NK Cell Based Non-Myeloablative Transplantation in Acute Myeloid Diseases
Sponsor
Masonic Cancer Center, University of Minnesota (Other)
Overall Status
Completed
CT.gov ID
NCT01370213
Collaborator
(none)
25
4
2
67
6.3
0.1
Study Details
Study Description
Brief Summary
This is a phase II multi-institutional therapeutic study of NK-cell based nonmyeloablative haploidentical transplantation for the treatment of high-risk acute myeloid diseases. Enrollment will use a two-stage design. Stage 1 will enroll 15 patients unless an early stopping rule is met. If 9 or more of these first 15 patients achieve leukemia free neutrophil engraftment at day +28 accrual will move to stage 2. In stage 2, an additional 28 patients will be enrolled for a total of 43 patients. Patients will be followed for disease response for 2 years.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
A reduced intensity conditioning using Fludara, Cytoxan, and irradiation will start on day -22, followed by infusion of donor NK (natural killer) cells on day-17, 6 doses of interleukin-2 (IL-2) to promote NK expansion (day -17 to day -7), 2 doses of ATG for additional immunosuppression to promote engraftment (day -5 to -4), and infusion of a TCR α/β-depleted same donor graft on day 0.
Study Design
Study Type:
Interventional
Actual Enrollment
:
25 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Multi-Center Phase II Trial of NK Cell Based Non-Myeloablative Haploidentical Transplantation for Patients With High-Risk Acute Myeloid Diseases
Study Start Date
:
Sep 1, 2011
Actual Primary Completion Date
:
Apr 1, 2016
Actual Study Completion Date
:
Apr 1, 2017
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: CD34 Schema - High-Risk Acute Myeloid Disease Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and filgrastim mobilized CD34+ selected peripheral blood stem cell graft from the same donor. |
Drug: Preparative Regimen
Preparative Regimen:
1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant, 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pretransplant, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pretransplant,
Other Names:
Biological: NK Cells
CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pretransplant.
Other Names:
Drug: Interleukin-2
Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion
Other Names:
Biological: CD34 Graft/Anti-thymocyte globulin
Single donor filgrastim mobilized CD34+ selected peripheral blood stem cell graft (minimum cell dose of 5 x 10^6/kg) on day 0. Rabbit anti-thymocyte globulin (ATG) will be administered on day -1 (0.5 mg/kg) and day +1 and +2 (2.5 mg/kg) pretransplant per institutional guidelines. ATG dosing not identical for all patients.
Other Names:
|
| Experimental: TCRα/β Schema - High-Risk Acute Myeloid Disease Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and same donor TCR α/β-depleted cells infusion. |
Drug: Preparative Regimen
Preparative Regimen:
1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant, 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pretransplant, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pretransplant,
Other Names:
Biological: NK Cells
CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pretransplant.
Other Names:
Drug: Interleukin-2
Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion
Other Names:
Biological: Donor TCR α/β-depleted Graft/ATG
Single donor TCR α/β-depleted filgrastim-mobilized peripheral blood stem cells (PBSC) graft (minimum cell dose of 5 x 10^6/kg) on day 0. ATG will be administered on days -6 and -5 (3mg/kg) for most patients.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Donor Neutrophil Engraftment [Day 28]
The rate of donor neutrophil engraftment in the absence of leukemia at day +28 will be determined. Successful neutrophil engraftment is defined as an absolute donor-derived neutrophil count of >500 cells/μl. Leukemia free is defined as <5% bone marrow blasts, absence of blasts with Auer rods; absence of extramedullary disease; but cytogenetic or molecular minimal residual disease is allowed.
Secondary Outcome Measures
- Number of Participants With Disease Free Survival [At 6 Months]
- Number of Participants With Treatment Related Mortality (TRM) [At 6 Months]
Cumulative incidence will be used to estimate TRM.
- Number of Participants Who Relapse [2 Years]
Cumulative incidence will be used to estimate relapse.
- Number of Participants With Early In Vivo Expansion of Natural Killer (NK) Cells [Day 12]
Successful in vivo donor NK cell expansion will be defined by measuring an absolute circulating donor-derived NK cell count of >100 cells/μl in patient's peripheral blood 12 days after infusion.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 75 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
- Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)
RAEB-1 or RAEB-2 fitting within one of the following disease groups:
-
Primary induction failure (PIF): Patients who have not achieved a complete remission (CR) after two induction cycles of cytotoxic therapy (i.e. 7+ 3, MEC, FLAG, etc.) and having ≤ 10,000 absolute circulating blasts measured at least 21 days from prior therapy. Hydroxyurea may be used to control blasts count. Demethylating agents do not count as induction therapy; however early re-induction therapy based on residual disease on a day 14 BM will count as a 2nd cycle
-
Relapsed Disease with low disease burden (AML or MDS with ≤ 10,000 absolute circulating blasts. No re-induction attempts are required, but a maximum of 2 reinduction attempts are allowed to be eligible.
-
CR3 or greater: This will include CRp defined as CR without platelet recovery to 100,000/mcL.
-
CR1 or CR2 with high risk features: Includes therapy induced, prior MDS or MPD, high risk cytogenetic or molecular phenotype with no available donor (sibling or unrelated adult)
Patients with known prior central nervous system (CNS) involvement are eligible provided that it has been treated and CSF is clear for at least 2 weeks prior to enrollment. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment.
-
Available related HLA-haploidentical adult donor by at least Class I serologic typing at the A&B locus
-
Karnofsky score > 50%
-
Adequate organ function within 28 days of study registration defined as:
-
Hepatic: AST ≤ 3 x upper limit of institutional normal, total bilirubin ≤ 2.0 mg/dl
-
Renal: estimated glomerular filtration rate (GFR) ≥ 50 mL/min/1.73m^2
-
Pulmonary: Oxygen saturation ≥ 90% on room air and DLCOcor ≥ 40%
-
Cardiac: Ejection Fraction ≥ 35% and no uncontrolled angina, severe uncontrolled ventricular or arterial arrhythmias, or any evidence of acute ischemia or active conduction system abnormalities (rate controlled atrial fibrillation is not an exclusion)
-
Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to NK cell infusion (except for those prescribed as part of the study)
-
Women of child bearing potential must have a negative pregnancy test within 28 days prior to study registration and agree to use adequate birth control during study treatment
-
Voluntary written consent
Exclusion Criteria:
-
Biphenotypic leukemia
-
Allogeneic transplant for AML within previous 6 months
-
New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that has not been evaluated with bronchoscopy, if feasible. 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 any of the study agents
-
Received any investigational drugs within the 14 days before 1st dose of fludarabine
-
Requires agents other than hydroxyurea to control blast count
Donor Selection:
-
Related donor (sibling, parent, offspring, parent or offspring of an HLA identical sibling) 12-75 years of age. (It is recognized individual institutions may have differing donor age guidelines. This is acceptable as long as no donor is younger than 12 years or older than 75 years).
-
Body weight of at least 40 kilograms
-
In general good health as determined by the medical provider
-
HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A&B locus
-
Able and willing to have up to 4 separate apheresis collections
-
Not pregnant
-
Voluntary written consent
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Emory University | Atlanta | Georgia | United States | 30322 |
| 2 | University of Minnesota, Masonic Cancer Center | Minneapolis | Minnesota | United States | 55455 |
| 3 | Washington University | Saint Louis | Missouri | United States | 63110 |
| 4 | Ohio State University | Columbus | Ohio | United States | 43210 |
Sponsors and Collaborators
- Masonic Cancer Center, University of Minnesota
Investigators
- Principal Investigator: Jeffrey Miller, M.D., Masonic Cancer Center, University of Minnesota
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT01370213
Other Study ID Numbers:
- 2011LS027
- MT2011-05
First Posted:
Jun 9, 2011
Last Update Posted:
May 13, 2020
Last Verified:
Apr 1, 2020
Keywords provided by Masonic Cancer Center, University of Minnesota
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | CD34+ Selection Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion and ATG at Different Time Schema |
|---|---|---|---|
| Arm/Group Description | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and filgrastim mobilized CD34+ selected peripheral blood stem cell graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5 (3 mg/kg/day) pre-tx. | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | PPatients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered (3 mg/kg/day) pre-tx on different days per institutional guidelines |
| Period Title: Overall Study | |||
| STARTED | 7 | 17 | 1 |
| COMPLETED | 6 | 15 | 1 |
| NOT COMPLETED | 1 | 2 | 0 |
Baseline Characteristics
| Arm/Group Title | CD34+ Selection Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion and ATG at Different Time Schema | Total |
|---|---|---|---|---|
| Arm/Group Description | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and filgrastim mobilized CD34+ selected peripheral blood stem cell graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered (3 mg/kg/day) pre-tx on different days per institutional guidelines | Total of all reporting groups |
| Overall Participants | 7 | 17 | 1 | 25 |
| Age (Count of Participants) | ||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
3
42.9%
|
11
64.7%
|
0
0%
|
14
56%
|
| >=65 years |
4
57.1%
|
6
35.3%
|
1
100%
|
11
44%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
1
14.3%
|
5
29.4%
|
0
0%
|
6
24%
|
| Male |
6
85.7%
|
12
70.6%
|
1
100%
|
19
76%
|
Outcome Measures
| Title | Number of Participants With Donor Neutrophil Engraftment |
|---|---|
| Description | The rate of donor neutrophil engraftment in the absence of leukemia at day +28 will be determined. Successful neutrophil engraftment is defined as an absolute donor-derived neutrophil count of >500 cells/μl. Leukemia free is defined as <5% bone marrow blasts, absence of blasts with Auer rods; absence of extramedullary disease; but cytogenetic or molecular minimal residual disease is allowed. |
| Time Frame | Day 28 |
Outcome Measure Data
| Analysis Population Description |
|---|
| CD34 Schema - out of 7 patients, 2 patients were NA due to leukemia, 1 died, and 1 was not evaluable so 3 were analyzed (4 were not). TCRα/β Schema - out of 17 patients, 6 patients were NA due to leukemia, 2 were not evaluable. TCRα/β Schema + ATG - 1 patient was given ATG at a different time so their results were reported separately |
| Arm/Group Title | CD34+ Selection Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion and ATG at Different Time Schema |
|---|---|---|---|
| Arm/Group Description | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and filgrastim mobilized CD34+ selected peripheral blood stem cell graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on different days per institutional guidelines |
| Measure Participants | 3 | 9 | 1 |
| Count of Participants [Participants] |
3
42.9%
|
7
41.2%
|
1
100%
|
| Title | Number of Participants With Disease Free Survival |
|---|---|
| Description | |
| Time Frame | At 6 Months |
Outcome Measure Data
| Analysis Population Description |
|---|
| CD34 Schema - of 7, 1 patient was not evaluable. TCRα/β Schema - of 17, 15 patients evaluable for DFS , 2 patients were not evaluable. TCRα/β Schema + ATG at different time - 1 patient given ATG at different time so results reported separately |
| Arm/Group Title | CD34+ Selection Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion and ATG at Different Time Schema |
|---|---|---|---|
| Arm/Group Description | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and filgrastim mobilized CD34+ selected peripheral blood stem cell graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on different days per institutional guidelines |
| Measure Participants | 6 | 15 | 1 |
| Count of Participants [Participants] |
1
14.3%
|
6
35.3%
|
1
100%
|
| Title | Number of Participants With Treatment Related Mortality (TRM) |
|---|---|
| Description | Cumulative incidence will be used to estimate TRM. |
| Time Frame | At 6 Months |
Outcome Measure Data
| Analysis Population Description |
|---|
| CD34 Schema - of 7 patients, 1 was not evaluable. TCRα/β Schema - of 17 patients, 8 died of disease, 2 did not have TRM at 6 months, 2 were not evaluable. TCRα/β Schema + ATG at different time - 1 patient given ATG at different time, results reported separately. |
| Arm/Group Title | CD34+ Selection Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion and ATG at Different Time Schema |
|---|---|---|---|
| Arm/Group Description | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and filgrastim mobilized CD34+ selected peripheral blood stem cell graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on different days per institutional guidelines |
| Measure Participants | 6 | 15 | 1 |
| Count of Participants [Participants] |
2
28.6%
|
5
29.4%
|
0
0%
|
| Title | Number of Participants Who Relapse |
|---|---|
| Description | Cumulative incidence will be used to estimate relapse. |
| Time Frame | 2 Years |
Outcome Measure Data
| Analysis Population Description |
|---|
| CD34 Graft - of 7, 1 patient not evaluable, 2 patients did not clear disease, 2 died before 2 years. TCRα/β Schema - of 17, 7 didn't achieve remission, 2 died before 2 years, 2 were not evaluable. TCRα/β Schema + ATG at different time - 1 patient received ATG at different time, results reported separately. |
| Arm/Group Title | CD34+ Selection Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion and ATG at Different Time Schema |
|---|---|---|---|
| Arm/Group Description | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and filgrastim mobilized CD34+ selected peripheral blood stem cell graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on different days per institutional guidelines |
| Measure Participants | 2 | 6 | 1 |
| Count of Participants [Participants] |
2
28.6%
|
6
35.3%
|
0
0%
|
| Title | Number of Participants With Early In Vivo Expansion of Natural Killer (NK) Cells |
|---|---|
| Description | Successful in vivo donor NK cell expansion will be defined by measuring an absolute circulating donor-derived NK cell count of >100 cells/μl in patient's peripheral blood 12 days after infusion. |
| Time Frame | Day 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| CD34 Graft - of 7, 1 NA due to missing data/tests not performed, 1 not evaluable. TCRα/β Schema - of 17 patients, 15 were evaluable for outcome measure criteria, 2 were not evaluable. TCRα/β Schema + ATG at different time - 1 given ATG at different time, results reported separately. |
| Arm/Group Title | CD34+ Selection Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion Schema : High-Risk Acute Myeloid Disease | TCR α/β Depletion and ATG at Different Time Schema |
|---|---|---|---|
| Arm/Group Description | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and filgrastim mobilized CD34+ selected peripheral blood stem cell graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and TCR α/β-depleted haploidentical graft from the same donor. Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant (pre-tx), 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pre-tx, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pre-tx NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pre-tx Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on day -6 (0.5 mg/kg) and day -5(3 mg/kg/day) pre-tx. | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and same donor TCR α/β-depleted cells infusion. Preparative Regimen: Preparative Regimen: 1) fludarabine 40 mg/m^2 x 4 doses on Days -22 through -19 pretransplant, 2) cyclophosphamide 50 mg/kg x 2 doses on Days -20 and -19 pretransplant, 3) total body irradiation 200 cGy twice a day (BID) (at least 6 hours apart) on Day -18 pretransplant, NK Cells: CD3^- CD19^- selected, interleukin-2 (IL-2) activated, haploidentical donor natural killer (NK) cells infused on Day -17 pretransplant. Interleukin-2: Interleukin-2 6 million units (MU) subcutaneously (SQ) every other day for 6 doses beginning evening of NK cell infusion Anti-thymocyte globulin: rabbit anti-thymocyte globulin will be administered on different days per institutional guidelines |
| Measure Participants | 5 | 15 | 1 |
| Count of Participants [Participants] |
1
14.3%
|
6
35.3%
|
1
100%
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | High-Risk Acute Myeloid Disease | |
| Arm/Group Description | Patients with high risk acute myeloid disease treated with preparative regimen including Fludara, Cytoxan and total body irradiation followed by haploidentical donor NK cells, Interleukin-2, rabbit anti-thymocyte globulin, and same donor TCR α/β-depleted cells infusion. Data is reported in a combined manner because the AE data was originally reported in the older database as a single arm. Data was separated out for the outcome measures because there was still access to this data externally. At this point, we are unable to separate the individual instance of adverse events by arm because we cannot access the source data. | |
All Cause Mortality |
||
| High-Risk Acute Myeloid Disease | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| High-Risk Acute Myeloid Disease | ||
| Affected / at Risk (%) | # Events | |
| Total | 19/25 (76%) | |
| Blood and lymphatic system disorders | ||
| Disseminated Intravascular Coagulation | 1/25 (4%) | |
| Cardiac disorders | ||
| Acute Coronary Syndrome | 1/25 (4%) | |
| Atrial Fibrillation | 1/25 (4%) | |
| Heart Failure | 1/25 (4%) | |
| Pericardial Effusion | 1/25 (4%) | |
| Eye disorders | ||
| Retrobulbar Optic Neuritis | 1/25 (4%) | |
| Gastrointestinal disorders | ||
| Nausea | 1/25 (4%) | |
| General disorders | ||
| Fever | 1/25 (4%) | |
| Graft Failure | 1/25 (4%) | |
| Hypocellular Bone Marrow | 2/25 (8%) | |
| Multi-Organ Failure | 1/25 (4%) | |
| Disease Relapse | 1/25 (4%) | |
| Infections and infestations | ||
| Cytomegalovirus | 3/25 (12%) | |
| Sepsis | 2/25 (8%) | |
| Nervous system disorders | ||
| Encephalopathy | 1/25 (4%) | |
| Renal and urinary disorders | ||
| Acute Kidney Injury | 3/25 (12%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Adult Respiratory Distress Syndrome | 1/25 (4%) | |
| Hypoxia | 1/25 (4%) | |
| Pneumonitis | 2/25 (8%) | |
| Respiratory Failure | 2/25 (8%) | |
| Upper Respiratory Infection | 1/25 (4%) | |
| Skin and subcutaneous tissue disorders | ||
| Maculo-Papular Rash | 1/25 (4%) | |
| Vascular disorders | ||
| Hypotension | 2/25 (8%) | |
Other (Not Including Serious) Adverse Events |
||
| High-Risk Acute Myeloid Disease | ||
| Affected / at Risk (%) | # Events | |
| Total | 25/25 (100%) | |
| Blood and lymphatic system disorders | ||
| Febrile Neutropenia | 18/25 (72%) | |
| Cardiac disorders | ||
| Acute Coronary Syndrome | 1/25 (4%) | |
| Atrial Fibrillation | 2/25 (8%) | |
| Sinus Tachycardia | 1/25 (4%) | |
| Eye disorders | ||
| Eye Irritation | 1/25 (4%) | |
| Vision Changes, NOS | 1/25 (4%) | |
| Gastrointestinal disorders | ||
| Abdominal Pain | 2/25 (8%) | |
| Dyspepsia | 1/25 (4%) | |
| Epigastric Pain | 2/25 (8%) | |
| Nausea | 3/25 (12%) | |
| Vomiting - Intermittent | 1/25 (4%) | |
| Anorexia | 1/25 (4%) | |
| Ascites | 1/25 (4%) | |
| Gastrointestinal Bleeding | 1/25 (4%) | |
| General disorders | ||
| Lethargy | 1/25 (4%) | |
| Chills | 24/25 (96%) | |
| Edema | 15/25 (60%) | |
| Erythema at Central Venous Catheter Site | 1/25 (4%) | |
| Fever | 19/25 (76%) | |
| Infusion Related Reaction | 16/25 (64%) | |
| Injection Site Reaction | 13/25 (52%) | |
| Infections and infestations | ||
| Eye Infection | 1/25 (4%) | |
| Infection, NOS | 1/25 (4%) | |
| Investigations | ||
| Creatinine Increased | 2/25 (8%) | |
| Weight Gain | 3/25 (12%) | |
| Musculoskeletal and connective tissue disorders | ||
| Back Pain | 3/25 (12%) | |
| Shoulder Pain | 1/25 (4%) | |
| Ankle Sprain | 1/25 (4%) | |
| Facial, Jaw, Parotid Pain | 1/25 (4%) | |
| Foot Pain | 1/25 (4%) | |
| Leg Weakness | 1/25 (4%) | |
| Nervous system disorders | ||
| Headache | 3/25 (12%) | |
| Psychiatric disorders | ||
| Vivid Dreams | 1/25 (4%) | |
| Renal and urinary disorders | ||
| Acute Kidney Injury | 2/25 (8%) | |
| Urinary Frequency | 1/25 (4%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea | 14/25 (56%) | |
| Hemoptysis | 1/25 (4%) | |
| Hypoxia | 14/25 (56%) | |
| Pneumonitis/Pulmonary Infiltrates | 5/25 (20%) | |
| Skin and subcutaneous tissue disorders | ||
| Maculo-Papular Rash | 1/25 (4%) | |
| Pustular Folliculitis, Scalp | 1/25 (4%) | |
| Skin Nodules | 1/25 (4%) | |
| Rash | 14/25 (56%) | |
| Vascular disorders | ||
| Hypertension | 23/25 (92%) | |
| Hypotension | 1/25 (4%) | |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Jeffrey Miller |
|---|---|
| Organization | Masonic Cancer Center, University of Minnesota |
| Phone | 612-626-4024 |
| mille011@umn.edu |
Responsible Party:
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT01370213
Other Study ID Numbers:
- 2011LS027
- MT2011-05
First Posted:
Jun 9, 2011
Last Update Posted:
May 13, 2020
Last Verified:
Apr 1, 2020