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Natural Killer (NK) Cells With HLA Compatible Hematopoietic Transplantation for High Risk Myeloid Malignancies

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ClinicalTrials.gov Identifier: NCT01823198
Recruitment Status : Recruiting
First Posted : April 4, 2013
Last Update Posted : September 18, 2018
Sponsor:
Collaborators:
Cancer Prevention Research Institute of Texas
CML Program Project Grant
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential participant.

The goal of this clinical research study is to find the highest tolerable dose of immune cells called natural killer (NK) cells that can be given with chemotherapy and a stem cell transplant to patients with AML and MDS. Researchers want to learn if adding NK cells will help make the stem cell transplant more effective in treating the disease. The safety of this treatment will also be studied.

NK cells may kill cancer cells that remain in your body after your last chemotherapy treatment. The NK cells will be separated from blood from a relative of yours or from umbilical cord blood. These separated NK cells will then be grown in the lab to increase the number of NK cells that can be given to you by vein.

The chemotherapy given on this study will consist of the following drugs:

  • Busulfan is designed to kill cancer cells by binding to DNA (the genetic material of cells), which may cause cancer cells to die. Busulfan is commonly used in stem cell transplants.
  • Fludarabine is designed to interfere with the DNA of cancer cells, which may cause the cancer cells to die.
  • IL-2 (interleukin-2) is a naturally occurring protein (cytokine) that can enhance NK cell function.

This is an investigational study. Busulfan, fludarabine, and IL-2 are FDA approved and commercially available for the treatment of other types of cancer. Their use for the treatment of AML and MDS is investigational. The use of NK cells is investigational. The NK cell process is not FDA approved or commercially available. It is currently being used for research purposes only.

Up to 72 patients will take part in this study. All will be enrolled at MD Anderson.


Condition or disease Intervention/treatment Phase
Leukemia Drug: Busulfan Drug: Fludarabine Procedure: Alloreactive NK infusion Drug: Interleukin-2 Procedure: Stem Cell Infusion Drug: G-CSF Drug: Tacrolimus Drug: Methotrexate Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Natural Killer (NK) Cells With HLA Compatible Hematopoietic Transplantation for High Risk Myeloid Malignancies
Actual Study Start Date : June 2013
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2021


Arm Intervention/treatment
Experimental: + Chemotherapy + NK Cell infusion + Stem Cell Transplant
Busulfan "test dose" of 32 mg/m2 within 2 weeks of the preparative regimen. Fludarabine 40 mg/m2 by vein on Day -13 to Day -10. Busulfan adjusted dose determined to achieve systemic exposure represented by an average daily AUC of 6000 µMol-min ± 5% for the entire 4-day treatment period on Day -13 to Day -10. Patients over age 60 and/or with performance status =2 receive and AUC of 4000 microM x min for each dose. Alloreactive NK infusion on Day -8. Alloreactive NK cell infusion given at one of 4 dose levels based on the number of NK cells (CD3-,CD 56+ cells)/kg recipient body weight. Dose levels are: 10^6, 10^7, 3 x 10^7, 10^8. Interleukin-2 0.5 million units subcutaneously on Day -8 to Day -4. Hematopoietic stem cell infusion on Day 0.
Drug: Busulfan

32 mg/m2 test dose based on actual body weight given by vein within 2 weeks of the preparative regimen.

Busulfan adjusted dose determined to achieve a systemic exposure represented by an average daily AUC of 6000 µMol-min ± 5% on Day -13 to Day -10. Patients over age 60 and/or with performance status =2 receive and AUC of 4000 microM x min for each dose. If it is not feasible to perform the pharmacokinetic studies, Busulfan dose of 130 mg/m2 administered (100 mg/m2 for age over 60 or PS=2).

PK-guided daily high-dose Busulfan dose(s) started immediately upon completion of the daily fludarabine doses.

Other Names:
  • Busulfex
  • Myleran

Drug: Fludarabine
40 mg/m2 by vein dosed per actual body weight/actual body surface area on Day -13 to Day -10.

Procedure: Alloreactive NK infusion
Alloreactive NK cell infusion given by vein on Day -8 at one of 4 dose levels based on the number of NK cells (CD3-,CD 56+ cells)/kg recipient body weight. Dose levels are: 10^6, 10^7, 3 x 10^7, 10^8.
Other Name: Immune cells

Drug: Interleukin-2
0.5 million units subcutaneously on Day -8 to Day -4.
Other Names:
  • IL-2
  • Aldesleukin
  • Proleukin

Procedure: Stem Cell Infusion
Peripheral blood progenitor cells infused on Day 0 or on arrival of the unrelated donor cells.

Drug: G-CSF
5 mcg/kg/day subcutaneously beginning on Day +7, and continuing until absolute neutrophil count (ANC) is > 500 x 10/L for 3 consecutive days.
Other Names:
  • Filgrastim
  • Neupogen

Drug: Tacrolimus
Starting dose of 0.015 mg/kg as a 24 hour continuous infusion daily adjusted with a goal to achieve a therapeutic level of 5-15 ng/ml. Tacrolimus is changed to oral dosing when tolerated and can be tapered off after Day +90 if no GvHD is present.
Other Name: Prograf

Drug: Methotrexate
5 mg/m2 administered intravenously on Days 1, 3, 6 and 11 post transplant.




Primary Outcome Measures :
  1. Maximum Tolerated Natural Killer (NK) Cell Dose [ Time Frame: 42 days ]
    Optimal NK cell dose determined in each of three distinct patient subgroups, A = KIR mismatched haplo donors, B = KIR mismatched cord blood donors, C = matched SIB donors. Same dose-finding design used within each subgroup. Four NK cell doses studied are: 106, 107, 3 x 107, and 108 NK cells. Cohorts of 2 patients used, starting at lowest NK cell dose level. Dose-limiting toxicity (DLT) defined as any of the events graft failure, severe (grade 3,4) infusional toxicity, severe grade 4 organ toxicity, or death by day 42.



Information from the National Library of Medicine

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Ages Eligible for Study:   7 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with age </= 65 years with one of the following:
  2. 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.
  3. Acute myeloid leukemia in first remission with any of the following high risk features defined as: (i) Adverse cytogenetics: -5, del 5q, -7, del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, +8 or complex karyotype [> 3 abnormalities] (ii) Preceding myelodysplastic or myeloproliferative syndrome; (iii) Presence of high risk molecular abnormalities including FLT3 mutations, DNMT3A, TET2; ras; kit; (iv) FAB M6 or M7 classification; (v) treatment-related AML. (vi) residual cytogenetic or molecular abnormalities
  4. Myelodysplastic syndromes with intermediate, high or very high risk R-IPSS score, CMML or therapy related MDS.
  5. CML which: (i) failed to achieve a cytogenetic remission to tyrosine kinase inhibitor treatment or has a cytogenetic relapse; or (ii) has ever been in accelerated phase or blast crisis.
  6. Patient must have an identified a 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.
  7. Zubrod performance status 0 to 2 or Karnofsky of at least 60.
  8. Left ventricular ejection fraction >/= 45%. No uncontrolled arrhythmias or uncontrolled symptomatic cardiac disease.
  9. FEV1, FVC and DLCO >/= 50% of expected, corrected for hemoglobin.
  10. Adequate liver function: a. Bilirubin </= 1.5 mg/dl (unless Gilbert's syndrome). b. SGPT </= 200 IU/ml unless related to patient malignancy. c. Hepatitis B surface antigen negative and hepatitis C antibody negative. d. No evidence of chronic active hepatitis or cirrhosis. e. Patients with a history of hepatitis C, but have a negative viral load, are eligible. f. The protocol chairman will determine the eligibility of patients related to hepatic abnormalities.
  11. Serum creatinine <1.5 mg%.
  12. Patient or patient's legal representative, parent(s) or guardian able to sign informed consent. Patients aged 7 to <18 to provide assent.
  13. Pediatric patients (age 7-18 years) will be entered only after 3 adult patients have been entered without dose limiting toxicity.

Exclusion Criteria:

  1. Uncontrolled infection, not responding to appropriate antimicrobial agents after seven days of therapy. The Protocol PI is the final arbiter of eligibility.
  2. Pleural/pericardial effusion or ascites >1L.
  3. Patients who are known to be HIV-seropositive.
  4. Pregnancy: Positive pregnancy test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization.
  5. Women of child bearing potential not willing to use an effective contraceptive measure while on study.
  6. Patients who are known to have allergy to mouse proteins.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01823198


Contacts
Contact: Richard E. Champlin, MD, BS 713-792-8750

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Cancer Prevention Research Institute of Texas
CML Program Project Grant
Investigators
Principal Investigator: Richard E. Champlin, MD, BS M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01823198     History of Changes
Other Study ID Numbers: 2012-0819
RP110553-P3 ( Other Identifier: CPRIT )
NCI-2013-00993 ( Registry Identifier: NCI CTRP )
First Posted: April 4, 2013    Key Record Dates
Last Update Posted: September 18, 2018
Last Verified: September 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Leukemia
Acute myeloid leukemia
AML
Myelodysplastic syndromes
MDS
Blood And Marrow Transplantation
Myeloproliferative Diseases
High Risk Myeloid Malignancies
Allogeneic stem cell transplant
Natural Killer Cells
NK
Immune cells
Stem cell transplant
Busulfan
Busulfex
Myleran
Interleukin-2
IL-2
Aldesleukin
Proleukin
Thymoglobulin
Antithymocyte globulin
ATG
G-CSF
Filgrastim
Neupogen
Tacrolimus
Prograf
Methotrexate

Additional relevant MeSH terms:
Leukemia
Neoplasms
Neoplasms by Histologic Type
Methotrexate
Fludarabine phosphate
Tacrolimus
Busulfan
Fludarabine
Aldesleukin
Interleukin-2
Lenograstim
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Calcineurin Inhibitors
Adjuvants, Immunologic
Alkylating Agents
Antineoplastic Agents, Alkylating