Acute Myelogenous Leukemia
Conditions
Keywords
AML, Relapsed, Refractory
Brief summary
A phase II trial of CD3/CD19 depleted, IL-15 activated, donor natural killer (NK) cells in adults and subcutaneous IL-15 given after a preparative regimen for the treatment of relapsed or refractory acute myelogenous leukemia (AML). The primary objective is to study the potential efficacy of NK cells and IL-15 to achieve complete remission while maintaining safety.
Interventions
BIOLOGICALIL-15
Preparative Regimen: Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4 (if \< 4 months from prior transplant, omit day -4 dose) IL-15 Activated Donor NK Cells: The apheresis product (collected day -1) will be enriched for NK cells with the large-scale CliniMacs® device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to remove B-lymphocytes. The NK cell enriched product will be activated by overnight incubation with10 ng/ml IL-15 under GMP conditions and infused on day 0. IL-15 to Facilitate NK Cell Survival and Expansion: IL-15 at 2 mcg/kg subcutaneously (SC) beginning day +1, once a day for 5 days followed by a 2 day rest, and then once a day for 5 days for 10 doses total
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
(Recipient): * Meets ONE of the following disease criteria: 1. Primary AML induction failure: no CR after 2 or more induction attempts 2. Relapsed AML or Secondary AML (from MDS or treatment related): not in CR after 1 or more cycles of standard re-induction therapy 3. AML relapsed \> 2 months after transplant: No re-induction required, and no more than 1 re-induction cycle is allowed. 4. Relapsed AML for patients \> 60 years of age the 1 cycle of standard chemotherapy is not required if either of the following criteria is met: * Relapse within 6 months of last chemotherapy * BM blast count \< 30% within 10 days of starting protocol therapy * Available related HLA-haploidentical donor (aged 14 to 75 years) by at least Class I serologic typing at the A&B locus * Karnofsky Performance Status ≥ 60% * Patients must have adequate organ within 14 days (28 days for pulmonary and cardiac) of study registration * Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to NK cell infusion (excluding preparative regimen pre-medications). * Agrees to use contraception prior to study entry and for the duration of study participation.
Exclusion criteria
(Recipient): * Bi-phenotypic acute leukemia. * Transplant \< 60 days prior to study enrollment. * Active autoimmune disease. * History of severe asthma * Uncontrolled intercurrent illness * New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that has not been evaluated with bronchoscopy * Pleural effusion large enough to be detectable on chest x-ray. * Pregnant women * History of HIV, active or chronic hepatitis B, hepatitis C or HTLV-I infection * Known hypersensitivity to any of the study agents used * Received investigational drugs within the 14 days of study registration. * Known active CNS involvement. Criteria For Initial Donor Selection: * Related donors (sibling, parent, offspring, parent or offspring of an HLA identical sibling). * 14-75 years of age. * At least 40 kilogram body weight. * In general good health as determined by the evaluating medical provider. * HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A&B locus. * Not pregnant. * Able and willing to undergo apheresis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| < 5% Marrow Blast, no Circulating Peripheral Blasts and Neutrophil Count of > 1 x 10^9/L | Day 42 post NK cell infusion | Without platelet recovery |
Secondary
| Measure | Time frame |
|---|---|
| In Vivo Expansion (>100) of NK Cells (Defined at CD56+/CD3- Lymphocytes) | Day 14 post NK cell infusion |
| Proportion of Patients Experiencing Grade, 3, 4, and 5 Toxicities (Assessed by CTCAE v. 4) | Days 1-5 and Days 8-12, 24 hours after the last IL-15 dose, Day +28, Day +42 |
| Treatment Related Mortality | 6 months post-therapy |
| Number of Subjects Achieving Complete Response, Defined as in Vivo Donor Derived NK Cell Expansion of > 100 Donor Derived NK Cells. | Day 42 post NK cell infusion |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Preparative Regimen and SubQ rHuIL-15 Preparative Regimen of Fludarabine and Cyclophosphamide
IL-15 Activation of Donor NK Cells:
IL-15 to Facilitate NK Cell Survival and Expansion
IL-15: Preparative Regimen:
Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4 (if \< 4 months from prior transplant, omit day -4 dose)
IL-15 Activated Donor NK Cells:
The apheresis product (collected day -1) will be enriched for NK cells with the large-scale CliniMacs® device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to remove B-lymphocytes. The NK cell enriched product will be activated by overnight incubation with10 ng/ml IL-15 under GMP conditions and infused on day 0.
IL-15 to Facilitate NK Cell Survival and Expansion:
IL-15 at 2 mcg/kg subcutaneously (SC) beginning day +1, once a day for 5 days followed by a 2 day rest, and then once a day for 5 days for 10 doses total | 17 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Preparative Regimen and SubQ rHuIL-15 |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 57 Years STANDARD_DEVIATION 14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 3 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Region of Enrollment United States | 17 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 17 |
| serious Total, serious adverse events | 12 / 17 |
Outcome results
Primary
< 5% Marrow Blast, no Circulating Peripheral Blasts and Neutrophil Count of > 1 x 10^9/L
Without platelet recovery
Time frame: Day 42 post NK cell infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preparative Regimen and SubQ rHuIL-15 | < 5% Marrow Blast, no Circulating Peripheral Blasts and Neutrophil Count of > 1 x 10^9/L | 5 Participants |
Secondary
In Vivo Expansion (>100) of NK Cells (Defined at CD56+/CD3- Lymphocytes)
Time frame: Day 14 post NK cell infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preparative Regimen and SubQ rHuIL-15 | In Vivo Expansion (>100) of NK Cells (Defined at CD56+/CD3- Lymphocytes) | 4 Participants |
Secondary
Number of Subjects Achieving Complete Response, Defined as in Vivo Donor Derived NK Cell Expansion of > 100 Donor Derived NK Cells.
Time frame: Day 42 post NK cell infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preparative Regimen and SubQ rHuIL-15 | Number of Subjects Achieving Complete Response, Defined as in Vivo Donor Derived NK Cell Expansion of > 100 Donor Derived NK Cells. | 1 Participants |
Secondary
Proportion of Patients Experiencing Grade, 3, 4, and 5 Toxicities (Assessed by CTCAE v. 4)
Time frame: Days 1-5 and Days 8-12, 24 hours after the last IL-15 dose, Day +28, Day +42
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preparative Regimen and SubQ rHuIL-15 | Proportion of Patients Experiencing Grade, 3, 4, and 5 Toxicities (Assessed by CTCAE v. 4) | 10 Participants |
Secondary
Treatment Related Mortality
Time frame: 6 months post-therapy
Population: 1 patient left the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Preparative Regimen and SubQ rHuIL-15 | Treatment Related Mortality | 2 Participants |