Back to resultsStudy of Blinatumomab in Japanese Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia
Primary Purpose
Relapsed Refractory B Precursor Acute Lymphoblastic Leukemia
Status
Completed
Phase
Phase 1
Locations
Japan
Study Type
Interventional
Intervention
Blinatumomab
Sponsored by
About this trial
This is an interventional treatment trial for Relapsed Refractory B Precursor Acute Lymphoblastic Leukemia focused on measuring Amgen
Eligibility Criteria
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
Sites / Locations
- National Hospital Organization Nagoya Medical Center
- Nagoya University Hospital
- Kyushu University Hospital
- Gunmaken Saiseikai Maebashi Hospital
- Sapporo Hokuyu Hospital
- Kobe University Hospital
- Kanagawa Childrens Medical Center
- Nagasaki University Hospital
- Niigata Cancer Center Hospital
- Okayama University Hospital
- Osaka City General Hospital
- Osaka Metropolitan University Hospital
- Saitama Childrens Medical Center
- Jichi Medical University Hospital
- National Cancer Center Hospital
- National Center for Child Health and Development
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Blinatumomab 9-28 µg/day Phase 1b Adult Population
Blinatumomab 5-15 µg/m^2/day Phase 1b Pediatric Population
Blinatumomab 9-28 µg/day Phase 2 Adult Population
Blinatumomab 9-28 µg/day Adult Expansion Population
Blinatumomab 5-15 µg/m^2/day Pediatric Expansion Population
Arm 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 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.
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.
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.
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.
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.
Outcomes
Primary Outcome Measures
Phase 1b: Number of Participants With Dose-limiting Toxicities
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.
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
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.
Expansion Cohort: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related TEAEs
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
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
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
Phase 1b Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment
M1 remission for pediatric participants was defined as ≤ 5% blasts (M1 bone marrow) in the bone marrow and no evidence of disease.
Phase 1b and Phase 2: Duration of Response
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.
Phase 1b and Phase 2: Relapse-free Survival
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.
Phase 1b and Phase 2: Overall Survival
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.
Phase 2: Best Overall Response Within 2 Cycles of Treatment
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.
Phase 2: Percentage of Participants Who Received an Allogeneic Hematopoietic Stem Cell Transplant (HSCT) During Blinatumomab Induced Remission
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.
Phase 2: 100-Day Mortality After Allogeneic HSCT
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.
Phase 1b and Phase 2: Number of Participants With TEAEs
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.
Phase 1b and Phase 2: Serum Blinatumomab Concentration at Steady State
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).
Phase 1b and Phase 2: Systemic Clearance of Blinatumomab
Systemic clearance (CL) was calculated as CL = R0/Css, where R0 is the infusion rate (µg/hour or µg/m²/hour).
Phase 1b and Phase 2: Terminal Half-life of Blinatumomab
Phase 1b and Phase 2: Volume of Distribution of Blinatumomab
Phase 1b and Phase 2: Number of Participants Who Developed Anti-Blinatumomab Antibodies
Antibodies to blinatumomab were detected using an electrochemiluminescence (ECL)-based assay.
Phase 1b and Phase 2: Interleukin-2 Concentration
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).
Phase 1b and Phase 2: Interleukin-6 Concentration
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).
Phase 1b and Phase 2: Interleukin-10 Concentration
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).
Phase 1b and Phase 2: Tumor Necrosis Factor-Alpha (TNFα) Concentration
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).
Phase 1b and Phase 2: Interferon Gamma (IFN-γ) Concentration
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).
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
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.
Expansion Cohort Pediatric: Percentage of Participants With M1 Remission Within 2 Cycles of Treatment
M1 remission for pediatric participants was defined as ≤ 5% blasts (M1 bone marrow) in the bone marrow and no evidence of disease.
Full Information
NCT ID
NCT02412306
First Posted
March 12, 2015
Last Updated
December 8, 2022
Sponsor
Amgen
Collaborators
Amgen Astellas Biopharma K.K.
1. Study Identification
Unique Protocol Identification Number
NCT02412306
Brief Title
Study of Blinatumomab in Japanese Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia
Official Title
A Phase 1b/2 Study of Blinatumomab in Japanese Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (Horai Study)
Study Type
Interventional
2. Study Status
Record Verification Date
December 2022
Overall Recruitment Status
Completed
Study Start Date
June 4, 2015 (Actual)
Primary Completion Date
February 6, 2019 (Actual)
Study Completion Date
July 4, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Amgen
Collaborators
Amgen Astellas Biopharma K.K.
4. Oversight
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsed Refractory B Precursor Acute Lymphoblastic Leukemia
Keywords
Amgen
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
66 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Blinatumomab 9-28 µg/day Phase 1b Adult Population
Arm Type
Experimental
Arm 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 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.
Arm Title
Blinatumomab 5-15 µg/m^2/day Phase 1b Pediatric Population
Arm Type
Experimental
Arm 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. 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.
Arm Title
Blinatumomab 9-28 µg/day Phase 2 Adult Population
Arm Type
Experimental
Arm 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 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.
Arm Title
Blinatumomab 9-28 µg/day Adult Expansion Population
Arm Type
Experimental
Arm 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 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.
Arm Title
Blinatumomab 5-15 µg/m^2/day Pediatric Expansion Population
Arm Type
Experimental
Arm 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. 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.
Intervention Type
Drug
Intervention Name(s)
Blinatumomab
Other Intervention Name(s)
Blincyto®
Intervention Description
Continuous intravenous infusion over four weeks per treatment cycle
Primary Outcome Measure Information:
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
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
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.
Secondary Outcome Measure Information:
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
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
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.
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.
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.
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
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.
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)
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.
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).
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).
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
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
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.
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
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
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
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
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
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
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
0 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
MD
Organizational Affiliation
Amgen
Official's Role
Study Director
Facility Information:
Facility Name
National Hospital Organization Nagoya Medical Center
City
Nagoya-shi
State/Province
Aichi
ZIP/Postal Code
460-0001
Country
Japan
Facility Name
Nagoya University Hospital
City
Nagoya-shi
State/Province
Aichi
ZIP/Postal Code
466-8560
Country
Japan
Facility Name
Kyushu University Hospital
City
Fukuoka-shi
State/Province
Fukuoka
ZIP/Postal Code
812-8582
Country
Japan
Facility Name
Gunmaken Saiseikai Maebashi Hospital
City
Maebashi-shi
State/Province
Gunma
ZIP/Postal Code
371-0821
Country
Japan
Facility Name
Sapporo Hokuyu Hospital
City
Sapporo-shi
State/Province
Hokkaido
ZIP/Postal Code
003-0006
Country
Japan
Facility Name
Kobe University Hospital
City
Kobe-shi
State/Province
Hyogo
ZIP/Postal Code
650-0017
Country
Japan
Facility Name
Kanagawa Childrens Medical Center
City
Yokohama-shi
State/Province
Kanagawa
ZIP/Postal Code
232-8555
Country
Japan
Facility Name
Nagasaki University Hospital
City
Nagasaki-shi
State/Province
Nagasaki
ZIP/Postal Code
852-8501
Country
Japan
Facility Name
Niigata Cancer Center Hospital
City
Niigata-shi
State/Province
Niigata
ZIP/Postal Code
951-8566
Country
Japan
Facility Name
Okayama University Hospital
City
Okayama-shi
State/Province
Okayama
ZIP/Postal Code
700-8558
Country
Japan
Facility Name
Osaka City General Hospital
City
Osaka-shi
State/Province
Osaka
ZIP/Postal Code
534-0021
Country
Japan
Facility Name
Osaka Metropolitan University Hospital
City
Osaka-shi
State/Province
Osaka
ZIP/Postal Code
545-8586
Country
Japan
Facility Name
Saitama Childrens Medical Center
City
Saitama-shi
State/Province
Saitama
ZIP/Postal Code
330-8777
Country
Japan
Facility Name
Jichi Medical University Hospital
City
Shimotsuke-shi
State/Province
Tochigi
ZIP/Postal Code
329-0498
Country
Japan
Facility Name
National Cancer Center Hospital
City
Chuo-ku
State/Province
Tokyo
ZIP/Postal Code
104-0045
Country
Japan
Facility Name
National Center for Child Health and Development
City
Setagaya-ku
State/Province
Tokyo
ZIP/Postal Code
157-8535
Country
Japan
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
IPD Sharing Time Frame
Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
IPD Sharing Access Criteria
Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
IPD Sharing URL
https://www.amgen.com/datasharing
Citations:
PubMed Identifier
32564243
Citation
Horibe K, Morris JD, Tuglus CA, Dos Santos C, Kalabus J, Anderson A, Goto H, Ogawa C. A phase 1b study of blinatumomab in Japanese children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Int J Hematol. 2020 Aug;112(2):223-233. doi: 10.1007/s12185-020-02907-9. Epub 2020 Jun 20.
Results Reference
background
PubMed Identifier
31971321
Citation
Kiyoi H, Morris JD, Oh I, Maeda Y, Minami H, Miyamoto T, Sakura T, Iida H, Tuglus CA, Chen Y, Dos Santos C, Kalabus J, Anderson A, Hata T, Nakashima Y, Kobayashi Y. Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia. Cancer Sci. 2020 Apr;111(4):1314-1323. doi: 10.1111/cas.14322. Epub 2020 Feb 11.
Results Reference
background
PubMed Identifier
34185953
Citation
Kobayashi Y, Oh I, Miyamoto T, Lee WS, Iida H, Minami H, Maeda Y, Jang JH, Yoon SS, Yeh SP, Tran Q, Morris J, Franklin J, Kiyoi H. Efficacy and safety of blinatumomab: Post hoc pooled analysis in Asian adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Asia Pac J Clin Oncol. 2022 Jun;18(3):311-318. doi: 10.1111/ajco.13609. Epub 2021 Jun 29.
Results Reference
background
PubMed Identifier
35790143
Citation
Goto H, Ogawa C, Iida H, Horibe K, Oh I, Takada S, Maeda Y, Minami H, Nakashima Y, Morris JD, Kormany W, Chen Y, Miyamoto T. Safety and Efficacy of Blinatumomab in Japanese Adult and Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Final Results from an Expansion Cohort. Acta Haematol. 2022;145(6):592-602. doi: 10.1159/000525835. Epub 2022 Jul 5.
Results Reference
background
Links:
URL
http://www.amgentrials.com
Description
AmgenTrials clinical trials website
Learn more about this trial
Study of Blinatumomab in Japanese Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia
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