B-cell Acute Lymphoblastic Leukemia, Refractory B Acute Lymphoblastic Leukemia, Relapsed B-cell Acute Lymphoblastic Leukemia
Conditions
Brief summary
The investigator is testing the ability of a biologically active therapy in blinatumomab, an anti-CD19/CD3 bispecific T-cell engager, to further reduce residual leukemia immediately prior to HCT to improve post-HCT outcomes.
Detailed description
The investigator is testing the ability of a biologically active therapy in blinatumomab, an anti-CD19/CD3 bispecific T-cell engager, to further reduce residual leukemia immediately prior to HCT to improve post-HCT outcomes. This Phase 2 study will determine the effectiveness of delivering 1 to 2 cycles of blinatumomab (Days 1-28) as bridging therapy in children, adolescent and young adults with relapse or persistent MRD B-ALL. Eligible subjects will receive 1 or 2, 28-day cycles of blinatumomab prior to proceeding to HCT. Centralized MRD assessment will be performed after completion of the 28-days of blinatumomab using both flow cytometry (University of Washington, Brent Wood, MD) and High-Throughput Deep Sequencing (HTS) MRD technologies (Adaptive Technologies, Seattle, WA). Subjects who achieve flow cytometry negative MRD (\<0.01%) after a single cycle of blinatumomab can proceed directly to HCT whereas subjects who remain MRD positive by flow cytometry may receive a 2nd cycle of blinatumomab. Subjects who remain MRD positive by flow cytometry after a 2nd cycle of blinatumomab will come off study.
Interventions
DRUGBlinatumomab
Blinatumomab will be given as a 28-day continuous infusion with 14-days in between Cycle 1 and Cycle 2 as per the package insert and FDA approved labeling. Patient weight greater than or equal to 45kg will receive 28 mcg/day Patient weight less than 45kg will receive 15 mcg/m2/day
Sponsors
Amgen
Michael Burke
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single Group Assignment
Eligibility
Sex/Gender
ALL
Age
No minimum to 25 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of B-ALL in hematologic complete remission (defined as an M1 marrow, \< 5% blasts) with MRD in the bone marrow (≥ 0.01%) by multi-parameter flow cytometry and that meets one of the following: * Patients in first relapse or greater; OR • Patients with very-high risk biology ALL that is proceeding to HCT in first remission (e.g. Induction failure, Severe-hypodiploidy, Ph-like ALL); OR • Patients who have persistent MRD after Consolidation therapy (End of Consolidation (EOC) MRD positive ≥ 0.01%); AND with the intent of going on to an allogeneic hematopoietic cell transplantation (HCT) independent of this study * Patients must have an available donor and have intention of proceeding directly to HCT after completion of 1 to 2 cycles of Bridging therapy with blinatumomab. * Age ≤ 25 years at time of study enrollment * Karnofsky Performance Status ≥ 50% for patients 16 years and older and Lansky Play Score ≥ 50 for patients under 16 years of age (see Appendix 1) * Have acceptable organ function as defined within 7 days of study registration: Renal: creatinine clearance ≥ 60 mL/min/1.73m2 or serum creatinine based on age/gender Hepatic: ALT \< 5 x upper limit of normal (ULN) and total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age Cardiac: left ventricular ejection fraction ≥ 40% by ECHO/MUGA * At least 7 days must have elapsed from prior chemotherapy. * Patients who have experienced their relapse after HCT are eligible, provided they have no evidence of acute or chronic Graft-versus-Host Disease (GVHD) and are off all transplant immune suppression therapy for at least 7-days (e.g. steroids, cyclosporine, tacrolimus). Steroid therapy for non-GVHD and/or non-leukemia therapy is acceptable. * Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair. * Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last dose of monoclonal antibody (i.e. Inotuzumab = 12 days). * Immunotherapy: At least 42 days after the completion of any type of immunotherapy (e.g. tumor vaccines or CAR T-cell therapy). * XRT: Cranio or craniospinal XRT is prohibited during protocol therapy. ≥ 90 days must have elapsed if prior TBI, cranio or craniospinal XRT * Sexually active females of child-bearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device \[IUD\], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment and for 2 months after the last dose of chemotherapy. Sexually active men must agree to use barrier contraceptive for the duration of treatment and for 2 months after the last dose of chemotherapy. * Voluntary written consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
Exclusion criteria
* History of CNS3 disease and/or active central nervous system (CNS) disease (≥ CNS2) * Receiving concomitant chemotherapy, radiation therapy; immunotherapy or other anti-cancer therapy other than is specified in the protocol. * Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) * Pregnant or lactating. The agents used in this study are known to be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. All females of childbearing potential must have a blood test or urine study within 7-days prior to the start of blinatumomab to rule out pregnancy. * Known allergy to blinatumomab * Participating in a concomitant Phase 1 or 2 study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects in Complete Remission (CR) | 1 or 2 Months depending on the number of cycles of blinatumomab | The primary efficacy variable is the percent of subjects that remain in Complete Remission (CR) after completion of 1 or 2 cycles of blinatumomab. Complete remission was defined as \<5% blasts in the bone marrow. Complete remission was further defined as minimal residual disease (MRD) positive (\>/= to 0.01%) or MRD negative (\<0.01%) as measured by flow cytometry of the bone marrow. |
| Percentage of Subjects Flow Cytometry (FC) -Minimal Residual Disease (MRD) Negative Defined as <0.01% Leukemia | 1 to 2 Months depending on the number of cycles of blinatumomab | The primary efficacy variable is the percent of subjects that become Flow Cytometry-MRD negative (FC-MRD negative) \< 0.01% after completion of 1 or 2 cycles of blinatumomab. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects That Are High-Throughput Deep Sequencing (HTS)-Minimal Residual Disease (MRD) Negative Defined as Undetectable | After completion of Blinatumomab bridging therapy (1 participant's course consisted of 1 cycle, the other participant's course consisted of 2 cycles) | The percent of subjects that achieve MRD negative by molecular High-Throughput Deep Sequencing (HTS-MRD negative) (MRD undetectable) after completion of Blinatumomab bridging therapy, which may consist of 1 to 2 cycles of Blinatumomab. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Blinatumomab Up to 2 cycles of continuous infusion blinatumomab will be given based on the end of Cycle 1 disease response. Cycle 2 of blinatumomab can be given to subjects who have achieved remission (\< 5% marrow blasts) after Cycle 1 but have persistent disease identified by multi-parameter flow cytometry (minimal residual disease (MRD) positive ≥ 0.01%) after Cycle 1.
Blinatumomab: Blinatumomab will be given as a 28-day continuous infusion with 14-days in between Cycle 1 and Cycle 2 as per the package insert and FDA approved labeling.
Patient weight greater than or equal to 45kg will receive 28 mcg/day
Patient weight less than 45kg will receive 15 mcg/m2/day | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | Blinatumomab |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 14 years |
| CNS Status (from initial diagnosis) CNS I | 2 Participants |
| CNS Status (from initial diagnosis) CNS II | 0 Participants |
| CNS Status (from initial diagnosis) CNS III | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Peripheral White Blood Cell Count (from initial diagnosis) | 4.7 10*3 cells/mcL |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 2 |
| other Total, other adverse events | 0 / 2 |
| serious Total, serious adverse events | 0 / 2 |
Outcome results
Primary
Percentage of Subjects Flow Cytometry (FC) -Minimal Residual Disease (MRD) Negative Defined as <0.01% Leukemia
The primary efficacy variable is the percent of subjects that become Flow Cytometry-MRD negative (FC-MRD negative) \< 0.01% after completion of 1 or 2 cycles of blinatumomab.
Time frame: 1 to 2 Months depending on the number of cycles of blinatumomab
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinatumomab | Percentage of Subjects Flow Cytometry (FC) -Minimal Residual Disease (MRD) Negative Defined as <0.01% Leukemia | 100 percent of participants FC-MRD Negative |
Primary
Percentage of Subjects in Complete Remission (CR)
The primary efficacy variable is the percent of subjects that remain in Complete Remission (CR) after completion of 1 or 2 cycles of blinatumomab. Complete remission was defined as \<5% blasts in the bone marrow. Complete remission was further defined as minimal residual disease (MRD) positive (\>/= to 0.01%) or MRD negative (\<0.01%) as measured by flow cytometry of the bone marrow.
Time frame: 1 or 2 Months depending on the number of cycles of blinatumomab
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinatumomab | Percentage of Subjects in Complete Remission (CR) | 100 percentage of patients MRD negative |
Secondary
Percentage of Subjects That Are High-Throughput Deep Sequencing (HTS)-Minimal Residual Disease (MRD) Negative Defined as Undetectable
The percent of subjects that achieve MRD negative by molecular High-Throughput Deep Sequencing (HTS-MRD negative) (MRD undetectable) after completion of Blinatumomab bridging therapy, which may consist of 1 to 2 cycles of Blinatumomab.
Time frame: After completion of Blinatumomab bridging therapy (1 participant's course consisted of 1 cycle, the other participant's course consisted of 2 cycles)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinatumomab | Percentage of Subjects That Are High-Throughput Deep Sequencing (HTS)-Minimal Residual Disease (MRD) Negative Defined as Undetectable | 100 percentage of patients MRD negative |