Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, Biphenotypic/Undifferentiated Leukemia, Chronic Myelogenous Leukemia, Myelodysplasia, Relapsed Large Cell Lymphoma, Mantle Cell Lymphoma, Hodgkin Lymphoma, Burkitt Lymphoma, Relapsed T-Cell Lymphoma, Lymphoplasmacytic Lymphoma
Conditions
Keywords
AML, ALL, CML, MCL
Brief summary
This is an single arm, open label, interventional phase II trial evaluating the efficacy of umbilical cord blood (UCB) hematopoietic stem and progenitor cells (HSPC) expanded in culture with stimulatory cytokines (SCF, Flt-3L, IL-6 and thromopoietin) on lympho-hematopoietic recovery. Patients will receive a uniform myeloablative conditioning and post-transplant immunoprophylaxis.
Interventions
25 mg/m2 IV over 1 hour (\<10 kg: 0.83 mg/kg IV over 1 hour)
60 mg/kg IV over 2 hours
DRUGTotal Body Irradiation (TBI)
165 cGy twice daily
DRUGTacrolimus (Tac)
Tacrolimus will start day -3 and will be administered as a continuous IV infusion at a starting dose of 0.03 mg/kg/day. Goal trough levels will be 10-15 ng/mL for the first 14 days post-transplant and then decreased to a goal of 5-10 ng/ml thereafter.
DRUGMycophenolate Mofetil (MMF)
MMF 3 gram/day IV/PO for adult patients divided in 2 or 3 doses. Pediatric patients will receive MMF at the dose of 15 mg/kg/dose (max 1 gram per dose) every 8 hours beginning day -3.
5 ug/kg/d until the absolute neutrophil count (ANC) is \>2500/uL for 2 consecutive days
DRUGBusulfan (BU)
BU IV once daily with dose based on Pharmacokinetics (PK) calculator over 3 hours
DRUGMelphalan
50 mg/m2/day (1.7 mg/kg/day if \< 10 kg) IV over 30 min
DRUGMGTA 456 Infusion
The target cell dose is \>10 x 106 CD34/kg with a maximum TNC 2.7 x 108/kg for children (\<18 years) and 8.1 × 108 cells/kg \[expanded product only\] for adults based on the highest cell dose windows evaluated in prior studies.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 55 Years
Healthy volunteers
No
Inclusion criteria
Age, Unit Cell Dose and HLA Match Criteria * Subjects must be ≤55 years of age * Subjects must weigh \>11 kg * Subjects must have a partially HLA matched UCB unit with a pre-cryopreserved TNC dose \>1.0 x 107 per kilogram recipient weight. HLA matching is initially based on a minimum of 5 of 8 HLA alleles at high resolution A, B, C, DRB1 typing; searches will be performed according to the current Magenta Cord Blood Search Algorithm. Eligible Diseases: * Acute myelogenous leukemia (AML) in morphological complete remission with: * Minimal residual disease (MRD) by flow cytometry, or * Intermediate to high risk leukemia in first (CR1) based on institutional criteria, eg. not favorable risk AML which is defined as having one of the following: * t(8,21) without cKIT mutation * inv(16) or t(16;16) without cKIT mutation * Normal karyotype with mutated NPM1 but FLT3-ITD wild type * Normal karyotype with double mutated CEBPA * Acute promyelocytic leukemia (APL) in first molecular remission at the end of consolidation * Any second or subsequent CR, or * Secondary AML with prior malignancy that has been in remission for at least 12 months. * Acute lymphocytic leukemia (ALL) at the following stages: * High risk first morphological, cytogenetic and molecular CR with: * MRD by flow cytometry, or * Diagnosis of Philadelphia chromosome (Ph)+ ALL, or * MLL rearrangement at diagnosis with slow early response at Day 14, or * Hypodiploidy (\< 44 chromosomes or DNA index \< 0.81) at diagnosis, or * End of induction M3 bone marrow, or * End of induction M2 with M2-3 at Day 42. * High risk second CR based on institutional criteria (eg, for children, bone marrow relapse \<36 months from induction or T-lineage bone marrow relapse or very early isolated central nervous system (CNS) relapse \<6 months from diagnosis, or slow re-induction (stage M2-3 at day 28 after induction) regardless of length remission. All patients with MRD by flow cytometry. * Any third or subsequent CR. * Secondary ALL * Biphenotypic/undifferentiated leukemia in morphological, cytogenetic and molecular CR . * Chronic Myelogenous Leukemia (CML) in high risk first chronic phase (failure of two tyrosine kinase inhibitors (TKI) or TKI intolerance), accelerated phase or second chronic phase. * Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt \<5% blasts) or other high risk features, including multiple cytopenias, high risk cytogenetics or lack of response to standard therapy.. * Relapsed large-cell lymphoma, mantle-cell lymphoma and Hodgkin lymphoma that is chemotherapy sensitive and ineligible for an autologous transplant. * Burkitt's lymphoma in CR2 or subsequent CR. * Relapsed T-cell lymphoma that is chemotherapy sensitive in CR/PR that is ineligible for an autologous transplant. Organ Specific Inclusion Criteria * Karnofsky score ≥70 (16 years and older), Lansky play score \>50 (children 2-16 years, or 'adequate' score for children \<2 years, as detailed in Appendix II. * Adequate organ function defined as: * Renal: Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then creatinine clearance \>40 ml/min or GFR ≥70 mL/min/1.73 m2.normal for age * Hepatic: Bilirubin \<3x upper limit of normal (ULN) and AST, ALT and alkaline phosphatase \<5x ULN. * Pulmonary function: DLCO, FEV1, FEC (diffusion capacity) \>5030% of predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation \>95% on room air. * Cardiac: No uncontrolled arrhythmia and left ventricular ejection fraction at rest must be \>3545%. * Available 'back-up' HSPC graft (e.g, second UCB unit, haploidentical related donor). * Females of child bearing potential and sexually active males must agree to use adequate birth control during study treatment. * Voluntary written consent signed (adult or parental) before performance of any study-related procedure not part of normal medical care.
Exclusion criteria
* Patients with a HLA matched sibling donor or a HLA matched unrelated donor who is available for marrow or peripheral blood stem cell collection at the desired time of transplant. * Pregnant or breast feeding. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Females of childbearing potential must have a blood test or urine study within 14 days prior to study enrollment to rule out pregnancy. * Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology. * Active bacterial, viral or fungal infection (currently taking medication and persistence of clinical signs and symptoms) with a minimum of 4 weeks of anti-fungal treatment * Prior autologous or allogeneic transplant. * Other active malignancy. * Subjects \>2 3 years of age unable to receive TBI 1320 cGy due to extensive prior therapy including \>12 months alkylator therapy or \>6 months alkylator therapy with extensive radiation, or prior Y-90 ibritumomab (Zevalin) or I-131 tostumomab (Bexxar), as part of their salvage therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Neutrophil Recover | Day 14 | Percentage of participants with neutrophil recovery by day 14 after transplantation in recipients of MGTA-456. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Graft Failure | 2 Years | Incidence of secondary graft failure |
| Platelet Recovery | Day 42 | Incidence of platelet recovery at day 42 |
| Treatment Related Mortality (TRM) | 6 Months | Incidence of TRM at 6 months |
| Grades II-IV Acute GVHD | Day 100 | Incidence of grades II-IV acute GVHD at day 100 |
| Grades III-IV Acute GVHD | Day 100 | Incidence of grades III-IV acute GVHD at day 100 |
| Number of Days Alive Without Hospitalization | Day 0 and Day 100 | Number of days alive without hospitalization between days 0 and 100 after transplantation |
| Relapse | 2 Years | Incidence of relapse at 2 years |
| Non-catheter Associated Bacterial Infections | Day 100 | Incidence of non-catheter associated bacterial infections by day 100 |
| Overall Survival (OS) | 2 Years | Incidence of overall survival (OS) at 2 years |
| Event-Free Survival (EFS) | 2 Years | Incidence of event-free survival (EFS) at 2 years |
| Chronic GVHD | 1 Year | Incidence of chronic GVHD at 1 year |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FLU, CY, TBI + MGTA-456 Infusion All patients aged 3-55 years will be conditioned with cyclophosphamide (CY) 120 mg/kg total dose, fludarabine (FLU) 75 m/m2 total dose and total body irradiation (TBI) 1320 cGy total dose as well as tacrolimus (Tac) and mycophenolate mofetil (MMF) immunoprophylaxis and granulocyte-colony stimulating factor (G-CSF) | 16 |
| BU,FLU, MEL + MGTA-456 Infusion All young children \<3 years of age at the time of diagnosis will receive MGTA-456 on the day of transplantation after a non-TBI containing myeloablative conditioning as TBI may have a damaging effect on brain development in the very young child. All patients aged 0-3 years will be conditioned with busulfan (BU), FLU and melphalan (MEL) as well as Tac/MMF immunoprophylaxis and G-CSF | 2 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Non-treatment | 4 | 0 |
Baseline characteristics
| Characteristic | Total | FLU, CY, TBI + MGTA-456 Infusion | BU,FLU, MEL + MGTA-456 Infusion |
|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 5 Participants | 2 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 11 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 13 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 10 Participants | 0 Participants |
| Region of Enrollment United States | 18 participants | 16 participants | 2 participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 1 Participants |
| Sex: Female, Male Male | 12 Participants | 11 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 16 | 2 / 2 |
| other Total, other adverse events | 0 / 16 | 0 / 2 |
| serious Total, serious adverse events | 0 / 16 | 0 / 2 |
Outcome results
Primary
Percentage of Participants With Neutrophil Recover
Percentage of participants with neutrophil recovery by day 14 after transplantation in recipients of MGTA-456.
Time frame: Day 14
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FLU, CY, TBI + MGTA-456 Infusion | Percentage of Participants With Neutrophil Recover | 31 Percentage of participants |
| BU,FLU, MEL + MGTA-456 Infusion | Percentage of Participants With Neutrophil Recover | 50 Percentage of participants |
Secondary
Chronic GVHD
Incidence of chronic GVHD at 1 year
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FLU, CY, TBI + MGTA-456 Infusion | Chronic GVHD | 13 Percentage of participants |
| BU,FLU, MEL + MGTA-456 Infusion | Chronic GVHD | 0 Percentage of participants |
Secondary
Event-Free Survival (EFS)
Incidence of event-free survival (EFS) at 2 years
Time frame: 2 Years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FLU, CY, TBI + MGTA-456 Infusion | Event-Free Survival (EFS) | 69 Percentage of participants |
| BU,FLU, MEL + MGTA-456 Infusion | Event-Free Survival (EFS) | 0 Percentage of participants |
Secondary
Grades III-IV Acute GVHD
Incidence of grades III-IV acute GVHD at day 100
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FLU, CY, TBI + MGTA-456 Infusion | Grades III-IV Acute GVHD | 19 Percentage of participants |
| BU,FLU, MEL + MGTA-456 Infusion | Grades III-IV Acute GVHD | 0 Percentage of participants |
Secondary
Grades II-IV Acute GVHD
Incidence of grades II-IV acute GVHD at day 100
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FLU, CY, TBI + MGTA-456 Infusion | Grades II-IV Acute GVHD | 25 Percentage of participants |
| BU,FLU, MEL + MGTA-456 Infusion | Grades II-IV Acute GVHD | 0 Percentage of participants |
Secondary
Non-catheter Associated Bacterial Infections
Incidence of non-catheter associated bacterial infections by day 100
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FLU, CY, TBI + MGTA-456 Infusion | Non-catheter Associated Bacterial Infections | 6 Percentage of participants |
| BU,FLU, MEL + MGTA-456 Infusion | Non-catheter Associated Bacterial Infections | 0 Percentage of participants |
Secondary
Number of Days Alive Without Hospitalization
Number of days alive without hospitalization between days 0 and 100 after transplantation
Time frame: Day 0 and Day 100
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FLU, CY, TBI + MGTA-456 Infusion | Number of Days Alive Without Hospitalization | 67.5 Days |
| BU,FLU, MEL + MGTA-456 Infusion | Number of Days Alive Without Hospitalization | 33 Days |
Secondary
Overall Survival (OS)
Incidence of overall survival (OS) at 2 years
Time frame: 2 Years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FLU, CY, TBI + MGTA-456 Infusion | Overall Survival (OS) | 69 Percentage of participants |
| BU,FLU, MEL + MGTA-456 Infusion | Overall Survival (OS) | 0 Percentage of participants |
Secondary
Platelet Recovery
Incidence of platelet recovery at day 42
Time frame: Day 42
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FLU, CY, TBI + MGTA-456 Infusion | Platelet Recovery | 56 Percentage of participants |
| BU,FLU, MEL + MGTA-456 Infusion | Platelet Recovery | 50 Percentage of participants |
Secondary
Relapse
Incidence of relapse at 2 years
Time frame: 2 Years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FLU, CY, TBI + MGTA-456 Infusion | Relapse | 25 Percentage of participants |
| BU,FLU, MEL + MGTA-456 Infusion | Relapse | 50 Percentage of participants |
Secondary
Secondary Graft Failure
Incidence of secondary graft failure
Time frame: 2 Years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FLU, CY, TBI + MGTA-456 Infusion | Secondary Graft Failure | 37.5 Percentage of participants |
| BU,FLU, MEL + MGTA-456 Infusion | Secondary Graft Failure | 0 Percentage of participants |
Secondary
Treatment Related Mortality (TRM)
Incidence of TRM at 6 months
Time frame: 6 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FLU, CY, TBI + MGTA-456 Infusion | Treatment Related Mortality (TRM) | 6 Percentage of participants |
| BU,FLU, MEL + MGTA-456 Infusion | Treatment Related Mortality (TRM) | 50 Percentage of participants |