search
Back to results

Donor Natural Killer Cells and Donor Stem Cell Transplant in Treating Patients With High Risk Myeloid Malignancies

Primary Purpose

Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Acute Erythroid Leukemia, Acute Megakaryoblastic Leukemia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Aldesleukin
Allogeneic CD56-positive CD3-negative Natural Killer Cells
Allogeneic Hematopoietic Stem Cell Transplantation
Busulfan
Fludarabine Phosphate
Laboratory Biomarker Analysis
Peripheral Blood Stem Cell Transplantation
Pharmacological Study
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive

Eligibility Criteria

7 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Acute myeloid leukemia who fail to achieve complete remission with one course of induction chemotherapy or after relapse; patients must have less than 20% bone marrow or peripheral blood blasts

  • Acute myeloid leukemia in first remission with any of the following high risk features defined as:

    • Adverse cytogenetics: -5, deletion (del) 5q, -7, del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, +8 or complex karyotype (> 3 abnormalities)
    • Preceding myelodysplastic or myeloproliferative syndrome
    • Presence of high risk molecular abnormalities including FLT3 mutations, DNMT3A, TET2; ras; kit
    • French-American-British (FAB) monosomy (M)6 or M7 classification
    • Treatment related acute myeloid leukemia (AML)
    • Residual cytogenetic or molecular abnormalities
  • Myelodysplastic syndromes with intermediate, high or very high risk Revised International Prognostic Scoring System (R-IPSS) score, chronic myelomonocytic leukemia (CMML) or therapy related myelodysplastic syndromes (MDS)

  • Chronic myeloid leukemia (CML) which:

    • Failed to achieve a cytogenetic remission to tyrosine kinase inhibitor treatment or has a cytogenetic relapse
    • Has ever been in accelerated phase or blast crisis
  • Patient must have an identified HLA (A,B,C,DR) compatible related or unrelated donor who is age 16 years of age or older and weighs at least 110 pounds for the stem cell donation
  • Zubrod performance status 0 to 2 or Karnofsky of at least 60
  • Left ventricular ejection fraction >= 45%; no uncontrolled arrhythmias or uncontrolled symptomatic cardiac disease
  • Forced expiratory volume in one second (FEV1) >= 50% of expected, corrected for hemoglobin
  • Forced vital capacity (FVC) >= 50% of expected, corrected for hemoglobin
  • Diffusing capacity of the lung for carbon monoxide (DLCO) >= 50% of expected, corrected for hemoglobin
  • Bilirubin =< 1.5 mg/dl (unless Gilbert's syndrome)
  • Serum glutamate pyruvate transaminase (SGPT) =< 200 IU/ml unless related to patient malignancy
  • Hepatitis B surface antigen negative and hepatitis C antibody negative
  • No evidence of chronic active hepatitis or cirrhosis
  • Patients with a history of hepatitis C, but have a negative viral load, are eligible
  • The protocol chairman will determine the eligibility of patients related to hepatic abnormalities
  • Serum creatinine < 1.5 mg%
  • Patient or patient's legal representative, parent(s) or guardian able to sign informed consent; patients aged 7 to < 18 to provide assent
  • Pediatric patients (age 7-18 years) will be entered only after 3 adult patients have been entered without dose limiting toxicity

Exclusion Criteria:

  • Uncontrolled infection, not responding to appropriate antimicrobial agents after seven days of therapy; the protocol principal investigator (PI) is the final arbiter of eligibility
  • Pleural/pericardial effusion or ascites > 1 L
  • Patients who are known to be human immunodeficiency virus (HIV)-seropositive
  • Pregnancy: positive pregnancy test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization
  • Women of child bearing potential not willing to use an effective contraceptive measure while on study
  • Patients who are known to have allergy to mouse proteins

Sites / Locations

  • M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (NK cells, PBSC transplant)

Arm Description

Patients receive fludarabine phosphate IV over 1 hour and busulfan IV over 3 hours on days -13 to -10. Patients then receive allogeneic CD56-positive CD3-negative natural killer cells IV over 1 hour on day -8. Patients also receive aldesleukin SC QD on days -8 to -4. Patients then undergo allogeneic PBSC transplant on day 0.

Outcomes

Primary Outcome Measures

Optimal natural killer cell dose based on incidence of dose-limiting toxicity
The Bayesian model averaging (BMA)-continual reassessment method (CRM) will be applied. The data will be analyzed by fitting the CRM model to the final data and summarizing the posterior distributions of the probability of overall toxicity and of each adverse event in the definition of toxicity at the maximum tolerated dose and at the other doses, by tabulating the counts and rates of all secondary events both overall and cross-tabulated with dose, and fitting appropriate logistic or ordinal outcome regression models to assess possible patterns of change with dose.

Secondary Outcome Measures

Overall survival time
Will assess overall survival time.
Disease-free survival time
Will assess disease-free survival time.
Incidence of graft versus host disease
Will assess incidence of graft versus host disease.
Incidence of grade 3 toxicities
It will be determined if any grade 3 toxicities occur in increased frequency compared to historical experience with this regime without natural killer cells.

Full Information

First Posted
March 28, 2013
Last Updated
July 31, 2022
Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)
search

1. Study Identification

Unique Protocol Identification Number
NCT01823198
Brief Title
Donor Natural Killer Cells and Donor Stem Cell Transplant in Treating Patients With High Risk Myeloid Malignancies
Official Title
NK Cells With HLA Compatible Hematopoietic Transplantation for High Risk Myeloid Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Completed
Study Start Date
June 11, 2013 (Actual)
Primary Completion Date
May 10, 2022 (Actual)
Study Completion Date
May 10, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase I/II trial studies the side effects and best dose of donor natural killer cells when given together with donor stem cell transplant and to see how well they work in treating patients with myeloid malignancies that are likely to come back or spread. Giving chemotherapy, such as busulfan and fludarabine phosphate, before a donor peripheral 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.
Detailed Description
PRIMARY OBJECTIVES: I. Assess the safety of infusing ex vivo expanded natural killer (NK) cells in patients receiving busulfan-fludarabine phosphate (fludarabine) with an allogeneic human leukocyte antigen (HLA) matched hematopoietic transplantation for myeloid malignancies. Two sources of NK cells could be studied, depending on what donor source is available: cells from the HLA matched related donor or cells from an unrelated cord blood unit. II. For each source of NK cells: the maximum tolerated cell dose; the phenotype and function of the ex vivo expanded NK cells and their survival in vivo; the rate of engraftment, graft-vs.-host disease (GVHD), immune reconstitution, relapse rates and survival for patients receiving this regimen will be determined. OUTLINE: This is a phase I, dose-escalation study of NK cells followed by a phase II study. Patients receive fludarabine phosphate intravenously (IV) over 1 hour and busulfan IV over 3 hours on days -13 to -10. Patients then receive allogeneic CD56-positive CD3-negative natural killer cells IV over 1 hour on day -8. Patients also receive aldesleukin subcutaneously (SC) once daily (QD) on days -8 to -4. Patients then undergo allogeneic peripheral blood stem cell (PBSC) transplant on day 0.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Acute Erythroid Leukemia, Acute Megakaryoblastic Leukemia, Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome, Acute Myeloid Leukemia in Remission, Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Blasts Under 20 Percent of Bone Marrow Nucleated Cells, Blasts Under 20 Percent of Peripheral Blood White Cells, Chronic Myelomonocytic Leukemia, High Risk Myelodysplastic Syndrome, Myelodysplastic Syndrome, Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Therapy-Related Acute Myeloid Leukemia, Therapy-Related Myelodysplastic Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
63 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (NK cells, PBSC transplant)
Arm Type
Experimental
Arm Description
Patients receive fludarabine phosphate IV over 1 hour and busulfan IV over 3 hours on days -13 to -10. Patients then receive allogeneic CD56-positive CD3-negative natural killer cells IV over 1 hour on day -8. Patients also receive aldesleukin SC QD on days -8 to -4. Patients then undergo allogeneic PBSC transplant on day 0.
Intervention Type
Biological
Intervention Name(s)
Aldesleukin
Other Intervention Name(s)
125-L-Serine-2-133-interleukin 2, Proleukin, r-serHuIL-2, Recombinant Human IL-2, Recombinant Human Interleukin-2
Intervention Description
Given SC
Intervention Type
Biological
Intervention Name(s)
Allogeneic CD56-positive CD3-negative Natural Killer Cells
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Allogeneic Hematopoietic Stem Cell Transplantation
Other Intervention Name(s)
Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT
Intervention Description
Undergo allogeneic PBSC transplant
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Procedure
Intervention Name(s)
Peripheral Blood Stem Cell Transplantation
Other Intervention Name(s)
PBPC transplantation, PBSCT, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplant, Peripheral Stem Cell Transplantation
Intervention Description
Undergo allogeneic PBSC transplant
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Optimal natural killer cell dose based on incidence of dose-limiting toxicity
Description
The Bayesian model averaging (BMA)-continual reassessment method (CRM) will be applied. The data will be analyzed by fitting the CRM model to the final data and summarizing the posterior distributions of the probability of overall toxicity and of each adverse event in the definition of toxicity at the maximum tolerated dose and at the other doses, by tabulating the counts and rates of all secondary events both overall and cross-tabulated with dose, and fitting appropriate logistic or ordinal outcome regression models to assess possible patterns of change with dose.
Time Frame
Up to 42 days
Secondary Outcome Measure Information:
Title
Overall survival time
Description
Will assess overall survival time.
Time Frame
Up to 5 years
Title
Disease-free survival time
Description
Will assess disease-free survival time.
Time Frame
Up to 5 years
Title
Incidence of graft versus host disease
Description
Will assess incidence of graft versus host disease.
Time Frame
Up to 5 years
Title
Incidence of grade 3 toxicities
Description
It will be determined if any grade 3 toxicities occur in increased frequency compared to historical experience with this regime without natural killer cells.
Time Frame
Up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
7 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Acute myeloid leukemia who fail to achieve complete remission with one course of induction chemotherapy or after relapse; patients must have less than 20% bone marrow or peripheral blood blasts Acute myeloid leukemia in first remission with any of the following high risk features defined as: Adverse cytogenetics: -5, deletion (del) 5q, -7, del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, +8 or complex karyotype (> 3 abnormalities) Preceding myelodysplastic or myeloproliferative syndrome Presence of high risk molecular abnormalities including FLT3 mutations, DNMT3A, TET2; ras; kit French-American-British (FAB) monosomy (M)6 or M7 classification Treatment related acute myeloid leukemia (AML) Residual cytogenetic or molecular abnormalities Myelodysplastic syndromes with intermediate, high or very high risk Revised International Prognostic Scoring System (R-IPSS) score, chronic myelomonocytic leukemia (CMML) or therapy related myelodysplastic syndromes (MDS) Chronic myeloid leukemia (CML) which: Failed to achieve a cytogenetic remission to tyrosine kinase inhibitor treatment or has a cytogenetic relapse Has ever been in accelerated phase or blast crisis Patient must have an identified HLA (A,B,C,DR) compatible related or unrelated donor who is age 16 years of age or older and weighs at least 110 pounds for the stem cell donation Zubrod performance status 0 to 2 or Karnofsky of at least 60 Left ventricular ejection fraction >= 45%; no uncontrolled arrhythmias or uncontrolled symptomatic cardiac disease Forced expiratory volume in one second (FEV1) >= 50% of expected, corrected for hemoglobin Forced vital capacity (FVC) >= 50% of expected, corrected for hemoglobin Diffusing capacity of the lung for carbon monoxide (DLCO) >= 50% of expected, corrected for hemoglobin Bilirubin =< 1.5 mg/dl (unless Gilbert's syndrome) Serum glutamate pyruvate transaminase (SGPT) =< 200 IU/ml unless related to patient malignancy Hepatitis B surface antigen negative and hepatitis C antibody negative No evidence of chronic active hepatitis or cirrhosis Patients with a history of hepatitis C, but have a negative viral load, are eligible The protocol chairman will determine the eligibility of patients related to hepatic abnormalities Serum creatinine < 1.5 mg% Patient or patient's legal representative, parent(s) or guardian able to sign informed consent; patients aged 7 to < 18 to provide assent Pediatric patients (age 7-18 years) will be entered only after 3 adult patients have been entered without dose limiting toxicity Exclusion Criteria: Uncontrolled infection, not responding to appropriate antimicrobial agents after seven days of therapy; the protocol principal investigator (PI) is the final arbiter of eligibility Pleural/pericardial effusion or ascites > 1 L Patients who are known to be human immunodeficiency virus (HIV)-seropositive Pregnancy: positive pregnancy test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization Women of child bearing potential not willing to use an effective contraceptive measure while on study Patients who are known to have allergy to mouse proteins
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Richard E Champlin
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
University of Texas MD Anderson Cancer Center Website

Learn more about this trial

Donor Natural Killer Cells and Donor Stem Cell Transplant in Treating Patients With High Risk Myeloid Malignancies

We'll reach out to this number within 24 hrs