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
Overview
- Phase
- Phase 3
- Intervention
- Blinatumomab
- Conditions
- Leukemia, Acute Lymphoblastic
- Sponsor
- Amgen
- Enrollment
- 111
- Locations
- 1
- Primary Endpoint
- Kaplan Meier Estimate: Event-Free Survival (EFS; Primary Analysis)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
B-precursor ALL is an aggressive malignant disease. Therapy is usually stratified according to risk characteristics to ensure that appropriate treatment is administered to patients with high-risk of relapse. In general, pediatric treatment regimens are more intense than those employed in adults and include courses of combination chemotherapy. Standard of care chemotherapy is associated with considerable toxicity. There is a lack of novel treatment options for subjects who relapse or are refractory to treatment. Therefore, innovative therapeutic approaches are urgently needed. Blinatumomab is a bispecific single-chain antibody construct designed to link B cells and T cells resulting in T cell activation and a cytotoxic T cell response against CD19 expressing cells. This study will evaluate the event-free survival (EFS) after treatment with blinatumomab when compared to standard of care (SOC) chemotherapy. The effect of blinatumomab on overall survival and reduction of minimal residual disease compared to SOC chemotherapy will also be investigated.
Detailed Description
Patients will be randomized in a 1:1 ratio to receive either one cycle of blinatumomab or one block of standard high-risk consolidation chemotherapy. Blinatumomab is administered as a continuous intravenous infusion (CIVI). One cycle of blinatumomab treatment includes 4 weeks of CIVI of blinatumomab. After completing consolidation therapy, the patients should undergo alloHSCT depending on their bone marrow status. The patients will be followed up until the last subject on study is 36 months following alloHSCT or has died, whichever is first.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects with Philadelphia chromosome negative (Ph-) high-risk (HR) first relapse B-precursor acute lymphoblastic leukemia (ALL; as defined by International Berlin-Frankfurt-Muenster study group/International study for treatment of childhood relapsed ALL \[I-BFM SG/IntReALL\] criteria)
- •Subjects with bone marrow blast percentage \< 5% (M1) or bone marrow blast percentage \< 25% and ≥5% (M2) marrow at the time of randomization,
- •Age \> 28 days and \< 18 years at the time of informed consent/assent
- •Subject's legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated
- •Availability of the following material from relapse diagnosis for central analysis of minimal residual disease (MRD) by polymerase chain reaction (PCR): clone-specific primers and reference deoxyribonucleic acid (DNA), as well as primer sequences and analyzed sequences of clonal rearrangements (cases with isolated extramedullary relapse or cases with technical and/or logistic hurdles to obtain and process bone marrow material are exempt from providing this material. In these cases, central MRD analysis only by Flow is permitted).
Exclusion Criteria
- •Clinically relevant central nervous system (CNS) pathology requiring treatment (eg, unstable epilepsy). Evidence of current CNS (CNS 2, CNS 3) involvement by ALL. Subjects with CNS relapse at the time of relapse are eligible if CNS is successfully treated prior to enrollment
- •Peripheral neutrophils \< 500/μL prior to start of treatment
- •Peripheral platelets \< 50,000/μL prior to start of treatment
- •Currently receiving treatment in another investigational device or drug study or less than 4 weeks since ending treatment on another investigational device or drug study(s), procedures required by IntReALL high-risk (HR) guidelines are allowed
- •Chemotherapy related toxicities that have not resolved to ≤ grade 2 (except for parameters defined in Exclusion Criteria 202, 203, 204, and 217)
- •Symptoms and/or clinical signs and/or radiological and/or sonographic signs that indicate an acute or uncontrolled chronic infection, any other concurrent disease or medical condition that could be exacerbated by the treatment or would seriously complicate compliance with the protocol
- •Abnormal renal or hepatic function prior to start of treatment (day 1) as defined below
- •Abnormal serum creatinine based on age/gender
- •Total bilirubin \> 3.0 mg/dL prior to start of treatment (unless related to Gilbert's or Meulengracht disease)
- •Documented infection with human immunodeficiency virus (HIV)
Arms & Interventions
Blinatumomab
15 μg/m\^2/day as a continuous intravenous infusion (CIVI) for 4 weeks
Intervention: Blinatumomab
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).
Intervention: Dexamethasone
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).
Intervention: Vincrisitne
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).
Intervention: Daunorubicin
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).
Intervention: Methotrexate
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).
Intervention: Ifosfamide
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).
Intervention: PEG-asparaginase
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).
Intervention: Erwinia-asparaginase
Outcomes
Primary Outcomes
Kaplan Meier Estimate: Event-Free Survival (EFS; Primary Analysis)
Time Frame: As of the primary analysis 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: EFS (Final Analysis)
Time Frame: At final analysis, overall median follow-up time for EFS was 51.9 months.
EFS is calculated from the time of randomization until the date of relapse or M2 marrow after having achieved a 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 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.
Secondary Outcomes
- Kaplan Meier Estimate: Overall Survival (OS)(At final analysis, overall median follow-up time for OS was 55.2 months.)
- Percentage of Participants With an MRD Response Within 29 Days of Treatment Initiation(Up to End of Treatment (Cycle 1, Day 29))
- Cumulative Incidence of Relapse (CIR)(At final analysis, the overall maximum follow-up time was 82.0 months.)
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs)(From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.)
- Number of Participants With TEAEs of Interest(From first dose of IP through the last dose of IP (up to Day 29) plus 30 days.)
- Number of Participants With Shifts From Baseline Grade 0 or 1 to Worst Postbaseline Grade 3 or 4 Clinical Chemistry and Hematology Values(Up to Day 29 (± 2 days).)
- Kaplan-Meier Estimate of 100-Day Mortality After Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT)(From the date of alloHSCT until death/censor date; median follow up time was 1742.0 days for blinatumomab and 1619.0 days for HC3.)
- Number of Participants With Anti-Blinatumomab Antibodies Postbaseline (Blinatumomab Arm Only)(Day 1 to Day 29.)
- Pharmacokinetics: Concentration at Steady State (Css) (Blinatumomab Arm Only)(Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15)
- Pharmacokinetics: Clearance (CL) (Blinatumomab Arm Only)(Day 1: at least 10 hours after infusion start and up to 24 hours; Day 15)