Neoplasms

Blood and Lymph Conditions

All Conditions

Immune System Diseases

Rare Diseases

Leukemia

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Acute Graft Versus Host Disease

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All Drugs and Chemicals

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

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Antibodies

Dexamethasone

Dexamethasone acetate

Immunoglobulins

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.

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.

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.

Dexamthasone

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).

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).

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 blinatumomab

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

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)

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

Amgen

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.

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.

Age, Continuous

Age, Customized

Sex: Female, Male

Race (NIH/OMB)

Age at Diagnosis

A scale to assess a patient's disease status. 0 = Fully active, able to carry out all pre-disease performance without restriction;

1. = Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature;
2. = Ambulatory and capable of all self-care, unable to carry out any work activities. Up and about \> 50% of waking hours;
3. = Capable of only limited self-care, confined to bed or chair \> 50% of waking hours;
4. = Completely disabled, confined to bed or chair;
5. = Dead.

Eastern Cooperative Oncology Group (ECOG) Performance Scale

Criteria #1:Primary refractory or first relapse with remission duration of \< 12 months.

Criteria #2: Relapse any time within 12 months of allo-HSCT (if none of the above).

Criteria #3: Relapsed or refractory after first salvage therapy or beyond (if none of the above).

Key Entry Criterion

Participants enrolled in the study who received at least 1 infusion of blinatumomab.

Study Director

Interim Analysis

Final Analysis

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.

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

Percentage of Participants With a Hematological Response of Complete Remission (CR) During the First 2 Treatment Cycles With Blinatumomab

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

Cycle 1: 9 μg/day

Cycle 1: 28 μg/day

Cycle 2: 28 μg/day

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.

Pharmacokinetic (PK) Parameter: Concentration of Blinatumomab at Steady State (Css)

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.

Pharmacokinetic (PK) Parameter: Clearance

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.

Pharmacokinetic (PK) Parameter: Terminal Half-Life

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.

Pharmacokinetic (PK) Parameter: Volume of Distribution

Kaplan-Meier Estimates for Overall Survival (OS)

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.

Kaplan-Meier Estimate for Relapse-Free Survival (RFS)

Interim Analysis: MRD Response

Interim Analysis: MRD Complete Response

Final Analysis: MRD Response

Final Analysis: MRD Complete Response

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.

Percentage of Participants With Minimal Residual Disease (MRD) Response During the First Two Treatment Cycles

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.

Percentage of Participants Who Received an Allogenic Hematopoietic Stem Cell Transplant (alloHSCT) After Achieving CR/CRh* During Treatment

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.

100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant

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.

Kaplan-Meier Estimates for Time to a ≥ Ten-Point Decrease From Baseline in Global Health Status Quality of Life

Any TEAE

TEAE Grade ≥ 3

Serious AE

TEAE leading to drug discontinuation

Serious AE leading to drug discontinuation

TEAE leading to drug interruption

Serious AE leading to drug interruption

Fatal AE

All enrolled participants who received any infusion of blinatumomab.

Number of Participants With Treatment-Emergent Adverse Events (TEAE)

Any Treatment-related TEAE

Related TEAE Grade ≥ 3

Related Serious AE (SAE)

Related TEAE leading to drug discontinuation

Related SAE leading to drug discontinuation

Related TEAE leading to drug interruption

Related SAE leading to drug interruption

Related fatal AE

Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (TEAE)

Binding antibody positive at anytime

Neutralizing antibody positive at anytime

Enrolled participants who received any infusion of blinatumomab with available post-baseline antibody results.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy and Safety of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)	NCT03476239	Acute Lymphobla...	Blinatumomab Dexamthasone	18 Years -	Amgen
Efficacy and Safety of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)	NCT03476239	Acute Lymphobla...	Blinatumomab Dexamthasone	18 Years -	Amgen
Efficacy and Safety of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)	NCT03476239	Acute Lymphobla...	Blinatumomab Dexamthasone	18 Years -	Amgen

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