Phase 3 Trial of Blinatumomab vs Standard Chemotherapy in Pediatric Subjects With HIgh-Risk (HR) First Relapse B-precursor Acute Lymphoblastic Leukemia (ALL)
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|ClinicalTrials.gov Identifier: NCT02393859|
Recruitment Status : Active, not recruiting
First Posted : March 20, 2015
Results First Posted : July 13, 2020
Last Update Posted : December 8, 2020
|Condition or disease||Intervention/treatment||Phase|
|Leukemia, Acute Lymphoblastic||Drug: Blinatumomab Drug: Dexamethasone Drug: Vincrisitne Drug: Daunorubicin Drug: Methotrexate Drug: Ifosfamide Drug: PEG-asparaginase Drug: Erwinia-asparaginase||Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||111 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase 3 Trial to Investigate the Efficacy, Safety, and Tolerability of Blinatumomab as Consolidation Therapy Versus Conventional Consolidation Chemotherapy in Pediatric Subjects With HR First Relapse B-precursor ALL|
|Actual Study Start Date :||November 10, 2015|
|Actual Primary Completion Date :||July 17, 2019|
|Estimated Study Completion Date :||November 14, 2022|
Active Comparator: High Risk Consolidation 3 (HC3) Chemotherapy
One week of treatment with HC3 followed by 3 weeks of no treatment. The standard intensive consolidation chemotherapy course HC3 includes dexamethasone (10 mg/m^2/day intravenous [IV] on Days 1-6), vincrisitne (1.5 mg/m^2/day IV on Days 1 and 6), daunorubicin (30 mg/m^2 IV over 24 hours on Day 5), methotrexate (1 g/m^2 IV over 36 hours on Day 1), ifosfamide (800 mg/m^2 IV for 1 hour on Days 2-4), and pegylated [PEG]-asparaginase (1000 U/m^2 IV for 2 hours or intramuscularly [IM] on Day 6) or, if allergic, erwinia-asparaginase (20,000 units/m^2 IV or IM every 48 hours for a total of 6 doses).
10 mg/m^2/day intravenous (IV) on Days 1-6
1.5 mg/m^2/day IV on Days 1 and 6
30 mg/m^2 IV over 24 hours on Day 5
1 g/m^2 IV over 36 hours on Day 1
800 mg/m^2 IV for 1 hour on Days 2-4
1000 U/m^2 IV for 2 hours or intramuscularly (IM) on Day 6
In case of allergic reaction to PEG-asparaginase, participants could change to erwinia-asparaginase, 20,000 units/m2 every 48 hours for a total of 6 doses
15 μg/m^2/day as a continuous intravenous infusion (CIVI) for 4 weeks
15 μg/m^2/day as a continuous intravenous infusion (CIVI) for 4 weeks
Other Name: Blincyto, AMG103
- Kaplan Meier Estimate: Event-Free Survival (EFS) [ Time Frame: As of the data cutoff date (17 July 2019), overall median follow-up time for EFS was 22.4 months. ]
EFS is calculated from the time of randomization until the date of relapse or M2 marrow (representative bone marrow aspirate or biopsy with ≥ 5% and < 25% blasts) after having achieved a complete remission (CR), failure to achieve a CR at the end of treatment, second malignancy, or death due to any cause, whichever occurs first. Participants who failed to achieve a CR following treatment with investigational product (IP) or who died before the disease assessment at the end of treatment were considered treatment failures and assigned an EFS duration of 1 day. Participants still alive and event-free were censored on their last disease assessment date.
Participants were said to be in CR when they had the following:
- M1 marrow
- Peripheral blood without blasts
- Absence of extramedullary leukemic involvement
Months are calculated as days from randomization date to event/censor date, divided by 30.5.
- Kaplan Meier Estimate: Overall Survival (OS) [ Time Frame: As of the data cutoff date (17 July 2019), overall median follow-up time for OS was 19.5 months. ]
Overall survival (OS) was calculated from time of randomization until death due to any cause. Participants still alive were censored at the date they were last known to be alive.
Months were calculated as days from randomization date to event/censor date, divided by 30.5.
- Percentage of Participants With an MRD Response Within 29 Days of Treatment Initiation [ Time Frame: Up to End of Treatment (Cycle 1, Day 29). Data cutoff date was 17 July 2019. ]
At the end of the first treatment cycle (Day 29) a bone marrow aspiration/biopsy was performed and evaluated by the central MRD laboratory.
MRD response was defined as MRD level < 10^-4, by polymerase chain reaction (PCR) or flow cytometry, at the end of treatment with study drug. Participants who were part of the MRD Evaluable Set and were missing the end of treatment (Cycle 1 Day 29) assessment for a respective MRD assessment method were considered not to have achieved a response.
- Cumulative Incidence of Relapse (CIR) [ Time Frame: As of data cutoff date (17 July 2019), the overall maximum follow-up time was 44.1 months. ]
CIR estimate, presented as median months to relapse, calculated from date of achievement of first CR, using the cumulative incidence method (Fine JP, Gray RJ:1999). Deaths prior to relapse not considered related to an otherwise undocumented relapse were treated as a competing risk. Participants still alive without a date of relapse were censored at the time of last follow-up.
Relapse=presence of ≥1 of the following:
- isolated bone marrow relapse (M3 marrow [representative bone marrow aspirate or biopsy with ≥25% blasts] in the absence of extramedullary involvement)
- combined bone marrow relapse (M2 [representative bone marrow aspirate or biopsy with ≥5% and <25% blasts] or M3 marrow and ≥1 extramedullary manifestation of acute lymphoblastic leukemia)
- central nervous system extramedullary relapse
- testicular extramedullary relapse
- extramedullary relapse at other sites
Months were calculated as days from randomization to event/censor date, divided by 30.5.
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) [ Time Frame: From first dose of IP through the last dose of IP (up to Day 29) plus 30 days. Data cutoff date was 17 July 2019. ]Adverse event (AE): any untoward medical occurrence. Serious AE: an AE meeting at least 1 of the following serious criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event. Severity was graded according to the Common Terminology Criteria for AEs (CTCAE) version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Investigational product (IP) in the HC3 arm refers to dexamethasone, methotrexate, daunorubicin, erwinase, ifosfamide, asparaginase, and vincristine, and in the blinatumomab arm refers to blinatumomab. Treatment-related refers to the assessment of a relationship between IP and the event.
- Number of Participants With TEAEs of Interest [ Time Frame: From first dose of IP through the last dose of IP (up to Day 29) plus 30 days. Data cutoff date was 17 July 2019. ]TEAEs of interest included capillary leak system (CLS), cytokine release syndrome (CRS), decreased immunoglobulins (DI), elevated liver enzymes (ELE), embolic and thrombotic events (ETE), infections (INF), infusion reactions without considering duration (IRWCD), medication errors (ME), neurologic events (NE), neutropenia and febrile neutropenia (NFN), pancreatitis (PNC), tumor lysis syndrome (TLS), leukoencephalopathy (LE), immunogenicity (IM). Severity was graded according to the CTCAE version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death.
- Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values [ Time Frame: Up to Day 29 (± 2 days). Data cutoff date was 17 July 2019. ]Severity was graded according to the CTCAE version 4.03: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death. Increases (↑) or decreases (↓) in laboratory value grades (Gr) from baseline (BL) to worst postbaseline (→ PB) grade are presented. NA=not available.
- Kaplan-Meier Estimate of 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) [ Time Frame: From the date of alloHSCT until the data cut-off date of 17 July 2019; median follow up time was 652.0 days for blinatumomab and 541.0 days for HC3. ]
The analysis of 100-day mortality after alloHSCT was assessed for participants who received an alloHSCT while in remission and did not receive any additional anti-leukemic treatment. 100-day mortality after alloHSCT was calculated relative to the date of alloHSCT.
The 100-day mortality rate after alloHSCT was defined as the percentage of participants having died up to 100 days after alloHSCT, estimated using the estimated time to death in percent calculated by Kaplan-Meier methods. Participants still alive were censored at the date they were last known to be alive.
- Number of Participants With Anti-Blinatumomab Antibodies Postbaseline (Blinatumomab Arm Only) [ Time Frame: Day 1 to Day 29. Data cutoff date was 17 July 2019. ]
Participants receiving blinatumomab had blood samples analyzed for binding antibodies. Samples testing positive for binding antibodies were also tested for neutralizing antibodies.
Participants who were binding antibody-positive or neutralizing antibody-positive post-baseline with a negative or no result at baseline are presented.
- Pharmacokinetics: Concentration at Steady State (Css) [ Time Frame: Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15 ]
- Pharmacokinetics: Clearance (CL) [ Time Frame: Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15 ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02393859