Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Blinatumomab · 26 trials · 25 indications
The primary endpoint is EFS, defined as the time from diagnosis to resistance to induction, relapse, death from any cause or second malignancy (whichever occurs first), or time to last follow-up (censored) for patients without events.
Number and percentage of participants who experience one or more TEAE, serious TEAE, treatment-related adverse events, and adverse events of interest.
Time from randomization (enrollment) until treatment failure, relapse or death from any cause, whichever is earlier. Treatment failure is defined as not achieving a hematological complete CR with MRD response \<10-4 by the end of the initial disease assessment period. Relapse is defined as hematologic relapse, extramedullary relapse, and/or molecular relapse (MRD positivity \>= 10\^-3), whichever occurs earlier, in participants with prior achievement of hematologic CR with MRD response \<10\^-4. Participants without an event will be censored at their last evaluable disease assessment date.
OS is defined as time from randomization (enrollment) until death due to any cause.
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.
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.
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.
The Overall Survival (OS) is the time from treatment initiation to death from any cause.
The rate of achievement of complete remission (CR/CRh/CRi) with MRD-negativity (\<0.01%) after the first two cycles of therapy with blinatumomab. CR: Bone marrow blasts \<5%; absence of circulating blasts; absence of extramedullary disease; absolute neutrophil count (ANC) ≥1000/µL and platelets ≥100,000/µL; MRD+ or unknown. CR +CRh: Bone marrow blasts \<5%; absence of circulating blasts; absence of extramedullary disease; ANC ≥500/µL AND platelet count ≥50,000/µL. CR +CRi: Bone marrow blasts \<5%; absence of circulating blasts; absence of extramedullary disease; with residual thrombocytopenia (platelet count of \<100,000/µL) OR residual neutropenia (ANC \<1000/µL); not fulfilling criteria for CRh. MRD Negativity: No detectable cancer cells using sensitive tests, with less than 0.01% cancer cells. MRD positivity indicates a higher risk of relapse, while MRD negativity is linked to long-term remission and survival benefits.
The rate of achievement of complete remission (CR/CRh) after the first two cycles of therapy with blinatumomab. Complete Remission (CR): No detectable cancer cells in the bone marrow (less than 5% blast cells) and normal blood counts. CRh: No detectable cancer cells, with partial recovery of blood counts (ANC 500-1,000/µL, platelets 50,000-100,000/µL). The rate of achieving these states is calculated by the proportion of patients who reach CR/CRh within a set time. Higher rates of achievement indicate that a larger proportion of participants are responding positively to the treatment, with no detectable cancer cells in their bone marrow and recovery of blood counts.
the objective response rate to one 8-week cycle of blinatumomab following a debulking therapy with 2 R-CHOP cycles
Overall incidence and severity of treatment-emergent adverse events occurring during the blinatumomab investigative product (IP) treatment period graded by investigators according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and based on the scale: Grade 1 = Mild - transient or mild discomfort; Grade 2 = Moderate - mild to moderate limitation in activity, assistance may be needed; minimal medical intervention required; Grade 3 = Severe - marked limitation in activity, assistance usually required; medical intervention required, hospitalization is possible; Grade 4 = Life threatening - extreme limitation in activity, assistance required; medical intervention, hospitalization or hospice care probable; Grade 5 = death.
Overall incidence and severity of treatment-emergent adverse events deemed by investigators to be related to blinatumomab treatment. Severity was graded by investigators according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and based on the scale: Grade 1 = Mild - transient or mild discomfort; Grade 2 = Moderate - mild to moderate limitation in activity, assistance may be needed; minimal medical intervention required; Grade 3 = Severe - marked limitation in activity, assistance usually required; medical intervention required, hospitalization is possible; Grade 4 = Life threatening - extreme limitation in activity, assistance required; medical intervention, hospitalization or hospice care probable; Grade 5 = death.
Complete metabolic response (CMR) was determined by central radiographic assessment of positron emission tomography and computed tomography (PET/CT) scans using the Lugano Classification.
Complete metabolic response (CMR) was determined by central radiographic assessment of positron emission tomography and computed tomography (PET/CT) scans using the Lugano Classification.
Participants were evaluated for efficacy at the end of each treatment cycle via a central bone marrow aspiration and local peripheral blood counts. Complete remission was defined as meeting all 3 of the following criteria: * less than or equal to 5% blasts in the bone marrow; * no evidence of disease * full recovery of peripheral blood counts: platelets \> 100,000/μl, and absolute neutrophil count (ANC) \> 1000/μl. Complete remission with partial hematological recovery (CRh\*) was defined as meeting all 3 of the following criteria: * less than or equal to 5% blasts in the bone marrow * no evidence of disease * partial recovery of peripheral blood counts: platelets \> 50,000/μl, and ANC \> 500/μl. Participants without a post-baseline disease assessment were considered non-responders.
Overall response within the first treatment cycle was assessed according to Cheson criteria by a central reader. Response was evaluated using computerized tomography (CT) scans and positron emission tomography (PET) (to assess nodal disease/organ enlargement due to nodal/diffuse infiltration), and bone marrow biopsy (to assess bone marrow infiltration). Overall objective response rate (ORR) is the percentage of participants with a best overall response of complete response (CR) or partial response (PR). Complete response is defined as the disappearance of all evidence of disease and partial response is defined as regression of measureable disease and no new sites.
Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: Complete Remission (CR): * bone marrow blasts ≤ 5% * no evidence of disease * full recovery of peripheral blood counts: * platelets \> 100,000/μL, and * absolute neutrophil count (ANC) \> 1,000/μL Complete Remission With Partial Hematological Recovery (CRh\*): * bone marrow blasts ≤ 5% * no evidence of disease * partial recovery of peripheral blood counts: * platelets \> 50,000/μL, and * ANC \> 500/μL.
At the end of the first treatment cycle (Day 29) a bone marrow aspiration/biopsy was performed and evaluated by the central MRD laboratory. Complete MRD response is defined as no polymerase chain reaction (PCR) amplification of individual rearrangements of immunoglobulin (Ig)- or T-cell receptor (TCR)-genes detected after completion of the first cycle.
MRD Response is defined as: * If Philadelphia Chromosome (Ph) positive (+) or translocation (t) (4;11), response was achieved when Ph or t(4;11) was below detection limit and individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4. * If Ph and t(4;11) negative, response was achieved when individual rearrangements of immunoglobulin or T-cell receptor genes are below 10\^-4.
MRD negative response = MRD level \< 10\^-4 (0.01%).
An adverse event (AE) was any untoward medical occurrence in a clinical trial participant irrespective of a causal relationship with the trial treatment. TEAEs are any events that occurred after the participant received trial treatment. A serious TEAE was defined as any untoward medical occurrence that: was immediately life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was any other medically important serious event. Treatment-related TEAEs were any AEs that could be considered attributable to the trial treatment.
An AE was any untoward medical occurrence in a clinical trial participant irrespective of a causal relationship with the trial treatment. TEAEs were any events that occurred after the participant received trial treatment.
Investigators determined whether an adverse event (AE) qualified as a DLT per pre-specified protocol defined criteria. An AE was defined as any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment.
A TEAE was defined as any AE starting on or after first dose of blinatumomab or AMG 404. The investigator used clinical judgment to assess causal relationship. A serious AE (SAE) was defined as any AE that: * results in death, * immediately life-threatening, * requires in-patient hospitalization or prolongation of existing hospitalization, * results in persistent or significant disability/incapacity, * is a congenital anomaly/birth defect, and/or * other medically important serious AE. AEs of interest (EOIs) for blinatumomab included capillary leak syndrome, cytokine release syndrome, decreased immunoglobulins, elevated liver enzyme, embolic and thrombotic events, immunogenicity, infections, infusion reactions without considering duration, leukoencephalopathy, progressive multifocal leukoencephalopathy, neurologic events, neutropenia and febrile neutropenia, pancreatitis, and tumor lysis syndrome. EOIs for AMG 404 included non-infectious diarrhea and hemorrhages.
Dose-limiting toxicities were grade 3-5 adverse events that occurred during the DLT-evaluation period that were judged by the Investigator to be possibly, probably or definitely related to study drug administration. All toxicities were graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0: * Grade 3: Severe or medically significant but not immediately life-threatening. * Grade 4: Life-threatening. * Grade 5: Death.
The occurrence of any of the following toxicities during the DLT evaluation period was considered a DLT, if judged by the investigator to be related to the administration of blinatumomab: * Death * Any toxicity, regardless of grade, that lead to a participant's removal from the study by the investigator and/or sponsor * Persistent Common Terminology Criteria for Adverse Events (CTCAE) grade \>/= 2 non-hematologic adverse events (AEs) that were deemed intolerable by the participant or the treating physician and that did not respond to appropriate medical management within 5 days and lead to treatment discontinuation * Recurrent grade 2 seizures * All grade 3 and 4 AEs and laboratory abnormalities, which occurred during the SC administration portion of the treatment period with exceptions noted in protocol section 6.2.1.2.3.
All toxicities were graded using the CTCAE version 4.0: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = fatal.
An AE was defined as any untoward medical occurrence in a clinical study participant. The AE did not necessarily have a causal relationship with study treatment. The definition of AEs included worsening of a pre-existing medical condition. TEAEs included AEs starting on or after first dose of investigational product and up to the end of study date. All AEs were graded using the CTCAE version 4.0: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = fatal.
Best overall response rate (ORR) with the combination of blinatumomab and pembrolizumab in adult subjects with relapsed or refractory B-cell acute lymphoblastic leukemia will be defined as the Complete Response (CR) rate plus the Complete Response with Hematologic Recovery (CRh) rate after treatment of combination therapy. According to the National Comprehensive Cancer Network (NCCN) Guidelines for Acute Lymphoblastic Leukemia (version 1, 2015), CR is defined as \<5% lymphoblast in the bone marrow without evidence of circulating lymphoblasts or extramedullary disease. CRh is defined as for CR except with platelet count \>50,000/microliter, hemoglobin \>7 g/dL, and neutrophil (ANC) \>500/microliter.
Dose-limiting toxicities (DLTs) were defined as any Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade ≥ 3 adverse event related to blinatumomab, excluding specific CTCAE grade ≥ 3 adverse events considered consistent with the current known safety profile of blinatumomab, CTCAE grade ≥ 3 fever or infection, and laboratory parameters of CTCAE grade ≥ 3 not considered clinically relevant and/or responding to routine medical management.
Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central reference laboratory. Hematological remissions were defined by the following criteria: * Complete Remission (CR) is defined as ≤ 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. * Complete Remission With Partial Hematological Recovery (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.
TEAEs are defined as those that start between the start of the first infusion of blinatumomab and 30 days after the end of the last infusion during the treatment period. The severity of adverse events was assessed by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 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.
The maximum tolerated dose (MTD) was defined as one or fewer out of 6 participants experiencing a dose limiting toxicity (DLT) or the maximum administered dose (MAD). A dose limiting toxicity is any Grade ≥ 3 adverse event related to study drug, Grade 3 fatigue, headache, insomnia, fever, hypotension or infection were not considered dose limiting toxicities. Laboratory parameters of Grade ≥ 3 but not considered as clinically relevant and/or responding to routine medical management, thrombocytopenia, leukopenia (including neutropenia and lymphopenia), and anemia were not considered dose limiting toxicities.
Hematological assessments were performed from bone marrow biopsy samples. All hematological assessments of bone marrow were reviewed in a central laboratory. Complete remission (CR) was defined as * M1 bone marrow (bone marrow blasts \< 5%) * No evidence of circulating blasts or extra-medullary disease Complete remission includes participants with incomplete recovery of peripheral blood counts.
Participants reporting at least one occurence of any adverse event including clinical symptoms, laboratory abnormalities, serious adverse events, and treatment-limiting adverse events
| Arm | Type | Description |
|---|---|---|
| Medium Risk (MR) | OTHER | Subject is defined as MR if \> 6months of age at diagnosis, OR \< 6 months of age with White Blood cell Count (WBC) \< 300 at diagnosis and good prednisone response. Subject gets 1st cycle of blinatumomab. If MRD is \>0.01%, after 1st cycle of blinatumomab, subject will be allocated to HR treatment from that phase, and will be eligible for HSCT. If MRD is undetectable or \< 0.01% after the 1st cycle of blinatumomab (TP2) patient will be eligible for replacement of MARMA by 2nd cycle of blinatumomab after receipt of lymphoid style consolidation (Protocol IB) or of myeloid style consolidation (ADE/MAE). |
| High risk (HR) | OTHER | Subject is defined as HR if \< 6 months of age with WBC \> 300 at diagnosis OR poor prednisone response. Also MR patients with end of induction MRD ≥ 1%, or MRD \> 0.01% after the 1st cycle of blinatumomab, will be allocated to HR treatment. Subject gets 1 cycle of blinatumomab. Thereafter patient is eligible for hematopoietic stem cell transplantation (HSCT) with or without experimental therapy in an investigational window. |
| HyperCVAD + cIV Blinatumomab in Consolidation | ACTIVE_COMPARATOR | Participants with Ph-negative B-ALL will receive cIV blinatumomab infusion for cycles 1, 2, 5 and 6 (each cycle will be 35 days), in conjunction with chemotherapy (HyperCVAD) for cycles 3, 4, 7 and 8 (each cycle will be 2-4 weeks). |
| HyperCVAD + SC Blinatumomab in Consolidation | EXPERIMENTAL | Participants with Ph-negative B-ALL will receive SC injections of blinatumomab for cycles 1, 2, 5 and 6 (each cycle will be 35 days), in conjunction with chemotherapy (HyperCVAD) for cycles 3, 4, 7 and 8 (each cycle will be 2-4 weeks). |
| Safety Run-in: Blinatumomab alternating with low-intensity chemotherapy | EXPERIMENTAL | The safety run-in will be performed prior to initiating the phase 3 randomized part of the study. This safety run-in is to evaluate the safety and tolerability of blinatumomab alternating with low-intensity chemotherapy. The safety run-in also evaluates a shorter dose step interval from (4 days instead of 7 days) and a 1-week (instead of 2-week) drug free interval between blinatumomab cycles. Blinatumomab will be infused at a lower dose for 4 days and increase to a higher dose on Day 5 of the infusion for the remainder of the infusion. |
| Phase 3: Blinatumomab alternating with low-intensity chemotherapy | EXPERIMENTAL | Participants will receive blinatumomab alternating with low-intensity chemotherapy. |
| Phase 3: Standard of care (SOC) chemotherapy | ACTIVE_COMPARATOR | Participants will receive 1 of 2 SOC chemotherapy regimens (GMALL or HyperCVAD) per investigator's choice. |
| 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. |
| High Risk Consolidation 3 (HC3) Chemotherapy | ACTIVE_COMPARATOR | 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). |
| Blinatumomab in Newly Diagnosed CD19+ MPAL, Age ≥ 75 or Unfit for Intensive Chemotherapy | EXPERIMENTAL | Cohort A: Evaluate the efficacy of SC-blinatumomab in treating newly diagnosed CD19+ MPAL in patients ≥ 75 years old or those deemed unfit for intensive chemotherapy. * Each cycle = 34 days (26-day treatment period + 8-day treatment free interval between day 27 and day 34). * Cycle 1 receives treatment daily during the first week and 3 times (TIW) weekly (M/W/F) during weeks 2-4. * In subsequent cycles, the treatment will be administered TIW during weeks 1-4. * All subjects will be hospitalized for days 1-12 of cycle 1. * Other treatment doses will be given as outpatients. Subjects will remain in the outpatient department for 1-6 hours after each dose is given. * Treatment will be given with ability to delay cycle initiation based on blood counts or general physical/neurological examination findings per clinical indication and institutional standard practice. |
| Blinatumomab use in CD19+ MPAL in first or second CR/CRh/CRi with detectable MRD ≥0.1% | EXPERIMENTAL | Cohort B: Assess the ability of SC-blinatumomab to achieve MRD-negative CR in patients with CD19+ MPAL in CR/CRh/CRi with persistent MRD positivity (≥ 0.1%) after at least one line of treatment. * Each cycle = 34 days (26-day treatment period + 8-day treatment free interval between day 27 and day 34). * Cycle 1 receives treatment daily during the first week and 3 times (TIW) weekly (M/W/F) during weeks 2-4. * In subsequent cycles, the treatment will be administered TIW during weeks 1-4. * All subjects will be hospitalized for days 1-12 of cycle 1. * Other treatment doses will be given as outpatients. Subjects will remain in the outpatient department for 1-6 hours after each dose is given. * Treatment will be given with ability to delay cycle initiation based on blood counts or general physical/neurological examination findings per clinical indication and institutional standard practice. |
| Blinatumomab use in Morphologic R/R CD19+ MPAL | EXPERIMENTAL | Cohort C: Determine the efficacy of SC-blinatumomab in inducing CR, CRh, or CRi in patients with morphologic relapsed or refractory CD19+ MPAL. * Each cycle = 34 days (26-day treatment period + 8-day treatment free interval between day 27 and day 34). * Cycle 1 receives treatment daily during the first week and 3 times (TIW) weekly (M/W/F) during weeks 2-4. * In subsequent cycles, the treatment will be administered TIW during weeks 1-4. * All subjects will be hospitalized for days 1-12 of cycle 1. * Other treatment doses will be given as outpatients. Subjects will remain in the outpatient department for 1-6 hours after each dose is given. * Treatment will be given with ability to delay cycle initiation based on blood counts or general physical/neurological examination findings per clinical indication and institutional standard practice. |
| R-CHOP- blinatumomab | EXPERIMENTAL | Patients will first undergo a prior debulking therapy including 2 cycles of R-CHOP. At Day1 (D1) : Rituximab 375 mg/m² Intravenous (IV) + Cyclophosphamide 750 mg/m² IV + Doxorubicin 50 mg/m² IV + Vincristine 1.4 mg/m² IV. From D1 to D5 : Prednisone 60 mg/m² Per Os (PO). Patients with CR and no measurable lesion left will not be treated further in the setting of the present trial. All the remaining patients will be continuing and treating on study with a single cycle of blinatumomab induction therapy : Blinatumomab at 9 μg/d IV by continuous vein infusion from day 1-7, 28 μg/d from day 8-14 and 112 μg/d from day 15-56. Patients who achieve an objective response after induction are eligible to receive one further optional cycle of blinatumomab consolidation : blinatumomab 9 μg/d IV by continuous vein infusion from day 1-7, 28 μg/d from day 8-14 and 112 μg/day IV from day 15-28. |
| Blinatumomab 15 μg | EXPERIMENTAL | Participants received blinatumomab 15 μg/m²/day as a continuous intravenous infusion at a constant flow rate over 4 weeks followed by a 2-week treatment-free interval for up to 5 consecutive cycles. |
| Blinatumomab 5/15 μg | EXPERIMENTAL | Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, followed by 15 μg/m²/day starting from Week 2 of treatment. |
| Blinatumomab 5/15/30 μg | EXPERIMENTAL | Participants received blinatumomab by continuous intravenous infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose was 5 μg/m²/day for the first seven days of treatment, a dose of 15 μg/m²/day in the subsequent 7 days, followed by 30 μg/m²/day starting from Week 3 of treatment. |
| Phase 1b: R/R B-ALL | EXPERIMENTAL | Participants with R/R B-ALL will receive blinatumomab as SC injection to determine the pediatric recommended Phase 2 dose (RP2D). |
| Cohort Ph2-R | EXPERIMENTAL | Participants with R/R B-ALL will receive blinatumomab as SC injection at RP2D. |
| Cohort Ph2-M | EXPERIMENTAL | Participants with MRD+ B-ALL will receive blinatumomab as SC injection at RP2D. |
| Dose Escalation Phase: Blinatumomab Subcutaneous Formulation 1 (SC1) | EXPERIMENTAL | Cohorts of at least 3 adult participants with R/R B-ALL will be treated with escalating doses of blinatumomab to determine the maximum tolerated dose (MTD). The MTD will be defined as the dose for which the estimate of the toxicity rate from an isotonic regression (Yan et al, 2017) is closest to the target toxicity rate. Safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy will be assessed. |
| Dose Expansion Phase: Blinatumomab SC1 | EXPERIMENTAL | Up to 4 cohorts of adult participants with R/R B-ALL will be enrolled at different dose levels to support identification of the RP2D. Each cohort will aim to further assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. |
| Ph-IIC: Clinical PK Evaluation of SC Blinatumomab Formulations | EXPERIMENTAL | 1 cohort of adult participants will be enrolled into the Ph-IIC arm. The clinical PK evaluation cohort (Ph-IIC) will be conducted to compare the PK of SC1 and SC2 formulations at the preliminary RP2D determined from the dose expansion phase, in participants with R/R B-ALL. |
| Ph-IIR: Efficacy of SC Blinatumomab in Participants with R/R B-ALL | EXPERIMENTAL | The efficacy of SC blinatumomab (in the SC2 formulation) will be evaluated in adults and adolescents with R/R B-ALL. |
| Ph-IIM: Efficacy of SC Blinatumomab in Participants with MRD+ B-ALL | EXPERIMENTAL | The efficacy of SC blinatumomab (in the SC2 formulation) will be evaluated in adults and adolescents with MRD+ B-ALL. |
| Blinatumomab and AMG 404 | EXPERIMENTAL | - |
| Cohort Ia: Blinatumomab 9/28 µg/day + Pembrolizumab | EXPERIMENTAL | Participants received blinatumomab administered as a continuous intravenous infusion (CIVI) for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days then 28 µg/day for the remaining days of treatment. Starting on Day 15 participants also received 200 mg pembrolizumab administered by intravenous (IV) infusion every 3 weeks (Q3W) until disease progression or for up to 35 cycles. |
| Cohort IIa: Blinatumomab 9/28/56 µg/day + Pembrolizumab | EXPERIMENTAL | Participants received blinatumomab administered as a continuous intravenous infusion for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days, 28 µg/day for 7 days then 56 µg/day for the remaining days of treatment. Starting on Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles. |
| Cohort IIIa: Blinatumomab 9/28/112 µg/day + Pembrolizumab | EXPERIMENTAL | Participants received blinatumomab administered as a continuous intravenous infusion for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days, 28 µg/day for 7 days then 112 µg/day for the remaining days of treatment. Starting on Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles. |
| Expansion Cohort | EXPERIMENTAL | This cohort will test the maximum tolerated dose of blinatumomab in combination with pembrolizumab identified in Part 1 of the study. |
| Blinatumomab + Pembrolizumab | EXPERIMENTAL | Drug: blinatumomab Cycle 1 Blinatumomab Day 1-7 Continuous IV infusion for 28 days (9 mcg/day) Blinatumomab Day 8-28 Continuous IV infusion for 28 days (28 mcg/day) Cycle 2-5 Blinatumomab Day 1-28 Continuous IV infusion for 28 days (28 mcg/day) Cycle length 42 days Other Names: Blincyto Drug: pembrolizumab Cycle 1 Pembrolizumab Day 15 and 36 IV infusion over 30 minutes (200mg) Cycle 2-5 Pembrolizumab Day 15 and 36 IV infusion over 30 minutes (200mg) Other Names: * Keytruda * MK-3475 |
| Blinatumomab 9-28 µg/day Phase 1b Adult Population | EXPERIMENTAL | 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. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter. |
| Blinatumomab 5-15 µg/m^2/day Phase 1b Pediatric Population | EXPERIMENTAL | Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. For pediatric participants the initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter. |
| Blinatumomab 9-28 µg/day Phase 2 Adult Population | EXPERIMENTAL | Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter. |
| Blinatumomab 9-28 µg/day Adult Expansion Population | EXPERIMENTAL | Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. The initial dose for adults was 9 µg/day for the first week of cycle 1, escalated to 28 µg/day starting from Week 2 and all cycles thereafter. |
| Blinatumomab 5-15 µg/m^2/day Pediatric Expansion Population | EXPERIMENTAL | Participants received blinatumomab by CIV infusion over 4 weeks followed by a treatment-free interval of 2 weeks for up to 5 consecutive cycles. For pediatric participants the initial dose was 5 µg/m²/day for the first week of cycle 1, escalated to 15 µg/m²/day starting from week 2 and all cycles thereafter. |
| Name | Type | Description |
|---|---|---|
| Blinatumomab | DRUG | 1st cycle: 15 μg/m2/day as a 4 week continuous IV infusion for patients with a M1 marrow. For patients with a M2/M3 marrow a step-dosing strategy is required with a dose of 5 μg/m2/day in week 1 followed by 15 μg/m2/day in weeks 2, 3, and 4. |
| HyperCVAD | DRUG | HyperCVAD will administer as the chemo regimen as part of the standard of care (SOC) regimen. |
| Low-intensity chemotherapy regimen | DRUG | Intravenous (IV), oral (PO), subcutaneous (SC), or intrathecal (IT) administration. |
| SOC chemotherapy regimen | DRUG | Intravenous (IV), oral (PO), subcutaneous (SC), or intrathecal (IT) administration. |
| Dexamthasone | DRUG | 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. |
| Dexamethasone | DRUG | 10 mg/m\^2/day intravenous (IV) on Days 1-6 |
| Vincrisitne | DRUG | 1.5 mg/m\^2/day IV on Days 1 and 6 |
| Daunorubicin | DRUG | 30 mg/m\^2 IV over 24 hours on Day 5 |
| Methotrexate | DRUG | 1 g/m\^2 IV over 36 hours on Day 1 |
| Ifosfamide | DRUG | 800 mg/m\^2 IV for 1 hour on Days 2-4 |
| PEG-asparaginase | DRUG | 1000 U/m\^2 IV for 2 hours or intramuscularly (IM) on Day 6 |
| Erwinia-asparaginase | DRUG | 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 |
| Subcutaneous Blinatumomab | DRUG | Blinatumomab will be administered as a subcutaneous (SC) injection. |
| RCHOP | DRUG | D1 : Rituximab 375 mg/m² IV + Cyclophosphamide 750 mg/m² IV + Doxorubicin 50 mg/m² IV + Vincristine 1.4 mg/m² IV. From D1 to D5 : Prednisone 60 mg/m² PO. |
| Investigator's Choice Chemotherapy | DRUG | During the run-in period participants received 6 cycles of standard of care rituximab-chemotherapy dosed per investigator's institution standard as follows: * R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine,prednisone) * R-DA-EPOCH (rituximab and dose adjusted-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) or * R-CHOEP (rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide). |
| Blinatumomab (MT103) | BIOLOGICAL | Administered by continuous intravenous (CIV) over 4 weeks per cycle |
| AMG 404 | DRUG | AMG 404 will be administered as an intravenous infusion (IV). |
| Dexamethasone Premedication | DRUG | Dexamethasone will be administered orally or intravenously prior to blinatumomab treatment, as needed. |
| Pembrolizumab | DRUG | One cycle of pembrolizumab is a 200 mg IV injection lasting 30 minutes. One cycle will be given every 3 weeks until disease progression, or for a maximum of 35 cycles. |
Inclusion Criteria: 1. Patients with newly diagnosed B- precursor ALL or B-cell MPAL (single lineage) according to the WHO classification of tumours of haematopoietic and lymphoid tissues (revised 4th edition 2017), with KMT2A-rearrangement. 2. ≤ 365 days of age at the time of diagnosis of ALL. 3. ...