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

Study Overview
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Brief Summary
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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).

Detailed Description
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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).

Official Title
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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)

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Blinatumomab
* Drug: Dexamthasone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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 blinatumomab
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blinatumomab<br>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<br>* 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.<br>* Other names: MT103;Drug: Dexamthasone<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Within 2 cycles of treatment (12 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Hematological Response of Complete Remission (CR) During the First 2 Treatment Cycles With Blinatumomab | 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. | Within 2 cycles of treatment (12 weeks) | 
| 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 | 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. | Within 2 cycles of treatment (12 weeks) | 
| Pharmacokinetic (PK) Parameter: Concentration of Blinatumomab at Steady State (Css) | 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. | Cycle 1: Days 2, 15, and 29; Cycle 2: Days 2, 15, and 29 (approximately study days 44, 57, and 71) | 
| Pharmacokinetic (PK) Parameter: Clearance | Systemic clearance (CL) calculated as the average CL value during cycle 1 and cycle 2, where CL = infusion rate (μg/hour) / Css | Cycle 1: Days 2, 15 and 29; Cycle 2: Days 2, 15 and 29 (approximately study days 44, 57 and 71) | 
| Pharmacokinetic (PK) Parameter: Terminal Half-Life | 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. | Cycle 1 Day 29: prior to end of infusion and after the end of infusion at 3 hours and 6 hours | 
| Pharmacokinetic (PK) Parameter: Volume of Distribution | 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. | Cycle 1: Days 2, 15 and 29; Cycle 2: Days 2, 15, and 29 (approximately study days 44, 57 and 71) | 
| Kaplan-Meier Estimates for Overall Survival (OS) | 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. | 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 | 
| Kaplan-Meier Estimate for Relapse-Free Survival (RFS) | 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. | 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. | 
| Percentage of Participants With Minimal Residual Disease (MRD) Response During the First Two Treatment Cycles | 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. | Within 2 cycles of treatment (12 weeks) | 
| Percentage of Participants Who Received an Allogenic Hematopoietic Stem Cell Transplant (alloHSCT) After Achieving CR/CRh* During Treatment | 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. | 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. | 
| 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant | 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. | 100 days after HSCT | 
| Kaplan-Meier Estimates for Time to a ≥ Ten-Point Decrease From Baseline in Global Health Status Quality of Life | 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. | 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). | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAE) | 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. | From day 1 to 30 days after last infusion of blinatumomab; median (min, max) treatment duration was 30.9 (1, 142) days. | 
| Number of Participants With Treatment-Emergent Treatment-Related Adverse Events (TEAE) | 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. | From day 1 to 30 days after last infusion of blinatumomab; median (min, max) treatment duration was 30.9 (1, 142) days. | 
| Participants With Anti-Blinatumomab Antibody Formation | Anti-blinatumomab binding antibodies were evaluated with a validated blinatumomab anti-drug antibody assay. | Cycle 2, day 29 (after the completion of Cycle 2) and the SFU visit (30 days after last dose of blinatumomab) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed, Refractory, B-precursor, Acute Lymphoblastic, Leukemia ALL, Blinatumomab, Chinese Adult Subjects