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Slow accrual
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This trial is proposes to build on our experience and is designed to maximize early (day 3-14) and late (day 60-71) donor-derived natural killer (NK) cell expansion and function in vivo. The proposed platform will allow us the unique opportunity to compare in vivo function from a transplanted umbilical cord blood (UCB) source (presumed to contain NK progenitors requiring "education" in the recipient).
This single center study will determine the feasibility and safety of using a myeloablative conditioning regimen followed (on day 0) by transplantation with double T-cell depleted (TCD) umbilical cord blood (UCB) units where the unit with fewer mononuclear cells (MNCs)/kg will be selected for overnight IL-2 activation prior to infusion. Beginning on day +3, post transplant IL-2 will be administered thrice weekly, not on consecutive days, for a total of 6 doses to expand UCB derived progenitor cells. Post transplant immune suppression prophylaxis will not be administered with the intent to lessen toxicity and allow allogeneic NK cells to function longer providing better anti-leukemic therapy. However if either UCB unit has more than 5% T-cells, the patient will not receive either course of IL-2. Beginning on day +60 after transplantation, a second course of IL-2 will be administered thrice weekly, not on consecutive days, for a total of 6 doses with the purpose of enhancing the in vivo expansion and education of NK cells derived from engrafting UCB cells.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Patients with Acute Myelogenous Leukemia | Experimental | Patients with chemotherapy refractory Acute Myelogenous Leukemia (AML) after a double T-cell depleted (TCD) umbilical cord blood (UCB) transplantation where the smaller unit is activated overnight in interleukin-2 (IL-2). IL-2 will be given three times weekly for 6 doses beginning on days+3 and days +60 to expand UCB-derived natural killer (NK) cells in vivo. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Allopurinol | Drug | On Day 8 pre-transplant, start hydration with allopurinol per standard of care. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Disease Free Survival | The primary endpoint is a disease free survival at 3 months in patients with chemotherapy refractory AML after a double T-cell depleted (TCD) umbilical cord blood (UCB) transplantation where one TCD unit is activated overnight in IL-2 followed by the administration of two courses of IL-2 three times a week for 6 doses beginning on day +3 and on day +60 to expand UCB-derived NK cells in vivo. | At 3 months |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of Graft Failure | Incidence of graft failure defined as an absolute neutrophil count of less than 500/uL and a bone marrow that is less than 5% cellular (marrow aplasia) | Day 42 |
| Incidence of Acute Graft-Versus-Host Disease |
Not provided
Inclusion Criteria:
Aged 2 to 45 years with acute myeloid leukemia (AML) who meet one of the following criteria:
Patients with prior central nervous system (CNS) involvement are eligible provided that it has been treated and is in remission. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the protocol.
Have acceptable organ function within 14 days of study registration defined as:
Karnofsky Performance Status ≥ 70% (≥ 16 years) or Lansky Play Score ≥ 50 (pediatrics < 16 years)
Women of childbearing 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.
All patients will be questioned about prior exposure to antibody therapy (including OKT3, rituximab, trastuzumab, and gemtuzumab) without affect to eligibility. Patients with prior exposure will have a blood sample collected for human antimouse antibody (HAMA). For patients with no prior antibody therapy exposure, no further action will be taken.
Voluntary written consent
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michael Verneris, M.D. | Masonic Cancer Center, University of Minnesota | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Masonic Cancer Center, University of Minnesota | Minneapolis | Minnesota | 55455 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Patients With Acute Myelogenous Leukemia | Allopurinol: start on Day -8 per institutional guidelines Fludarabine: give on Days -7, -6 and -5, 25 mg/m^2 intravenously (IV) Cyclophosphamide: give on Days -7 and -6, 60 mg/kg IV along with mesna per institutional guidelines Total body irradiation: give on Days -5, -4, -3, and -2, 165 cGy twice daily Double T-cell depleted umbilical cord blood transplantation with activation of one of the units in interleukin-2 (IL-2): give on Day 0 IL-2: start on Day +3 and Day +60, 9 MU subcutaneously three times weekly for 6 doses Alternate preparative therapy for patients not able to receive additional radiation Levetiracetam (Keppra): begin on Day -10 per institutional guidelines Busulfan: give Day -9 through Day -6, 0.8 mg/kg (1.1 mg/kg if <12 kg) IV every 6 hours Cyclophosphamide: give Day -5 through Day -2, 50 mg/kg/day IV along with mesna per institutional guidelines |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Patients With Acute Myelogenous Leukemia | Allopurinol: start on Day -8 per institutional guidelines Fludarabine: give on Days -7, -6 and -5, 25 mg/m^2 intravenously (IV) Cyclophosphamide: give on Days -7 and -6, 60 mg/kg IV along with mesna per institutional guidelines Total body irradiation: give on Days -5, -4, -3, and -2, 165 cGy twice daily Double T-cell depleted umbilical cord blood transplantation with activation of one of the units in interleukin-2 (IL-2): give on Day 0 IL-2: start on Day +3 and Day +60, 9 MU subcutaneously three times weekly for 6 doses Alternate preparative therapy for patients not able to receive additional radiation Levetiracetam (Keppra): begin on Day -10 per institutional guidelines Busulfan: give Day -9 through Day -6, 0.8 mg/kg (1.1 mg/kg if <12 kg) IV every 6 hours Cyclophosphamide: give Day -5 through Day -2, 50 mg/kg/day IV along with mesna per institutional guidelines |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Disease Free Survival | The primary endpoint is a disease free survival at 3 months in patients with chemotherapy refractory AML after a double T-cell depleted (TCD) umbilical cord blood (UCB) transplantation where one TCD unit is activated overnight in IL-2 followed by the administration of two courses of IL-2 three times a week for 6 doses beginning on day +3 and on day +60 to expand UCB-derived NK cells in vivo. | Posted | Number | participants | At 3 months |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Patients With Acute Myelogenous Leukemia | Allopurinol: start on Day -8 per institutional guidelines Fludarabine: give on Days -7, -6 and -5, 25 mg/m^2 intravenously (IV) Cyclophosphamide: give on Days -7 and -6, 60 mg/kg IV along with mesna per institutional guidelines Total body irradiation: give on Days -5, -4, -3, and -2, 165 cGy twice daily Double T-cell depleted umbilical cord blood transplantation with activation of one of the units in interleukin-2 (IL-2): give on Day 0 IL-2: start on Day +3 and Day +60, 9 MU subcutaneously three times weekly for 6 doses Alternate preparative therapy for patients not able to receive additional radiation Levetiracetam (Keppra): begin on Day -10 per institutional guidelines Busulfan: give Day -9 through Day -6, 0.8 mg/kg (1.1 mg/kg if <12 kg) IV every 6 hours Cyclophosphamide: give Day -5 through Day -2, 50 mg/kg/day IV along with mesna per institutional guidelines |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infections and infestations - Other, blood culture w/gram positive cocci and CMV | Infections and infestations |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| febrile neutropenia | Blood and lymphatic system disorders |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Michael R Verneris | University of Minnesota, Pediatrics Blood and Marrow Transplant | 612-626-2961 | verneris@umn.edu |
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| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D000493 | Allopurinol |
| C024352 | fludarabine |
| C042382 | fludarabine phosphate |
| D014916 | Whole-Body Irradiation |
| D011827 | Radiation |
| D003520 | Cyclophosphamide |
| D000077287 | Levetiracetam |
| D002066 | Busulfan |
| D036101 | Cord Blood Stem Cell Transplantation |
| D007376 | Interleukin-2 |
| ID | Term |
|---|---|
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Fludarabine | Drug | On Days 7, 6 and 5 pre-transplant, 25 mg/m^2 intravenously over 1 hour. |
|
|
| Total body irradiation | Radiation | On Days 5, 4, 3, and 2 pre-transplant, 165 cGy times 2 (330 cGy daily, 1320 total dose) according to the University Of Minnesota Blood and Marrow Transplant Program total body irradiation (TBI) guidelines. |
|
|
| Cyclophosphamide | Drug | On Days 7 and 6 pre-transplant, 60 mg/kg intravenously (IV) over 2 hours with a high volume fluid flush and mesna per institutional guidelines. Alternate Preparative Therapy For Patients Not Able To Receive TBI: Days 5, 4, 3 and 2 pre-transplant; 50 mg/kg/day IV over 2 hours. |
|
|
| Levetiracetam | Drug | Alternate Preparative Therapy for Patients Not Able to Receive Total Body Irradiation (TBI): Hydration therapy on Day 10 pre-transplant. |
|
|
| Busulfan | Drug | Alternate Preparative Therapy For Patients Not Able To Receive TBI: Days 9, 8, 7 and 6 pre-transplant; 0.8 mg/kg (1.1 mg/kg if <12 kg) intravenously every 6 hours |
|
|
| Umbilical Cord Blood Transplantation | Biological | Day 0: Two UCB units will compose the graft. The infusion of the first UCB unit should begin within 15 minutes, and no later than 30 minutes after arrival on the Unit. The UCB unit without IL-2 activation will be infused first, followed by the IL-2 activated unit. Both cords will be infused within 30-60 minutes of each other as deemed clinically safe by the BMT attending. |
|
|
| Interleukin-2 | Biological | First Course of IL-2 (begin day +3) post-transplant: For patients ≥ 45 kg, IL-2 will be given at 9 million units every other day for a total of 6 doses subcutaneously. Patients weighing less than 45 kilograms, the IL-2 will be dosed at 5 million units/m^2 every other day for a total of 6 doses. Second Course of IL-2 (day +60): Patients will receive a second course of IL-2 beginning on Day +60 post transplant to expand and educate the NK cells derived from the UCB graft source. |
|
|
| Day 60 |
| Transplant-Related Mortality | Day 180 after Transplantation |
| Clinical Disease Response | Defined as leukemia clearance and complete remission. Patients will be followed for disease response for 1 year from transplantation unless: consent is withdrawal, patient is unevaluable - if a patient is not evaluable, follow only until the resolution or stabilization of treatment related toxicity, new anti-cancer treatment is started, patient is discharged to hospice (terminal) care. | 1 Year from Transplantation |
| Duration of Survival | 6 months after Transplantation. |
| Duration of Survival | 1 year after Transplantation. |
| Duration of Survival | 2 years after Transplantation. |
| Clinical Disease Response | Defined as leukemia clearance and complete remission. Patients will be followed for disease response for 2 years from transplantation unless: consent is withdrawal, patient is unevaluable - if a patient is not evaluable, follow only untilthe resolution or stabilization of treatment related toxicity, new anti-cancer treatment is started, patient is discharged to hospice (terminal) care. | 2 Years from Transplantation |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| Secondary | Incidence of Graft Failure | Incidence of graft failure defined as an absolute neutrophil count of less than 500/uL and a bone marrow that is less than 5% cellular (marrow aplasia) | Posted | Count of Participants | Participants | Day 42 |
|
|
|
| Secondary | Incidence of Acute Graft-Versus-Host Disease | Posted | Count of Participants | Participants | Day 60 |
|
|
|
| Secondary | Transplant-Related Mortality | Posted | Count of Participants | Participants | Day 180 after Transplantation |
|
|
|
| Secondary | Clinical Disease Response | Defined as leukemia clearance and complete remission. Patients will be followed for disease response for 1 year from transplantation unless: consent is withdrawal, patient is unevaluable - if a patient is not evaluable, follow only until the resolution or stabilization of treatment related toxicity, new anti-cancer treatment is started, patient is discharged to hospice (terminal) care. | Posted | Count of Participants | Participants | 1 Year from Transplantation |
|
|
|
| Secondary | Duration of Survival | Posted | Count of Participants | Participants | 6 months after Transplantation. |
|
|
|
| Secondary | Duration of Survival | Posted | Count of Participants | Participants | 1 year after Transplantation. |
|
|
|
| Secondary | Duration of Survival | Posted | Count of Participants | Participants | 2 years after Transplantation. |
|
|
|
| Secondary | Clinical Disease Response | Defined as leukemia clearance and complete remission. Patients will be followed for disease response for 2 years from transplantation unless: consent is withdrawal, patient is unevaluable - if a patient is not evaluable, follow only untilthe resolution or stabilization of treatment related toxicity, new anti-cancer treatment is started, patient is discharged to hospice (terminal) care. | Posted | Count of Participants | Participants | 2 Years from Transplantation |
|
|
|
| 2 |
| 3 |
| 3 |
| 3 |
| fever | General disorders |
|
| hepatobilliary disorders - Other, veno occlusive disease | Hepatobiliary disorders |
|
| chills | General disorders |
|
| injection site reaction | General disorders |
|
| cholecystitis | Hepatobiliary disorders |
|
| bruising | Injury, poisoning and procedural complications |
|
| Headache | Nervous system disorders |
|
| Hypoxia | Respiratory, thoracic and mediastinal disorders |
|
| pain of skin | Skin and subcutaneous tissue disorders |
|
| other, rash | Skin and subcutaneous tissue disorders |
|
| Hypertension | Vascular disorders |
|
| Hypotension | Vascular disorders |
|
| other, veno occlusive disease | Vascular disorders |
|
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| D006402 |
| Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D011878 | Radiotherapy |
| D013812 | Therapeutics |
| D008919 | Investigative Techniques |
| D055585 | Physical Phenomena |
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D000081 | Acetamides |
| D000577 | Amides |
| D000085 | Acetates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D011760 | Pyrrolidinones |
| D011759 | Pyrrolidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D002072 | Butylene Glycols |
| D006018 | Glycols |
| D000438 | Alcohols |
| D008698 | Mesylates |
| D000476 | Alkanesulfonates |
| D017738 | Alkanesulfonic Acids |
| D000473 | Alkanes |
| D006839 | Hydrocarbons, Acyclic |
| D013451 | Sulfonic Acids |
| D013456 | Sulfur Acids |
| D013457 | Sulfur Compounds |
| D033581 | Stem Cell Transplantation |
| D017690 | Cell Transplantation |
| D064987 | Cell- and Tissue-Based Therapy |
| D001691 | Biological Therapy |
| D014180 | Transplantation |
| D013514 | Surgical Procedures, Operative |
| D007378 | Interleukins |
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D008222 | Lymphokines |
| D011506 | Proteins |
| D001685 | Biological Factors |