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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia; Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Therapy-Related Acute Myeloid Leukemia; de Novo Myelodysplastic Syndrome; Acute Myeloid Leukemia With Gene Mutations; Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Melphalan; Drug: Mycophenolate Mofetil; Drug: Tacrolimus; Radiation: Total-Body Irradiation; Biological: Natural Killer Cell Therapy; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Bone Marrow Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation

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: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamide Monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Drug: Fludarabine; Given IV; Other Names: Fluradosa; Drug: Melphalan; Given IV; Other Names: CB-3025; L-PAM; L-Sarcolysin; Alanine Nitrogen Mustard; L-Phenylalanine Mustard; 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; Drug: Tacrolimus; Given IV and PO; Other Names: Prograf; Hecoria; FK 506; Fujimycin; Protopic; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; TBI; SCT_TBI; Whole Body Irradiation; Whole-Body Irradiation; Biological: Natural Killer Cell Therapy; Given IV; 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: BMT; Bone Marrow Transplant; Blood and Bone Marrow Transplant; Bone Marrow Grafting; Marrow Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo allogeneic PBSC or bone marrow transplant; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; PBSCT; Peripheral Stem Cell Transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Limiting Toxicities (DLTs)	Number of participants that experienced dose limiting toxicities.	Up to day 70 post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
100-day Treatment Related Mortality	Number of participants who died within 100 days post-transplant.	Up to 100 days post-transplant
Overall Survival	Number of participants with overall survival after 2 years.	Up to 2 years

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Samer Srour, M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• Ciurea SO, Kongtim P, Soebbing D, Trikha P, Behbehani G, Rondon G, Olson A, Bashir Q, Gulbis AM, Indreshpal K, Rezvani K, Shpall EJ, Bassett R, Cao K, Martin AS, Devine S, Horowitz M, Pasquini M, Lee DA, Champlin RE. Decrease post-transplant relapse using donor-derived expanded NK-cells. Leukemia. 2022 Jan;36(1):155-164. doi: 10.1038/s41375-021-01349-4. Epub 2021 Jul 26.

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2014
• Primary Completion (Actual): February 28, 2022
• Study Completion (Actual): February 28, 2022

Study Registration Dates

• First Submitted: July 17, 2013
• First Submitted That Met QC Criteria: July 17, 2013
• First Posted (Estimated): July 22, 2013

Study Record Updates

• Last Update Posted (Actual): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 22, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Disease; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Neoplastic Processes; Precancerous Conditions; Cell Transformation, Neoplastic; Carcinogenesis; Chronic Disease; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Recurrence; Preleukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Blast Crisis; Leukemia, Myeloid, Accelerated Phase; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Melphalan; Fludarabine; Tacrolimus; Mycophenolic Acid; Mechlorethamine; Nitrogen Mustard Compounds
• Other Study ID Numbers: 2012-0708 (Other Identifier: M D Anderson Cancer Center); P01CA049639 (U.S. NIH Grant/Contract); NCI-2013-02183 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P01 - 5P01; RP110553 05-07-04832; 05-07-04832

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No