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Natural Killer Cells Before and After Donor Stem Cell Transplant in Treating Patients With Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia

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ClinicalTrials.gov Identifier: NCT01904136
Recruitment Status : Active, not recruiting
First Posted : July 22, 2013
Last Update Posted : February 10, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE July 17, 2013
First Posted Date  ICMJE July 22, 2013
Last Update Posted Date February 10, 2021
Actual Study Start Date  ICMJE April 22, 2014
Estimated Primary Completion Date April 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 31, 2019)
Maximum tolerated doses (MTD) of natural killer (NK) cells [ Time Frame: Up to day 70 post-transplant ]
Will be defined by incidence of dose limiting toxicity including death, grade 3-4 toxicities, graft failure, or grade 3-4 graft versus host disease (GVHD). Dose-finding will be carried out using the time-to-event continual reassessment method of Cheung and Chappell. All adverse events will be tabulated by dose, and the fitted dose-toxicity curve will be summarized.
Original Primary Outcome Measures  ICMJE
 (submitted: July 17, 2013)
Maximum Tolerated Dose (MTD) of Expanded Natural Killer (NK) Cells [ Time Frame: 70 days after stem cell transplant ]
Dose-finding, "toxicity" defined as any of the events (i) death, (ii) grade 4 infusion reaction, (iii) grade 4 organ toxicity (not including mucositis or myelosuppression) (iv) graft failure, or (v) severe (grade 3 or 4) graft-versus-host disease (GVHD) within the 72-day window occurring between day -2 (the time of the first NK cell dose) and day 70 post stem cell transplant (SCT). Patient outcome is time of occurrence of toxicity or, if toxicity has not yet occurred by an observation time prior to day +70, the outcome will be the patient's follow up time (starting at day -2) without toxicity.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 31, 2019)
  • 100-day treatment related mortality [ Time Frame: Up to 100 days post-transplant ]
    Will be defined as death due to any cause without disease recurrence within 100 days post stem cell transplant (SCT). The method of Thall and Sung will be used, based on an historical rate of 35%.
  • Overall survival [ Time Frame: Up to 2 years ]
    Will be estimated using the Kaplan-Meier method, and distributions will be compared using log-rank tests.
  • Relapse-free survival [ Time Frame: Up to 2 years ]
    Will be estimated using the Kaplan-Meier method, and distributions will be compared using log-rank tests.
  • Time to engraftment [ Time Frame: Up to 2 years ]
    Will be estimated using the Kaplan-Meier method, and distributions will be compared using log-rank tests.
  • Time to graft failure [ Time Frame: Up to 2 years ]
    Will be estimated using the Kaplan-Meier method, and distributions will be compared using log-rank tests.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 17, 2013)
Treatment Related Mortality [ Time Frame: 100 days after stem cell trantsplant ]
Treatment related mortality defined as death due to any cause without disease recurrence within 100 days post stem cell transplant (SCT)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Natural Killer Cells Before and After Donor Stem Cell Transplant in Treating Patients With Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia
Official Title  ICMJE A Phase I/II Clinical Trial of NK Cells Administration to Prevent Disease Relapse for Patient With High-Risk Myeloid Malignancies Undergoing Haploidentical Stem-Cell Transplantation
Brief Summary This phase I/II studies the side effects and best dose of natural killer cells before and after donor stem cell transplant and to see how well they work in treating patients with acute myeloid leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia. Giving chemotherapy with or without total body irradiation before a donor peripheral blood stem cell or bone marrow 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.
Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate safety, tolerability and identify the maximum tolerated dose (MTD) of expanded natural killer (NK) cells to be used in patients with myeloid malignancies undergoing a haploidentical stem-cell transplant.

SECONDARY OBJECTIVES:

I. To determine survival of NK cells in vivo post-transplant. II. To determine the function of NK cells post-transplant and compare with a retrospective control treated with no NK cells.

III. To estimate the proportion of patients with engraftment/graft failure. IV. To estimate the non-relapse mortality (NRM) at day 100 post-transplant. V. To estimate the cumulative incidence of grade III-IV aGVHD (acute graft-versus-host disease) at day 100.

VI. To assess the rate of chronic graft-versus-host disease (GVHD) within the first year post transplantation.

VII. To assess immune reconstitution post-transplant. VIII. To assess disease response, disease-free survival (DFS) and overall survival (OS) after transplantation.

IX. To perform a retrospective comparison of patients treated on the study with NK cells will be performed with a Center for International Blood and Marrow Transplant Research (CIBMTR) control of similar patients who did not receive NK cells.

OUTLINE: This is a phase I, dose-escalation study of NK cells followed by a phase II study. Patients are assigned to 1 of 2 conditioning regimens.

MYELOABLATIVE CONDITIONING REGIMEN: Patients receive high-dose melphalan intravenously (IV) over 30 minutes on day -7, fludarabine IV over 1 hour on days -7 to -4, undergo total-body irradiation (TBI) on day -3, and NK cells IV over 30 minutes on day -2 or -1.

NON-MYELOABLATIVE CONDITIONING REGIMEN: Patients receive melphalan IV over 30 minutes on day -7, fludarabine IV over 1 hour on days -7 to -4, undergo TBI on day -3, and receive NK cells IV over 30 minutes on day -2 or -1.

TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell (PBSC) or bone marrow transplant on day 0.

POST-TRANSPLANT CYCLOPHOSPHAMIDE AND GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4, tacrolimus IV beginning on day 5 for 2 weeks and then orally (PO) for approximately 4 months, and mycophenolate mofetil PO thrice daily (TID) beginning on day 5 for approximately 6-7 months.

NK CELLS: Patients receive NK cells IV over 30 minutes on days 7 and 28-90.

After completion of study treatment, patients are followed up for 2 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • Acute Myeloid Leukemia With Gene Mutations
  • Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • de Novo Myelodysplastic Syndrome
  • Myelodysplastic Syndrome
  • Recurrent Acute Myeloid Leukemia
  • Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive
  • Therapy-Related Acute Myeloid Leukemia
Intervention  ICMJE
  • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
    Undergo allogeneic PBSC or bone marrow transplant
    Other Names:
    • Allogeneic
    • Allogeneic Hematopoietic Cell Transplantation
    • Allogeneic Stem Cell Transplantation
    • HSC
    • HSCT
    • Stem Cell Transplantation, Allogeneic
  • Procedure: Bone Marrow Transplantation
    Undergo allogeneic PBSC or bone marrow transplant
    Other Names:
    • Blood and Bone Marrow Transplant
    • BMT
    • Bone Marrow Grafting
    • Bone Marrow Transplant
    • Marrow Transplantation
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • (-)-Cyclophosphamide
    • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
    • Carloxan
    • Ciclofosfamida
    • Ciclofosfamide
    • Cicloxal
    • Clafen
    • Claphene
    • CP monohydrate
    • CTX
    • CYCLO-cell
    • Cycloblastin
    • Cycloblastine
    • Cyclophospham
    • Cyclophosphamid monohydrate
    • Cyclophosphamide Monohydrate
    • Cyclophosphamidum
    • Cyclophosphan
    • Cyclophosphane
    • Cyclophosphanum
    • Cyclostin
    • Cyclostine
    • Cytophosphan
    • Cytophosphane
    • Cytoxan
    • Fosfaseron
    • Genoxal
    • Genuxal
    • Ledoxina
    • Mitoxan
    • Neosar
    • Revimmune
    • Syklofosfamid
    • WR- 138719
  • Drug: Fludarabine
    Given IV
    Other Name: Fluradosa
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Melphalan
    Given IV
    Other Names:
    • Alanine Nitrogen Mustard
    • CB-3025
    • L-PAM
    • L-Phenylalanine Mustard
    • L-Sarcolysin
    • L-Sarcolysin Phenylalanine mustard
    • L-Sarcolysine
    • Melphalanum
    • Phenylalanine Mustard
    • Phenylalanine Nitrogen Mustard
    • Sarcoclorin
    • Sarkolysin
    • WR-19813
  • Drug: Mycophenolate Mofetil
    Given PO
    Other Names:
    • CellCept
    • MMF
  • Biological: Natural Killer Cell Therapy
    Given IV
  • Procedure: Peripheral Blood Stem Cell Transplantation
    Undergo allogeneic PBSC or bone marrow transplant
    Other Names:
    • PBPC transplantation
    • PBSCT
    • Peripheral Blood Progenitor Cell Transplantation
    • Peripheral Stem Cell Support
    • Peripheral Stem Cell Transplant
    • Peripheral Stem Cell Transplantation
  • Drug: Tacrolimus
    Given IV and PO
    Other Names:
    • FK 506
    • Fujimycin
    • Hecoria
    • Prograf
    • Protopic
  • Radiation: Total-Body Irradiation
    Undergo TBI
    Other Names:
    • SCT_TBI
    • TBI
    • Total Body Irradiation
    • Whole Body Irradiation
    • Whole-Body Irradiation
Study Arms  ICMJE Experimental: Treatment (NK cells, allogeneic stem cell transplant)

MYELOABLATIVE CONDITIONING REGIMEN: Patients receive high-dose melphalan IV over 30 minutes on day -7, fludarabine IV over 1 hour on days -7 to -4, undergo TBI on day -3, and NK cells IV over 30 minutes on day -2 or -1.

NON-MYELOABLATIVE CONDITIONING REGIMEN: Patients receive melphalan IV over 30 minutes on day -7, fludarabine IV over 1 hour on days -7 to -4, undergo TBI on day -3, and receive NK cells IV over 30 minutes on day -2 or -1.

TRANSPLANT: Patients undergo allogeneic PBSC or bone marrow transplant on day 0.

POST-TRANSPLANT CYCLOPHOSPHAMIDE AND GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4, tacrolimus IV beginning on day 5 for 2 weeks and then PO for approximately 4 months, and mycophenolate mofetil PO TID beginning on day 5 for approximately 6-7 months.

NK CELLS: Patients receive NK cells IV over 30 minutes on days 7 and 28-90.

Interventions:
  • Procedure: Allogeneic Hematopoietic Stem Cell Transplantation
  • Procedure: Bone Marrow Transplantation
  • Drug: Cyclophosphamide
  • Drug: Fludarabine
  • Other: Laboratory Biomarker Analysis
  • Drug: Melphalan
  • Drug: Mycophenolate Mofetil
  • Biological: Natural Killer Cell Therapy
  • Procedure: Peripheral Blood Stem Cell Transplantation
  • Drug: Tacrolimus
  • Radiation: Total-Body Irradiation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: February 8, 2021)
90
Original Estimated Enrollment  ICMJE
 (submitted: July 17, 2013)
45
Estimated Study Completion Date  ICMJE April 30, 2021
Estimated Primary Completion Date April 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Eligibility for pediatric patients will be determined in conjunction with an MD Anderson Cancer Center (MDACC) pediatrician; patients age 2-17 years old may be enrolled after at least 4 adults (ages 18-65 years old) have been treated without toxicity
  • Patient with no matched related donor who has a related haploidentical donor identified (=< 7/8 allele match at the A, B, C, DR loci) who is willing to undergo a bone marrow harvest and an NK cell collection approximately 2 weeks of the recipient's admission for transplant; the donor must be 16 years of age or older and weigh at least 110 pounds
  • Patients with one of the following diseases: acute myeloid leukemia (AML): a. first complete remission with high-risk features defined as: (i) greater than 1 cycle of induction therapy required to achieve remission; (ii) preceding myelodysplastic syndrome (MDS); (iii) presence of FLT3 mutations or internal tandem duplication or other mutations associated with poor-risk AML (e.g. DNMT3A, TET2); (iv) French-American-British Classification (FAB) M6 or M7 classification; (v) adverse cytogenetics: -5, deletion (del) 5q, -7, del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, +8 or complex karyotype (> 3 abnormalities); (vi) treatment-related AML, or b. second or greater remission; patients beyond second remission have to be in complete remission (CR) at transplant to be eligible, or c. primary induction failure with partial response to therapy who achieve adequate cytoreduction
  • Patients with myelodysplastic syndromes (MDS): a. de novo MDS with intermediate or high-risk International Prognostic Scoring System (IPSS) scores; patients with intermediate-1 features should have failed to respond to hypomethylating agent therapy, or b. patients with treatment-related MDS
  • Chronic myeloid leukemia (CML): a. failed to achieve cytogenetic remission or have cytogenetic relapse after treatment with at least 2 tyrosine kinase inhibitors, or b. accelerated phase or blast phase at any time
  • Performance score of at least 70% by Karnofsky or 0 to 1 by Eastern Cooperative Oncology Group (ECOG) (age >= 12 years), or Lansky Play-performance scale of at least 70% or greater (age < 12 years)
  • Serum creatinine clearance equal or more than 50 ml/min (calculated with Cockcroft-Gault formula)
  • Bilirubin equal or less than 1.5 mg/dl except for Gilbert's disease
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) equal or less than 200 IU/ml for adults
  • Conjugated (direct) bilirubin less than 2 x upper limit of normal
  • Left ventricular ejection fraction equal or greater than 40%
  • Diffusing capacity of the lung for carbon monoxide (DLCO) equal or greater than 50% predicted corrected for hemoglobin; for children =< 7 years of age who are unable to perform pulmonary function tests (PFT), oxygen saturation >= 92% on room air by pulse oximetry
  • Patient or patient's legal representative, parent(s) or guardian should provide written informed consent; assent of a minor if participant's age is at least seven and less than eighteen years

Exclusion Criteria:

  • Human immunodeficiency virus (HIV) positive; active hepatitis B or C
  • Uncontrolled infections; principal investigator (PI) is the final arbiter of this criterion
  • Liver cirrhosis
  • Central nervous system (CNS) involvement within 3 months
  • Positive pregnancy test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization
  • Inability to comply with medical therapy or follow-up
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01904136
Other Study ID Numbers  ICMJE 2012-0708
NCI-2013-02183 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
P01 - 5P01
RP110553 05-07-04832
05-07-04832
2012-0708 ( Other Identifier: M D Anderson Cancer Center )
P01CA049639 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Samer Srour M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP