Measurable Residual Disease (MRD), Mixed Phenotype Acute Leukemia (MPAL)
Conditions
Brief summary
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
This is a multicenter, non-randomized, open-label, phase II study evaluating the efficacy of blinatumomab to achieve the following objectives: 1. The best morphologic response after the first two cycles of therapy in subjects with morphologic R/R CD19-positive MPAL 2. 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.
Interventions
DRUGBLINCYTO (Blinatumomab)
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).
Sponsors
University of Maryland, Baltimore
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Cohort A: Subjects with R/R CD19-positive MPAL CohortB: Subjects with CD19-positive MPAL in complete remission and detectable MRD
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort A response rate | through study completion, an average of 1 year | The rate of achievement of CR+CRh after the first 2 cycles of blinatumomab in Cohort A subjects |
| Cohort B response rate | through study completion, an average of 1 year | The rate of achievement of MRD-negativity (\< 0.01%) after the first 2 cycles of blinatumomab in Cohort B subjects |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort A survival | 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 | 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 |
| Cohort B survival | 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 | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| CD3-positive measurement | through study completion, an average of 1 year | \- Measurement of CD3-positive T-cells subset as well as function/activity to assess T-cell exhaustion |
| Leukemic blasts evaluation | through study completion, an average of 1 year | \- Evaluate changes to immunophenotypic characteristics of leukemic blasts in subjects whose disease do not respond to blinatumomab |
| CD 19 measurement | through study completion, an average of 1 year | \- Measurement of CD19 trafficking, as a potential mechanism of resistance to blinatumomab by performing flow cytometry, immunohistochemical staining, next generation mRNA sequencing of CD19, CD81, and CD21 exons |
| Subject response evaluation | through study completion, an average of 1 year | \- Evaluate subject responses according to disease-specific features in blasts such as chromosomal amplifications and rearrangements as well as somatic mutations as necessary |
Countries
United States
Outcome results
None listed