Acute Lymphoblastic LeukemiaPhase 3NCT03476239
Efficacy and Safety of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)
A Phase 3 study testing Blinatumomab and Dexamthasone in people with Acute Lymphoblastic Leukemia, run by Amgen at 23 sites in China.
Trial summary
This study is being done to evaluate the rate of hematological response (complete remission/complete remission with partial hematological recovery [CR/CRh*]) induced by blinatumomab in Chinese adults with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Lymphoblastic Leukemia
- What is being tested?
- Blinatumomab and Dexamthasone
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 121 participants
- Where
- 23 sitesChina
- Study dates
- 18 Oct 2017to 8 Apr 2021
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 37Show fewer
- 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.
Trial locations and contacts
23 sites in 1 country.
23 sites in 1 country
China23 sites
Peking University Third Hospital
Beijing, Beijing Municipality, 100191
Peking Union Medical College Hospital
Beijing, Beijing Municipality, 100730
Chinese People Liberation Army General Hospital
Beijing, Beijing Municipality, 100853
Peking University International Hosipital
Beijing, 102206
The First Hospital of Jilin University
Changchun, Jilin, 130021
Xiangya Hospital Central South University
Changsha, Hunan, 410008
West China Hospital, Sichuang University
Chengdu, Sichuan, 610041
Fujian Medical University Union Hospital
Fuzhou, Fujian, 350001
Guangdong Provincial Peoples Hospital
Guangzhou, Guangdong, 510080
The First Affiliated Hospital of Sun Yat-sen University
Guangzhou, Guangdong, 510080
Sun Yat-sen Memorial Hospital, Sun Yat-sen University
Guangzhou, Guangdong, 510120
Nanfang Hospital, Southern Medical University
Guangzhou, Guangdong, 510515
The First Affiliated Hospital, College of Medicine, Zhejiang University
Hangzhou, Zhejiang, 310003
Second Affiliated Hospital Zhejiang University College of Medicine
Hangzhou, Zhejiang, 310009
Anhui Provincial Hospital
Hefei, 230001
Jiangsu Province Hospital
Nanjing, Jiangsu, 210029
Huashan Hospital Affiliated to Fudan University
Shanghai, 200040
The First Hospital of China Medical University
Shenyang, Liaoning, 110001
The First Affiliated Hospital of Soochow University
Suzhou, Jiangsu, 215006
Institute of Hematology and Blood Diseases Hospital Peking Union Medical College
Tianjin, Tianjin Municipality, 300020
Tongji Hospital Tongji Medical College Huazhong University of Science and Technology
Wuhan, Hubei, 430030
The Second Affiliated Hospital of Xi an Jiaotong University
Xi'an, Shaanxi, 71004
Henan Cancer Hospital
Zhengzhou, Henan, 450008
About this study
Official title: An Open-label, Multicenter, Phase 3 Study to Evaluate Efficacy and Safety of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)
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).
Read the detailed description
This is an open label, single-arm, multicenter phase 3 study to evaluate efficacy and safety of the BiTE (bispecific T cell engager) antibody blinatumomab in Chinese adults with relapsed/refractory B-precursor ALL. The study will consist of a screening period, a treatment period, and a follow-up period.
Treatment will consist of up to 5 cycles of blinatumomab. Participants who achieve a bone marrow (BM) response (≤ 5% BM blasts) or CR/CRh*/CRi within 2 induction cycles of treatment may continue to receive up to 3 additional consolidation cycles of blinatumomab. Thirty days after end of the last dose of protocol-specified therapy, participants will have a safety follow-up visit.
If subjects are suitable for allogeneic stem cell transplantation (alloHSCT) after treatment with blinatumomab, they may undergo alloHSCT instead of receiving further consolidation cycles with blinatumomab.
Participants will be followed via clinic visit or telephone contact every 3 months after their safety follow-up visit until death has been observed or a maximum of 2 years after start of treatment, whichever occurs first.
A planned interim analysis to assess efficacy and safety of blinatumomab was to be based on the interim analysis set (N = 90). The efficacious benefit assessment based on an O'Brien-Fleming alpha spending function (O'Brien and Fleming, 1979) with the critical boundary 42.2% at the interim analysis and 39.2% at the primary analysis in CR/CRh* rate. If the interim analysis showed statistically efficacious and overall benefit-risk analysis to be promising per the data review team review, then the interim analysis could become the primary analysis of this study. In addition, the study would continue its enrollment until 120 participants had been enrolled and continued their participation in the study to complete protocol-specified procedures.
The data cutoff date of 12 April 2019 allowed for the 90th participant enrolled before 21 February 2019 to have had the opportunity to complete 2 cycles of treatment and the safety follow-up visit (if the participant had discontinued treatment after 2 cycles).
- Conditions
- Acute Lymphoblastic Leukemia
- Being tested
- Blinatumomab, Dexamthasone
- Keywords
- Relapsed, Refractory, B-precursor, Acute Lymphoblastic, Leukemia ALL, Blinatumomab, Chinese Adult Subjects
- Medical subject headings
- Precursor Cell Lymphoblastic Leukemia-Lymphoma, Recurrence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BlinatumomabDrug
Also called BLINCYTO®, AMG 103, MT103
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.
DexamthasoneDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Blinatumomab | Experimental | 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. Receives: Drug: Blinatumomab; Drug: Dexamthasone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Within 2 cycles of treatment (12 weeks)
Secondary outcomes (15)
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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Cycle 2, day 29 (after the completion of Cycle 2) and the SFU visit (30 days after last dose of blinatumomab)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Mar 2018
- Study start18 Oct 2017
- Primary completion21 Aug 2019
- Study completion8 Apr 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Acute Lymphoblastic LeukemiaStudies of the same condition, open and under way.
- More trials run by AmgenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- 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)
- Enrolment
- 121 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amgen
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- MD, Study director, Amgen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03476239
- Sponsor's protocol ID
- 20130316
- Status last verified
- Feb 2023
- First submitted
- 12 Mar 2018
- Last updated
- 8 Feb 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
Publications
Zhou H, Yin Q, Jin J, Liu T, Cai Z, Jiang B, Li D, Sun Z, Li Y, He Y, Ma L, Gao S, Hu J, He A, Du X, Liu D, Zhang X, Ke X, Zhuang J, Han Y, Wang X, Chen Y, Gordon P, Yu D, Zugmaier G, Wang J. Efficacy and safety of blinatumomab in Chinese adults with Ph-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia: A multicenter open-label single-arm China registrational study. Hematology. 2022 Dec;27(1):917-927. doi: 10.1080/16078454.2022.2111992.
PubMed 36000952
Study at a glance
From the registry record, last updated by the sponsor on 8 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-label, Multicenter, Phase 3 Study to Evaluate Efficacy and Safety of the BiTE Antibody Blinatumomab in Chinese Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)
- ClinicalTrials.gov ID
- NCT03476239
- Acronym / sponsor ID
- 20130316
- Conditions
- Acute Lymphoblastic Leukemia
- Keywords
- Relapsed, Refractory, B-precursor, Acute Lymphoblastic, Leukemia ALL, Blinatumomab, Chinese Adult Subjects
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 121 participants (actual)
- Lead sponsor
- AmgenIndustry (pharma, biotech, devices)
- Study start
- 18 Oct 2017 (actual)
- Primary completion
- 21 Aug 2019 (actual)
- Study completion
- 8 Apr 2021 (actual)
- First posted
- 26 Mar 2018 (actual)
- Results
- Posted 14 Sep 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
This is an open label, single-arm, multicenter phase 3 study to evaluate efficacy and safety of the BiTE (bispecific T cell engager) antibody blinatumomab in Chinese adults with relapsed/refractory B-precursor ALL. The study will consist of a screening period, a treatment period, and a follow-up period.
Treatment will consist of up to 5 cycles of blinatumomab. Participants who achieve a bone marrow (BM) response (≤ 5% BM blasts) or CR/CRh*/CRi within 2 induction cycles of treatment may continue to receive up to 3 additional consolidation cycles of blinatumomab. Thirty days after end of the last dose of protocol-specified therapy, participants will have a safety follow-up visit.
If subjects are suitable for allogeneic stem cell transplantation (alloHSCT) after treatment with blinatumomab, they may undergo alloHSCT instead of receiving further consolidation cycles with blinatumomab.
Participants will be followed via clinic visit or telephone contact every 3 months after their safety follow-up visit until death has been observed or a maximum of 2 years after start of treatment, whichever occurs first.
A planned interim analysis to assess efficacy and safety of blinatumomab was to be based on the interim analysis set (N = 90). The efficacious benefit assessment based on an O'Brien-Fleming alpha spending function (O'Brien and Fleming, 1979) with the critical boundary 42.2% at the interim analysis and 39.2% at the primary analysis in CR/CRh* rate. If the interim analysis showed statistically efficacious and overall benefit-risk analysis to be promising per the data review team review, then the interim analysis could become the primary analysis of this study. In addition, the study would continue its enrollment until 120 participants had been enrolled and continued their participation in the study to complete protocol-specified procedures.
The data cutoff date of 12 April 2019 allowed for the 90th participant enrolled before 21 February 2019 to have had the opportunity to complete 2 cycles of treatment and the safety follow-up visit (if the participant had discontinued treatment after 2 cycles).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- 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
| Arm | Type | Receives |
|---|---|---|
| Blinatumomab | Experimental | Drug: Blinatumomab, Drug: DexamthasoneTreatment 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (37 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BlinatumomabAlso: BLINCYTO®, AMG 103, MT103Blinatumomab 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. | Drug | Blinatumomab |
| DexamthasonePremedication 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. | Drug | Blinatumomab |
Primary outcome
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
Time frame: Within 2 cycles of treatment (12 weeks)
A CR is defined as having ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/μL, and absolute neutrophil count [ANC] > 1,000/μL). CRh* is defined as ≤ 5% blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts: platelets > 50,000/μl, and ANC > 500/μl. CR/CRh* rate is defined as the percentage of participants who achieve CR/CRh* within 2 cycles of treatment with blinatumomab. Participants without response assessment were accounted for in the denominator when calculating the response rate, ie, these participants were counted as non-responders. The interim analysis was to become the primary analysis by meeting pre-specified efficacy and safety criteria based on an O'Brien-Fleming alpha spending function with the critical boundary 42.2%. Results for both the interim and final analysis are reported.
15 secondary outcomes
Percentage of Participants With a Hematological Response of Complete Remission (CR) During the First 2 Treatment Cycles With Blinatumomab
Time frame: 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
Time frame: Within 2 cycles of treatment (12 weeks)
Pharmacokinetic (PK) Parameter: Concentration of Blinatumomab at Steady State (Css)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: Interim analysis: From first dose of blinatumomab to the data cutoff date of 12 April 2019; maximum time on follow-up for OS was 14.7 months. Final analysis: From first dose of blinatumomab to end of study; maximum time on follow-up for OS was 25.7 months
Kaplan-Meier Estimate for Relapse-Free Survival (RFS)
Time frame: Interim Analysis: From first onset of CR/CRh* to the data cutoff date of 12 April 2019; maximum time on follow-up for RFS was 12.4 months. Final Analysis: From first onset of CR/CRh* to end of study; maximum time on follow-up for RFS was 18.1 months.
Percentage of Participants With Minimal Residual Disease (MRD) Response During the First Two Treatment Cycles
Time frame: 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
Time frame: Interim analysis: Up to the data cutoff date of 12 April 2019; maximum time on follow-up was 14.7 months. Final analysis: Up to the end of study; maximum time on follow-up was 25.7 months.
100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplant
Time frame: 100 days after HSCT
Kaplan-Meier Estimates for Time to a ≥ Ten-Point Decrease From Baseline in Global Health Status Quality of Life
Time frame: EORTC QLQ C30 was completed on days 1, 8, 15, and 29 during Cycle 1; days 1, 15, and 29 during cycle 2 and each consolidation cycle, and at the SFU visit (30 days after last dose).
Number of Participants With Treatment-Emergent Adverse Events (TEAE)
Time frame: 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)
Time frame: 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
Time frame: Cycle 2, day 29 (after the completion of Cycle 2) and the SFU visit (30 days after last dose of blinatumomab)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Feb 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 36000952Zhou H, Yin Q, Jin J, Liu T, Cai Z, Jiang B, Li D, Sun Z, Li Y, He Y, Ma L, Gao S, Hu J, He A, Du X, Liu D, Zhang X, Ke X, Zhuang J, Han Y, Wang X, Chen Y, Gordon P, Yu D, Zugmaier G, Wang J. Efficacy and safety of blinatumomab in Chinese adults with Ph-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia: A multicenter open-label single-arm China registrational study. Hematology. 2022 Dec;27(1):917-927. doi: 10.1080/16078454.2022.2111992.
- AmgenTrials clinical trials websiteLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
MD study director
Amgen
23 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Blinatumomab and Dexamthasone in people with Acute Lymphoblastic Leukemia, run by Amgen at 23 sites in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 37 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 23 sites in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Sep 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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 (time frame: Within 2 cycles of treatment (12 weeks)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03476239, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Feb 2023.