Blinatumomab for Treatment of R/R or MRD-positive CD19-Positive MPAL

Study Overview
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Brief Summary
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This is a research study to find out if a drug called blinatumomab is effective for treating patients with relapsed or refractory (R/R) or measurable residual disease (MRD) CD19-positive mixed phenotypic acute leukemia (MPAL). Measurable Residual Disease (MRD) means that there are a small number of cancer cells remaining after treatment

Detailed Description
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This is a multicenter, non-randomized, open-label, phase II study evaluating the efficacy of blinatumomab to achieve the following objectives: The best morphologic response after the first two cycles of therapy in subjects with morphologic R/R CD19-positive MPAL MRD-negativity in subjects with CD19-positive MPAL in CR, or CRh, or CRi or CRp after receiving at least one chemotherapy block of standard ALL or AML treatment with MRD-positivity at a level of ≥ 0.1% using an assay with a minimum sensitivity of 0.01% The trial consists two groups (Group A and B) and three phases ( induction, consolidation and maintenance) of therapy. Subject will receive study drug blinatumomab by continuous IV infusion (CIV). Each treatment cycle consists of 28 days of blinatumomab CIV followed by a 14±3 days treatment-free interval for induction, 28±3 days treatment-free interval for consolidation, and 56±3 days treatment-free interval for maintenance Blinatumomab is approved by Food and Drug Administration [FDA] and European Medicines Agency [EMA] for use in people with another type of acute leukemia called acute lymphoblastic leukemia (ALL) but not MPAL.

Official Title
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A Multicenter Phase II Study of Blinatumomab for Treatment of Adult Patients With Morphologic Relapsed/Refractory or Measurable Residual Disease (MRD) CD19-Positive Mixed Phenotype Acute Leukemia (MPAL)

Conditions
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Mixed Phenotype Acute Leukemia (MPAL), Measurable Residual Disease (MRD)

Intervention / Treatment
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* Drug: BLINCYTO (Blinatumomab)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have histologically or cytologically confirmed R/R CD19-positive MPAL based on the WHO criteria, OR CD19-positive MPAL in CR/CRh/CRi/CRp after at least one chemotherapy block of standard ALL or AML therapy with detectable MRD ≥ 0.1%. Primary refractory MPAL is defined by absence of CR/CRh/CRi/CRp after at least one cycle of standard AML/ALL induction therapy. A patient has relapsed MPAL if they achieved a CR/CRh/CRi/CRp after induction therapy (CR1) and has then relapsed during, or after continuation of therapy. Age 18 years and older Subjects who have undergone allo-HSCT are eligible if they are ≥ 4 weeks post stem cell infusion, have no evidence of GVHD > Grade 2, and are at least ≥ 1 week off all immunosuppressive therapy Previous cytotoxic chemotherapy (except for hydroxyurea) must have been completed at least 2 weeks prior to day 1 of treatment on the study. Subjects with hematologic malignancies are expected to have hematologic abnormalities at study entry. ECOG performance status < 3 Subjects must have organ function as below: Direct bilirubin ≤ 2.5 mg/dL AST/ALT/Alkaline phosphatase ≤ 5 X institutional upper limit of normal Serum creatinine ≤ 3 mg/dL Subjects with a history of CNS leukemia must be clinically stable with a flow cytometric clear CSF in the 2 weeks prior to day 1 of blinatumomab administration. Subjects with history of CNS leukemia in Cohort A should have received one dose of intrathecal chemotherapy in the 4 weeks prior to day 1 of blinatumomab administration. Subject can receive subsequent prophylactic intrathecal chemotherapy. Female subjects of childbearing potential must have a negative pregnancy test Ability to understand and willingness to sign a written informed consent document Agree to comply with the study requirements and agree to come to the clinic/hospital for required study visits Exclusion Criteria: Subjects receiving any other investigational agents, or concurrent chemotherapy, radiation therapy, or immunotherapy not including corticosteroids or hydroxyurea Subjects with acute leukemia with any of the following cytogenetic abnormalities: t(15;17)(q24;q21) PML/RARA, t(8;21)(q22;q22) RUNX1/RUNX1T1, inv(16)(p13q22)/t(16;16)(p13;q22) CBFB-MYH11 A history or presence of clinically relevant CNS pathology (e.g., as epilepsy, paresis, aphasia, stroke, severe brain injuries, dementia, cerebellar disease, psychosis) Hyperleukocytosis with > 50,000 blasts/µL. Hydroxyurea for blast count control is permitted before starting treatment and up to maximum of 10 days after starting treatment on the study. The WBC need not reach 50,000/µL to start hydroxyurea during protocol; the decision to start hydroxyurea during this time is at the discretion of the treating physician Active, uncontrolled infection; subjects with infection under active treatment and controlled with antimicrobials are eligible Pregnant women Uncontrolled undercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled active seizure disorder, or psychiatric illness/social situations that per site Principal Investigator's judgment would limit compliance with study requirements

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Cohort A: Subjects with R/R CD19-positive MPAL CohortB: Subjects with CD19-positive MPAL in complete remission and detectable MRD
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subjects with R/R CD19-positive MPAL<br>Cohort A: Evaluate the efficacy of blinatumomab to achieve the best morphologic response after the first two cycles of therapy in subjects with morphologic R/R CD19-positive MPAL The treatment of blinatumomab consists of induction, consolidation and maintenance therapy Subject will receive study drug blinatumomab by continuous IV infusion (CIV) Each treatment cycle consists of 28 days of blinatumomab CIV followed by a 14±3 days treatment-free interval for induction, 28±3 days treatment-free interval for consolidation, and 56±3 days treatment-free interval for maintenance The initial dose of blinatumomab is 9 mcg/day for 7 days. The target dose for rest of treatment is 28 mcg/day | Drug: BLINCYTO (Blinatumomab)<br>* Blinatumomab (BLINCYTO , AMG 103, formerly also known as MT103 or bscCD19xCD3) is a novel single chain antibody construct in the class of the bispecific T-cell engager (BiTE®). Blinatumomab directs CD-3 positive effector memory T cells to CD19-positive target cells (Hoffmann et al, 2005; Dreier et al, 2002). The targeted CD19 antigen is constitutively expressed on normal B cells throughout a person's lifetime (Smet et al, 2011) and is highly conserved in B-cell malignancies (Tedder, 2009; Wang et al, 2012).<br>|
| Experimental: Subjects with CD19-positive MPAL in CR/CRh/CRi/CRp and detectable MRD<br>Cohort B: Evaluate the efficacy of blinatumomab to achieve MRD-negativity in subjects with CD19-positive MPAL in CR, or CRh, or CRi or CRp after receiving at least one chemotherapy block of standard ALL or AML treatment with MRD-positivity at a level of ≥ 0.1% using an assay with a minimum sensitivity of 0.01% The treatment of blinatumomab consists of induction, consolidation and maintenance therapy Subject will receive study drug blinatumomab by continuous IV infusion (CIV) Each treatment cycle consists of 28 days of blinatumomab CIV followed by a 14±3 days treatment-free interval for induction, 28±3 days treatment-free interval for consolidation, and 56±3 days treatment-free interval for maintenance. The dose of blinatumomab is 28 mcg/day | Drug: BLINCYTO (Blinatumomab)<br>* Blinatumomab (BLINCYTO , AMG 103, formerly also known as MT103 or bscCD19xCD3) is a novel single chain antibody construct in the class of the bispecific T-cell engager (BiTE®). Blinatumomab directs CD-3 positive effector memory T cells to CD19-positive target cells (Hoffmann et al, 2005; Dreier et al, 2002). The targeted CD19 antigen is constitutively expressed on normal B cells throughout a person's lifetime (Smet et al, 2011) and is highly conserved in B-cell malignancies (Tedder, 2009; Wang et al, 2012).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A response rate | The rate of achievement of CR+CRh after the first 2 cycles of blinatumomab in Cohort A subjects | through study completion, an average of 1 year | 
| Cohort B response rate | The rate of achievement of MRD-negativity (< 0.01%) after the first 2 cycles of blinatumomab in Cohort B subjects | through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A survival | To evaluate the following outcomes in subjects with R/R CD19-positive MPAL Achievement of MRD < 0.01% within 2 cycles of treatment with blinatumomab Relapsed free survival (RFS) Event free survival (EFS) Overall survival (OS) Proceeding to allogeneic hematopoietic stem cell transplantation (allo-HSCT) after blinatumomab treatment Overall incidence and severity of adverse events (AEs) CD19-negative and CD19-positive relapse post-blinatumomab The type of lineage switch, as applicable, post-blinatumomab CD19 expression in CSF relapse following blinatumomab, as applicable CAR T-cell treatment of subjects with CSF relapse following blinatumomab and those subjects' outcomes, as applicable | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 
| Cohort B survival | To evaluate the following outcomes in subjects with CD19-positive MPAL in CR/CRh/CRi/CRp after at least one chemotherapy block of standard ALL or AML treatment and detectable MRD at a level of ≥ 0.1% using an assay with a minimum sensitivity of 0.01% Achievement of undetectable MRD (< 0.01%) within one cycle of blinatumomab treatment RFS OS Proceeding to allo-HSCT after blinatumomab treatment Overall incidence and severity of AEs | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months |