Acute Myelogenous Leukemia
Conditions
Brief summary
This is a phase II trial designed to test the safety and efficacy (complete response \[CR\]) of related donor HLA-haploidentical NK-cell based therapy for the treatment of acute myelogenous leukemia (AML). Patients with newly diagnosed AML who failed to achieve a complete remission (CR) after one or two standard induction attempts receive after a preparative regimen of cyclophosphamide and fludarabine a single infusion of CD3-/CD19- NK cells or CD3-/CD56+ NK cells followed by a short course of Interleukin-2 (IL-2) to facilitate NK cell survival and expansion.
Detailed description
This trial uses a Simon's two-stage design to estimate the complete remission rate at day +42 post NK cell infusion. The trial includes an initial randomized sub- study of 24 patients during stage 1 to choose which of the enriched NK cell products (CD3-/CD19- versus CD3-/CD56+) should be used to complete the trial based on successful in vivo NK cell expansion. This parameter is defined as 40% donor DNA and 40% of lymphocytes are NK cells at day 7 post infusion OR 20% donor DNA and 20% of lymphocytes are NK cells at day 14 post infusion. Twelve patients will be randomized to each product. Enrollment Plan: Stage 1: Enroll 24 patients with 1:1 randomization for NK cell processing (CD3-/CD19- versus CD3-/CD56+) Stage 2: Enroll an additional 17 patients using the optimal NK cell product identified during stage 1. If neither product achieves success at the end of stage 1, the study will stop and the platform redesigned
Interventions
DEVICEInterventions
CliniMACS® CD3 and CD19 Reagent System
Sponsors
Masonic Cancer Center, University of Minnesota
University of Chicago
Ohio State University
Miltenyi Biotec B.V. & Co. KG
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
In summary, the study will take place in two parts: Stage 1: Enroll 24 patients with 1:1 randomization for NK cell processing (CD3-/CD19- versus CD3-/CD56+) Stage 2: Enroll an additional 17 patients using the optimal NK cell product identified during stage 1. If neither product achieves success at the end of stage 1, the study will stop and the platform redesigned
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Newly diagnosed with acute myelogenous leukemia (except acute promyelocytic leukemia) and has failed one or two prior standard induction attempts. Failure is defined as: * ≥ 30% bone marrow blasts with at least 20% cellularity at mid-cycle bone marrow biopsy or residual AML on subsequent\ day 28 bone marrow biopsy by morphology, flow, PCR or FISH * Patients enrolling after only 1 failed induction attempt must meet at least one of the following additional eligibility criteria of high risk: ≥ 60 years of age adverse cytogenetics or molecular characteristics * AML that progressed out of myelodysplastic syndrome (MDS) is eligible if the patient did not receive treatment directed at the MDS * HLA-haploidentical related donor (aged 12 to 70 years) * ≥ 18, but \< 75 years of age * Karnofsky performance status ≥ 60% * Adequate organ function within 14 days of study registration (30 days for pulmonary and cardiac) as defined in section 4.5 * Ability to be off prednisone and other immunosuppressive drugs for at least 3 days prior to the NK cell infusion (excluding preparative regimen pre-meds) * No prior hematopoietic transplant * Not pregnant or lactating * Sexually active females of childbearing potential and males with partners of child bearing potential must agree to use birth control
Exclusion criteria
* Pregnant or lactating as the treatments used in this study includes drugs that are FDA Pregnancy Category D. * Acute leukemias of ambiguous lineage * AML that transformed from previously treated myelodysplastic syndromes * Prior hematopoietic transplant * New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that has not been cleared by Pulmonary. Infiltrates attributed to infection must be stable/improving (with associated clinical improvement) after 1 week of appropriate therapy (4 weeks for presumed or documented fungal infections) * Uncontrolled bacterial, fungal, or viral infections including HIV - chronic asymptomatic viral hepatitis is allowed * Known hypersensitivity to one or more of the study agents used
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Endpoint of the Study is Complete Remission (±3 Days) | On Day+42 (+/- 3 days) after NK cell infusion | Both the number of patients with leukemia in complete remission and the number of patients with leukemia not in complete remission will be reported. Leukemia remission status will be assessed according to the Revised Recommendations of The International Working Group (J Clin Oncol 21:4642-4649, 2003). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Secondary Endpoint is the Expansion and Persistence of NK Cells to be Used for the Remainder of the Study. | Day+7 to Day+42 after NK cell infusion | Successful expansion and persistence of NK cells is defined as ≥ 100 donor derived NK cells per µl blood. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CD3-/CD19- NK Cells Followed by IL-2 After a preparative regimen (day -6 to day -1) of fludarabine and cyclophosphamide participants receive allogeneic CD3-/CD19- NK Cell Product (NK Cell, CD3-/CD56+: ≥ 3-fold enrichment) on Day 0, followed by administration of interleukin-2 (after the NK cell infusion every other day for a total of 6 doses). | 0 |
| CD3-/CD56+ NK Cells Followed by IL-2 After a preparative regimen (day -6 to day -1) of fludarabine and cyclophosphamide participants receive allogeneic CD3-/CD56+ Purified NK Cell Product (NK Cell, CD3-/CD56+: ≥ 70%) on Day 0, followed by administration of interleukin-2 (after the NK cell infusion every other day for a total of 6 doses). | 1 |
| Total | 1 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | CD3-/CD56+ NK Cells Followed by IL-2 | Total |
|---|---|---|
| Age, Customized Participant age (years) | 52 years | 52 years |
| Race and Ethnicity Not Collected | — | 0 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 1 / 1 |
| other Total, other adverse events | 0 / 0 | 1 / 1 |
| serious Total, serious adverse events | 0 / 0 | 1 / 1 |
Outcome results
Primary
The Primary Endpoint of the Study is Complete Remission (±3 Days)
Both the number of patients with leukemia in complete remission and the number of patients with leukemia not in complete remission will be reported. Leukemia remission status will be assessed according to the Revised Recommendations of The International Working Group (J Clin Oncol 21:4642-4649, 2003).
Time frame: On Day+42 (+/- 3 days) after NK cell infusion
Population: As a result of poor subject accrual (n=1), statistically relevant efficacy data cannot be defined according to the protocol.
Secondary
The Secondary Endpoint is the Expansion and Persistence of NK Cells to be Used for the Remainder of the Study.
Successful expansion and persistence of NK cells is defined as ≥ 100 donor derived NK cells per µl blood.
Time frame: Day+7 to Day+42 after NK cell infusion
Population: As a result of poor subject accrual (n=1), statistically relevant efficacy data cannot be defined according to the protocol.