CRh* within 2 cycles of treatment with blinatumomab. Participants without response assessment were accounted for in the denominator when calculating the response rate, ie, these participants were counted as non-responders. The interim analysis was to become the primary analysis by meeting pre-specified efficacy and safety criteria based on an O'Brien-Fleming alpha spending function with the critical boundary 42.2%. Results for both the interim and final analysis are reported.
    Time Frame Within 2 cycles of treatment (12 weeks)

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received any infusion of blinatumomab. The interim analysis was based on the first 90 participants who had a chance to complete ≥ 2 cycles of blinatumomab and the safety follow-up visit.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 120
    Interim Analysis
    45.6
    38%
    Final Analysis
    48.3
    40.3%
    2. Secondary Outcome
    Title Percentage of Participants With a Hematological Response of Complete Remission (CR) During the First 2 Treatment Cycles With Blinatumomab
    Description A CR is defined as having ≤ 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). CR rate is defined as the percentage of participants who achieved CR within 2 cycles of treatment with blinatumomab. Participants without response assessment were accounted for in the denominator when calculating the response rate, ie, these participants were counted as non-responders. Results for both the interim and final analysis are reported.
    Time Frame Within 2 cycles of treatment (12 weeks)

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received any infusion of blinatumomab. The interim analysis was based on the first 90 participants who had a chance to complete ≥ 2 cycles of blinatumomab and the safety follow-up visit.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 120
    Interim Analysis
    41.1
    34.3%
    Final Analysis
    43.3
    36.1%
    3. Secondary Outcome
    Title Percentage of Participants With a CR or CRh* or Complete Remission With Incomplete Hematological Recovery Without CRh* (CRi) (CR/CRh*/CRi) During the First 2 Treatment Cycles With Blinatumomab
    Description CRi is defined as ≤ 5% blasts in the bone marrow, no evidence of disease and incomplete recovery of peripheral blood counts: platelets > 100,000/μl or ANC > 1,000/μl (but not both). CR/CRh*/CRi rate is defined as the percentage of participants who achieve CR/CRh*/CRi within 2 cycles of treatment with blinatumomab. Participants without response assessment were accounted for in the denominator when calculating the response rate, ie, these participants were counted as non-responders. Results for both the interim and final analysis are reported.
    Time Frame Within 2 cycles of treatment (12 weeks)

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received any infusion of blinatumomab. The interim analysis was based on the first 90 participants who had a chance to complete ≥ 2 cycles of blinatumomab and the safety follow-up visit.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 120
    Interim Analysis
    47.8
    39.8%
    Final Analysis
    50.0
    41.7%
    4. Secondary Outcome
    Title Pharmacokinetic (PK) Parameter: Concentration of Blinatumomab at Steady State (Css)
    Description Blinatumomab serum concentration was quantified using a validated enzyme- linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) was 50 pg/mL. Blinatumomab serum steady-state concentrations (Css) was summarized as the average of the observed concentrations collected after 24 hours from the start of continuous IV infusion for each dose level. Cycle 1 day 2 values represent Css for the initial dose of blinatumomab (9 µg/day). Values collected from other time points were used to calculate Css of 28 µg/day dose in their respective cycles.
    Time Frame Cycle 1: Days 2, 15, and 29; Cycle 2: Days 2, 15, and 29 (approximately study days 44, 57, and 71)

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set consisting of all participants who received blinatumomab and had at least one PK sample collected. The number of participants analyzed for each time point reflects participants with available Css data; data below the lower limit of quantification and from subjects who did not receive the specified doses were excluded.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 118
    Cycle 1: 9 μg/day
    103
    (41)
    Cycle 1: 28 μg/day
    416
    (72)
    Cycle 2: 28 μg/day
    634
    (21)
    5. Secondary Outcome
    Title Pharmacokinetic (PK) Parameter: Clearance
    Description Systemic clearance (CL) calculated as the average CL value during cycle 1 and cycle 2, where CL = infusion rate (μg/hour) / Css
    Time Frame Cycle 1: Days 2, 15 and 29; Cycle 2: Days 2, 15 and 29 (approximately study days 44, 57 and 71)

    Outcome Measure Data

    Analysis Population Description
    Participants in the pharmacokinetic analysis set with available CL data at at least one post-baseline time point; data below the lower limit of quantification and from participants who did not receive the specified doses were excluded.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 108
    Geometric Mean (Geometric Coefficient of Variation) [L/hour]
    2.86
    (57)
    6. Secondary Outcome
    Title Pharmacokinetic (PK) Parameter: Terminal Half-Life
    Description Terminal half-life (t1/2,z) calculated as t1/2,z = ln(2)/lambda-z, where lambda-z was the first-order rate constant estimated via linear regression of the terminal log-linear decay phase from day 29 post-end of infusion collections.
    Time Frame Cycle 1 Day 29: prior to end of infusion and after the end of infusion at 3 hours and 6 hours

    Outcome Measure Data

    Analysis Population Description
    Participants in the pharmacokinetic analysis set with sufficient data on cycle 1 day 29 to calculate half-life. Data below the lower limit of quantification and from participants who did not receive the specified doses were excluded.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 9
    Geometric Mean (Geometric Coefficient of Variation) [hours]
    2.22
    (31)
    7. Secondary Outcome
    Title Pharmacokinetic (PK) Parameter: Volume of Distribution
    Description The volume of distribution (Vz) was calculated as Vz = CL/lambda-z, where lambda-z was the first-order rate constant estimated based on cycle 1 day 29 collections via linear regression of the terminal log-linear decay phase as determined from the noncompartmental analysis and where CL was the CL averaged over multiple cycles. Volume of distribution was estimated for participants who have sufficient evaluable PK data.
    Time Frame Cycle 1: Days 2, 15 and 29; Cycle 2: Days 2, 15, and 29 (approximately study days 44, 57 and 71)

    Outcome Measure Data

    Analysis Population Description
    Participants in the pharmacokinetic analysis set with sufficient data to calculate volume of distribution. Data below the lower limit of quantification and from participants who did not receive the specified doses were excluded.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 9
    Geometric Mean (Geometric Coefficient of Variation) [liters]
    7.15
    (61)
    8. Secondary Outcome
    Title Kaplan-Meier Estimates for Overall Survival (OS)
    Description Overall survival time was calculated from the time of first infusion of blinatumomab until death due to any cause. Participants still alive were censored at the date last known to be alive up until the data cut-off date (interim analysis) or end of study date (final analysis). Months are calculated as days from the first treatment to death/censor date, divided by 30.5. Results for both the interim and final analysis are reported.
    Time Frame Interim analysis: From first dose of blinatumomab to the data cutoff date of 12 April 2019; maximum time on follow-up for OS was 14.7 months. Final analysis: From first dose of blinatumomab to end of study; maximum time on follow-up for OS was 25.7 months

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received any infusion of blinatumomab. The interim analysis was based on the first 90 participants who had a chance to complete ≥ 2 cycles of blinatumomab and the safety follow-up visit.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 120
    Interim Analysis
    9.2
    Final Analysis
    9.1
    9. Secondary Outcome
    Title Kaplan-Meier Estimate for Relapse-Free Survival (RFS)
    Description Relapse-free survival time was calculated from the first onset of CR/CRh* within the first 2 cycles until the documented hematological relapse, extra-medullary disease, or death due to any cause, whichever occurred first. Participants who were still alive and relapse-free were censored at the date of last disease assessment. Months were calculated as days from the first onset of CR/CRh* within the 2 cycles until the documented hematological relapse/extra-medullary disease/death/censor date, divided by 30.5. Results for both the interim and final analysis are reported.
    Time Frame Interim Analysis: From first onset of CR/CRh* to the data cutoff date of 12 April 2019; maximum time on follow-up for RFS was 12.4 months. Final Analysis: From first onset of CR/CRh* to end of study; maximum time on follow-up for RFS was 18.1 months.

    Outcome Measure Data

    Analysis Population Description
    Enrolled participants who received any infusion of blinatumomab who achieved CR/CRh* during the first 2 cycles. The interim analysis was based on the first 90 participants who had a chance to complete ≥ 2 cycles of blinatumomab and the safety follow-up visit and who achieved CR/CRh* during the first 2 cycles.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 58
    Interim Analysis
    4.3
    Final Analysis
    5.4
    10. Secondary Outcome
    Title Percentage of Participants With Minimal Residual Disease (MRD) Response During the First Two Treatment Cycles
    Description The detection of MRD (the presence of a low number of leukemic cells that are not detectable by light microscopy) after induction therapy and/or consolidation therapy is an independent prognostic factor for poor outcome of ALL. Participants highly responsive to chemotherapy with a MRD-level < 1 × 10^-4 leukemic cells detectable by flow cytometry induced by induction treatment, have a favorable prognosis. MRD response is defined as < 1 ×10^-4 leukemic cells detectable as measured by flow cytometry. MRD complete response is defined as having no detectable leukemic cells by flow cytometry. Results for both the interim and final analysis are reported.
    Time Frame Within 2 cycles of treatment (12 weeks)

    Outcome Measure Data

    Analysis Population Description
    Participants who received any infusion of blinatumomab who achieved CR/CRh* within 2 cycles and had evaluable MRD assessment. The interim analysis was based on the first 90 participants who had a chance to complete ≥ 2 cycles of blinatumomab and the safety follow-up visit who achieved CR/CRh* within 2 cycles and had evaluable MRD assessment.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 58
    Interim Analysis: MRD Response
    82.9
    69.1%
    Interim Analysis: MRD Complete Response
    2.4
    2%
    Final Analysis: MRD Response
    84.5
    70.4%
    Final Analysis: MRD Complete Response
    1.7
    1.4%
    11. Secondary Outcome
    Title Percentage of Participants Who Received an Allogenic Hematopoietic Stem Cell Transplant (alloHSCT) After Achieving CR/CRh* During Treatment
    Description Percentage of participants who underwent allogenic HSCT while in remission among those who responded to treatment by achieving CR/CRh* during treatment. Results for both the interim and final analysis are reported.
    Time Frame Interim analysis: Up to the data cutoff date of 12 April 2019; maximum time on follow-up was 14.7 months. Final analysis: Up to the end of study; maximum time on follow-up was 25.7 months.

    Outcome Measure Data

    Analysis Population Description
    Enrolled participants who received any infusion of blinatumomab who achieved CR/CRh* during treatment. The interim analysis was based on the first 90 participants who had a chance to complete ≥ 2 cycles of blinatumomab and the safety follow-up visit and who achieved CR/CRh* during treatment.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 58
    Interim Analysis
    22.0
    18.3%
    Final Analysis
    27.6
    23%
    12. Secondary Outcome
    Title 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant
    Description 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. 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.
    Time Frame 100 days after HSCT

    Outcome Measure Data

    Analysis Population Description
    Participants who received any infusion of blinatumomab with a CR/CRh* response who underwent alloHSCT while in remission. The interim analysis was based on the first 90 participants who had a chance to complete ≥ 2 cycles of blinatumomab and the safety follow-up visit, achieved CR/CRh* and underwent alloHSCT while in remission.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 15
    Interim Analysis
    0.0
    0%
    Final Analysis
    6.7
    5.6%
    13. Secondary Outcome
    Title Kaplan-Meier Estimates for Time to a ≥ Ten-Point Decrease From Baseline in Global Health Status Quality of Life
    Description The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales, and 9 symptom scales/items. The GHS is reported in this outcome. For the GHS, scores range from 0 to 100 with a high score indicating better global health status/functioning. A ≥ 10-point decrease from baseline indicates a deterioration in quality of life. Months are calculated from start of blinatumomab date to deterioration/censor date, divided by 30.5.
    Time Frame EORTC QLQ C30 was completed on days 1, 8, 15, and 29 during Cycle 1; days 1, 15, and 29 during cycle 2 and each consolidation cycle, and at the SFU visit (30 days after last dose).

    Outcome Measure Data

    Analysis Population Description
    Participants who received blinatumomab treatment and had baseline and ≥ 1 postbaseline result for EORTC QLQ-C30 GHS. The interim analysis was based on the first 90 participants who had a chance to complete ≥ 2 cycles of blinatumomab and the safety follow-up visit who had a baseline and ≥ 1 postbaseline result for EORTC QLQ-C30 GHS.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 110
    Interim Analysis
    1.6
    Final Analysis
    3.7
    14. Secondary Outcome
    Title Number of Participants With Treatment-Emergent Adverse Events (TEAE)
    Description Adverse events (AEs) were evaluated for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death. An AE was considered "serious" if it resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions, was a congenital anomaly or birth defect or was a medically important condition.
    Time Frame From day 1 to 30 days after last infusion of blinatumomab; median (min, max) treatment duration was 30.9 (1, 142) days.

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received any infusion of blinatumomab.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 120
    Any TEAE
    120
    100%
    TEAE Grade ≥ 3
    115
    95.8%
    Serious AE
    40
    33.3%
    TEAE leading to drug discontinuation
    18
    15%
    Serious AE leading to drug discontinuation
    12
    10%
    TEAE leading to drug interruption
    31
    25.8%
    Serious AE leading to drug interruption
    13
    10.8%
    Fatal AE
    11
    9.2%
    15. Secondary Outcome
    Title Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (TEAE)
    Description Adverse events (AEs) were evaluated for severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, 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. An AE was considered "serious" if it resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions, was a congenital anomaly or birth defect or was a medically important condition.
    Time Frame From day 1 to 30 days after last infusion of blinatumomab; median (min, max) treatment duration was 30.9 (1, 142) days.

    Outcome Measure Data

    Analysis Population Description
    All enrolled participants who received any infusion of blinatumomab.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 120
    Any Treatment-related TEAE
    118
    98.3%
    Related TEAE Grade ≥ 3
    99
    82.5%
    Related Serious AE (SAE)
    29
    24.2%
    Related TEAE leading to drug discontinuation
    16
    13.3%
    Related SAE leading to drug discontinuation
    11
    9.2%
    Related TEAE leading to drug interruption
    25
    20.8%
    Related SAE leading to drug interruption
    10
    8.3%
    Related fatal AE
    6
    5%
    16. Secondary Outcome
    Title Participants With Anti-Blinatumomab Antibody Formation
    Description Anti-blinatumomab binding antibodies were evaluated with a validated blinatumomab anti-drug antibody assay.
    Time Frame Cycle 2, day 29 (after the completion of Cycle 2) and the SFU visit (30 days after last dose of blinatumomab)

    Outcome Measure Data

    Analysis Population Description
    Enrolled participants who received any infusion of blinatumomab with available post-baseline antibody results.
    Arm/Group Title Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    Measure Participants 91
    Binding antibody positive at anytime
    0
    0%
    Neutralizing antibody positive at anytime
    0
    0%

    Adverse Events

    Time Frame Mortality data are reported from enrollment to the end of study, maximum time on study was 26 months. Adverse events are reported from day 1 to 30 days after last infusion of blinatumomab; the median (min, max) treatment duration was 30.9 (1, 142) days.
    Adverse Event Reporting Description All-cause mortality is reported for all participants enrolled 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 Blinatumomab
    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. Treatment consisted of two induction cycles and up to 3 consolidation cycles of treatment for responders. In the first induction cycle, the initial dose of blinatumomab was 9 μg/day for days 1-7 and then escalated (dose step) to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by two weeks without blinatumomab treatment. In subsequent cycles (beginning with the second induction cycle and continuing through consolidation, for applicable participants) 28 μg/day was administered for all 4 weeks of continuous treatment, followed by a treatment-free interval of two weeks.
    All Cause Mortality
    Blinatumomab
    Affected / at Risk (%) # Events
    Total 81/121 (66.9%)
    Serious Adverse Events
    Blinatumomab
    Affected / at Risk (%) # Events
    Total 40/120 (33.3%)
    Blood and lymphatic system disorders
    Anaemia 2/120 (1.7%)
    Disseminated intravascular coagulation 1/120 (0.8%)
    Neutropenia 1/120 (0.8%)
    Cardiac disorders
    Cardiac arrest 1/120 (0.8%)
    Cardiac failure acute 1/120 (0.8%)
    Ear and labyrinth disorders
    Hypoacusis 1/120 (0.8%)
    Gastrointestinal disorders
    Gastrointestinal haemorrhage 1/120 (0.8%)
    Pancreatitis acute 1/120 (0.8%)
    Hepatobiliary disorders
    Liver injury 3/120 (2.5%)
    Immune system disorders
    Cytokine release syndrome 5/120 (4.2%)
    Infections and infestations
    Candida infection 1/120 (0.8%)
    Cytomegalovirus urinary tract infection 1/120 (0.8%)
    Device related infection 1/120 (0.8%)
    Neutropenic infection 1/120 (0.8%)
    Pneumonia 5/120 (4.2%)
    Respiratory tract infection 2/120 (1.7%)
    Sepsis 1/120 (0.8%)
    Fungaemia 1/120 (0.8%)
    Infection 1/120 (0.8%)
    Investigations
    Aspartate aminotransferase increased 1/120 (0.8%)
    Neutrophil count decreased 1/120 (0.8%)
    Platelet count decreased 2/120 (1.7%)
    White blood cell count decreased 1/120 (0.8%)
    Metabolism and nutrition disorders
    Hypercalcaemia 1/120 (0.8%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia 2/120 (1.7%)
    Central nervous system leukaemia 3/120 (2.5%)
    Transformation to acute myeloid leukaemia 1/120 (0.8%)
    Nervous system disorders
    Haemorrhage intracranial 2/120 (1.7%)
    Epilepsy 1/120 (0.8%)
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease 1/120 (0.8%)
    Pneumonitis 1/120 (0.8%)
    Respiratory failure 1/120 (0.8%)
    Other (Not Including Serious) Adverse Events
    Blinatumomab
    Affected / at Risk (%) # Events
    Total 120/120 (100%)
    Blood and lymphatic system disorders
    Anaemia 76/120 (63.3%)
    Coagulopathy 13/120 (10.8%)
    Leukocytosis 15/120 (12.5%)
    Leukopenia 38/120 (31.7%)
    Lymphocytosis 6/120 (5%)
    Lymphopenia 18/120 (15%)
    Neutropenia 30/120 (25%)
    Thrombocytopenia 37/120 (30.8%)
    Blood disorder 6/120 (5%)
    Cardiac disorders
    Sinus tachycardia 6/120 (5%)
    Gastrointestinal disorders
    Abdominal distension 10/120 (8.3%)
    Constipation 15/120 (12.5%)
    Diarrhoea 15/120 (12.5%)
    Haemorrhoids 6/120 (5%)
    Mouth ulceration 7/120 (5.8%)
    Nausea 14/120 (11.7%)
    Vomiting 15/120 (12.5%)
    Toothache 6/120 (5%)
    General disorders
    Asthenia 13/120 (10.8%)
    Chest pain 6/120 (5%)
    Oedema peripheral 13/120 (10.8%)
    Pyrexia 57/120 (47.5%)
    Hepatobiliary disorders
    Hepatic function abnormal 12/120 (10%)
    Liver injury 14/120 (11.7%)
    Immune system disorders
    Cytokine release syndrome 71/120 (59.2%)
    Infections and infestations
    Infection 8/120 (6.7%)
    Pneumonia 26/120 (21.7%)
    Upper respiratory tract infection 21/120 (17.5%)
    Urinary tract infection 7/120 (5.8%)
    Folliculitis 6/120 (5%)
    Investigations
    Activated partial thromboplastin time prolonged 12/120 (10%)
    Alanine aminotransferase increased 28/120 (23.3%)
    Albumin globulin ratio increased 6/120 (5%)
    Alpha hydroxybutyrate dehydrogenase increased 17/120 (14.2%)
    Anion gap increased 6/120 (5%)
    Aspartate aminotransferase increased 32/120 (26.7%)
    Beta 2 microglobulin increased 7/120 (5.8%)
    Bilirubin conjugated increased 18/120 (15%)
    Blast cell count increased 7/120 (5.8%)
    Blood albumin decreased 22/120 (18.3%)
    Blood alkaline phosphatase increased 18/120 (15%)
    Blood bilirubin increased 23/120 (19.2%)
    Blood calcium decreased 13/120 (10.8%)
    Blood fibrinogen decreased 9/120 (7.5%)
    Blood fibrinogen increased 15/120 (12.5%)
    Blood glucose increased 22/120 (18.3%)
    Blood immunoglobulin A decreased 20/120 (16.7%)
    Blood immunoglobulin G decreased 34/120 (28.3%)
    Blood immunoglobulin M decreased 18/120 (15%)
    Blood lactate dehydrogenase increased 54/120 (45%)
    Blood phosphorus increased 14/120 (11.7%)
    Blood potassium decreased 10/120 (8.3%)
    Blood triglycerides increased 14/120 (11.7%)
    Blood urea increased 9/120 (7.5%)
    Blood uric acid increased 15/120 (12.5%)
    C-reactive protein increased 60/120 (50%)
    Eosinophil count decreased 8/120 (6.7%)
    Fibrin D dimer increased 29/120 (24.2%)
    Fibrin degradation products increased 8/120 (6.7%)
    Gamma-glutamyltransferase increased 33/120 (27.5%)
    Globulins decreased 22/120 (18.3%)
    Haematocrit decreased 7/120 (5.8%)
    Haemoglobin decreased 8/120 (6.7%)
    Immunoglobulins decreased 18/120 (15%)
    Interleukin level increased 21/120 (17.5%)
    International normalised ratio increased 6/120 (5%)
    Lymphocyte count decreased 57/120 (47.5%)
    Lymphocyte count increased 15/120 (12.5%)
    Lymphocyte percentage decreased 11/120 (9.2%)
    Lymphocyte percentage increased 6/120 (5%)
    Monocyte count decreased 22/120 (18.3%)
    Monocyte percentage decreased 6/120 (5%)
    Neutrophil count decreased 58/120 (48.3%)
    Neutrophil count increased 19/120 (15.8%)
    Neutrophil percentage decreased 9/120 (7.5%)
    Neutrophil percentage increased 8/120 (6.7%)
    Platelet count decreased 53/120 (44.2%)
    Procalcitonin increased 21/120 (17.5%)
    Protein total decreased 21/120 (17.5%)
    Red blood cell count decreased 13/120 (10.8%)
    Reticulocyte count decreased 7/120 (5.8%)
    Reticulocyte count increased 17/120 (14.2%)
    Serum ferritin increased 14/120 (11.7%)
    White blood cell count decreased 65/120 (54.2%)
    White blood cell count increased 25/120 (20.8%)
    Blood cholesterol increased 6/120 (5%)
    Blood phosphorus decreased 6/120 (5%)
    Monocyte count increased 6/120 (5%)
    Reticulocyte percentage increased 9/120 (7.5%)
    Metabolism and nutrition disorders
    Decreased appetite 8/120 (6.7%)
    Hyperglycaemia 23/120 (19.2%)
    Hypertriglyceridaemia 15/120 (12.5%)
    Hyperuricaemia 24/120 (20%)
    Hypoalbuminaemia 22/120 (18.3%)
    Hypocalcaemia 27/120 (22.5%)
    Hypoglycaemia 8/120 (6.7%)
    Hypokalaemia 62/120 (51.7%)
    Hypomagnesaemia 10/120 (8.3%)
    Hyponatraemia 14/120 (11.7%)
    Hypophosphataemia 14/120 (11.7%)
    Hypoproteinaemia 21/120 (17.5%)
    Hyperlipidaemia 8/120 (6.7%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 14/120 (11.7%)
    Bone pain 9/120 (7.5%)
    Pain in extremity 6/120 (5%)
    Nervous system disorders
    Dizziness 11/120 (9.2%)
    Headache 10/120 (8.3%)
    Psychiatric disorders
    Insomnia 11/120 (9.2%)
    Respiratory, thoracic and mediastinal disorders
    Cough 15/120 (12.5%)
    Epistaxis 9/120 (7.5%)
    Hypoxia 6/120 (5%)
    Oropharyngeal pain 9/120 (7.5%)
    Skin and subcutaneous tissue disorders
    Rash 13/120 (10.8%)
    Pruritus 6/120 (5%)
    Vascular disorders
    Hypotension 7/120 (5.8%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

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

    Results Point of Contact

    Name/Title Study Director
    Organization Amgen Inc.
    Phone 866-572-6436
    Email medinfo@amgen.com
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT03476239
    Other Study ID Numbers:
    • 20130316
    First Posted:
    Mar 26, 2018
    Last Update Posted:
    May 2, 2022
    Last Verified:
    Mar 1, 2022