Chemotherapy, Total-Body Irradiation, Donor Natural Killer Cell Infusion, Aldesleukin, and UCB Transplant in Treating Patients With Relapsed or Refractory AML

Phase 2

Terminated

• Conditions: Leukemia
• Interventions: Biological: aldesleukin; Drug: cyclophosphamide; Drug: fludarabine phosphate; Procedure: umbilical cord blood transplantation; Radiation: total-body irradiation

• Registration Number: NCT00871689
• Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary

RATIONALE: Giving chemotherapy and total-body irradiation before a donor umbilical cord blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells and natural killer cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving interleukin-2 (IL-2, aldesleukin) after transplant may stimulate the natural killer cells to kill any remaining cancer cells.

PURPOSE: This phase II trial is studying the side effects of giving combination chemotherapy together with total-body irradiation followed by interleukin-2 (IL-2, aldesleukin), and umbilical cord blood transplant and to see how well it works in treating patients with relapsed or refractory acute myeloid leukemia.

Detailed Description

OBJECTIVES:

Primary

* To determine the rate of neutrophil engraftment and grade III-IV acute graft-versus-host disease (GVHD) following a T cell depleted (TCD) umbilical cord blood (UCB) transplantation without post-transplant immunosuppression followed by administration of interleukin-2 (IL-2, aldesleukin) (every other day) days +3 to +13 to expand NK cells in vivo.

Secondary

* To evaluate the safety of this regimen as assessed by monitoring the rates of graft failure, acute GVHD, and transplant-related mortality (TRM).

* To perform quantitative, phenotypic, and functional assessments of the in vivo expanded UCB-derived NK cells on (day +72).

* To assess clinical disease response (leukemia clearance and complete remission) and survival duration in these patients.

* To evaluate the tolerability of aldesleukin in these patients.

* To evaluate the tolerance of IL-2

OUTLINE:

* Preparative regimen: Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -7 to -5 and cyclophosphamide IV on days -7 and -6. Patients undergo total-body irradiation twice daily on days -5 to -2.

* Transplantation: Patients undergo T-cell depleted umbilical cord blood (UCB) transplantation on day 0.

* IL-2 (Aldesleukin) therapy: Patients receive aldesleukin subcutaneously on days +3 6 doses every other day) and +60 (6 doses every other day).

Patients are followed periodically for up to 2 years after transplant.

Study Timeline

• Study Start: 2009-01
• Study First Submitted: 2009-03-27
• Study First Submitted QC: 2009-03-27
• Study First Posted: 2009-03-30
• Primary Completion: 2010-03
• Study Completion: 2011-10
• Results First Submitted: 2012-06-11
• Results First Submitted QC: 2012-06-11
• Results First Posted: 2012-07-16
• Status Verified: 2017-12
• Last Update Submitted: 2017-12-03
• Last Update Posted: 2017-12-28

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 2

Inclusion Criteria

• Aged 0 to 45 years who meet one of the following criteria:

  • Primary induction failure defined as no complete remission (CR) after two or three induction cycles (no blast limit).

  • Relapsed acute myeloid leukemia (AML) with low disease burden

    • For patients 19 through 45 years of age: must have less than 10% marrow blasts at time of enrollment for patients who did not receive re-induction or measured at least 28 days from the start of re-induction therapy. Patients who have relapsed more than 12 months following a prior hematopoietic cell transplant (HCT) and did not reach CR following one re-induction cycle but have less than 10% marrow blasts are eligible.
    • For patients 0 through 18 years of age: must have less than 50% marrow blasts after no more than 3 induction attempts

  • CR3 or greater. This will include CRp defined as CR without platelet recovery to 100,000/mcL.

  • CR1 or CR2 with high risk features (therapy induced, prior myelodysplastic syndrome (MDS) or myeloproliferative disease (MPD), high risk cytogenetic or molecular phenotype) with no available alternate (sibling, URD or UCB) donors.

• 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 enrollment defined as:

  • Renal: creatinine ≤ 2.0 mg/dL (adult patients) or calculated creatinine clearance > 40 ml/min (pediatric patients)
  • Hepatic: bilirubin, AST/ALT, ALP ≤ 5 x upper limit of normal
  • Pulmonary function: DLCOcorr > 50% of normal, (oxygen saturation [>92%] can be used in child where PFT's cannot be obtained)
  • Cardiac: left ventricular ejection fraction ≥ 45%

• Karnofsky score (adults) > 70% or Lansky score > 50% (pediatrics)

• 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 anti-mouse antibody (HAMA). For patients with no prior antibody therapy exposure, no further action will be taken.

• Not receiving prednisone or other immunosuppressive medications

• Voluntary written consent

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Exclusion Criteria

• Active infection at time of enrollment or documented fungal infection within 3 months
• Evidence of HIV infection or known HIV positive serology
• 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. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy.
• If ≤ 18 years old, prior myeloablative transplant within the last 6 months. If > 18 years old prior myeloablative allotransplant or autologous transplant
• Extensive prior therapy including > 12 months of any alkylator chemotherapy (etoposide >100 mg/m^2 x 5 days, cyclophosphamide >1 gm/m^2 or mitoxantrone >8 gm/m^2) delivered at 3-4 week intervals or > 6 months alkylator therapy (as above) with extensive radiation (determined by Radiation Oncology, e.g. mantle irradiation for Hodgkin's) and/or prior radiation therapy that makes a patient ineligible for total body irradiation (TBI).

Criteria for Second Course of IL-2 (begin day +60):

• No Graft-Versus-Host Disease (GVHD), active infection or any other severe medical co-morbidity
• Absolute neutrophil count (ANC) > 1000 without growth factor support
• No grade 4 toxicity (except fevers) attributed to IL-2 during course #1

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
UCBT With Post-Transplant IL-2	aldesleukin	Patients receive cyclophosphamide, fludarabine phosphate, total-body irradiation, T cell depleted umbilical cord blood transplantation (UCBT), followed by interleukin-2 (IL-2, aldesleukin) every other day beginning day +3 for a total of 6 doses and again on day +60 every other day for 6 doses.
UCBT With Post-Transplant IL-2	umbilical cord blood transplantation	Patients receive cyclophosphamide, fludarabine phosphate, total-body irradiation, T cell depleted umbilical cord blood transplantation (UCBT), followed by interleukin-2 (IL-2, aldesleukin) every other day beginning day +3 for a total of 6 doses and again on day +60 every other day for 6 doses.
UCBT With Post-Transplant IL-2	total-body irradiation	Patients receive cyclophosphamide, fludarabine phosphate, total-body irradiation, T cell depleted umbilical cord blood transplantation (UCBT), followed by interleukin-2 (IL-2, aldesleukin) every other day beginning day +3 for a total of 6 doses and again on day +60 every other day for 6 doses.
UCBT With Post-Transplant IL-2	fludarabine phosphate	Patients receive cyclophosphamide, fludarabine phosphate, total-body irradiation, T cell depleted umbilical cord blood transplantation (UCBT), followed by interleukin-2 (IL-2, aldesleukin) every other day beginning day +3 for a total of 6 doses and again on day +60 every other day for 6 doses.
UCBT With Post-Transplant IL-2	cyclophosphamide	Patients receive cyclophosphamide, fludarabine phosphate, total-body irradiation, T cell depleted umbilical cord blood transplantation (UCBT), followed by interleukin-2 (IL-2, aldesleukin) every other day beginning day +3 for a total of 6 doses and again on day +60 every other day for 6 doses.

Primary Outcome Measures

Name	Time	Method
Number of Patients With Neutrophil Engraftment	Day 42	Number of patient with absolute neutrophils \>500\*10\^8/kg by 42 days post transplant.
Number of Patients With Grade III-IV Acute Graft-Versus-Host (GVHD) Disease	Day 100 Post Transplant	Number of patients with Grade III-IV GVHD. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body.; Acute GVHD usually happens within the first 3 months after transplant.

Secondary Outcome Measures

Name	Time	Method
Number of Patients With Successful Natural Killer Expansion	Day 72 Post Transplant	Successful in vivo donor NK cell expansion will be defined as an absolute circulating donor-derived NK cell count of \>100 cells/μl.
Incidence of Primary Graft Failure	Day 42	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) on day 42.
Number of Patients With Acute Graft-Versus-Host (GVHD) Disease	Day 100 Post Transplant	Number of patients with any grade of GVHD. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body.; Acute GVHD usually happens within the first 3 months after transplant.
Number of Patients With Transplant-Related Death (TRD)	1 Year Post Transplant	Number of patients whose death is related to study treatment received. TRD is defined as the number of patients that die without prior relapse.
Number of Patients With Complete Remission of Disease	Day 100	Disease response will be measured by rate of leukemic clearance (clearance of blasts in blood at timepoint 0) and complete remission (less than 5% blasts and recovery of hematopoiesis).
Median Overall Survival	Month 6	Average number of days the patients were alive after receiving UCB transplantation.

Trial Locations

Locations (1)

University of Minnesota Children's Hospital - Fairview; 🇺🇸 Minneapolis, Minnesota, United States