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Interleukin-21 (IL-21)- Expanded Natural Killer Cells for Induction of Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT02809092
Recruitment Status : Unknown
Verified September 2019 by Hospital de Clinicas de Porto Alegre.
Recruitment status was:  Active, not recruiting
First Posted : June 22, 2016
Last Update Posted : October 15, 2019
Information provided by (Responsible Party):
Hospital de Clinicas de Porto Alegre

Brief Summary:

Relapsed acute myeloblastic leukemia (AML) requires remission prior to allogeneic Hematopoietic Stem Cell Transplant (HSCT) for optimal survival, but is a disease with poor response to chemotherapy. Human leukocyte antigen (HLA) haploidentical, Natural killer (NK) enriched peripheral blood cell infusions have shown safety in patients with poor prognosis AML. Though not powered for such an assessment, this trial showed a promising but not statistically significant trend in remission rate. NK cell therapy was limited by small numbers of NK cells attainable through leukapheresis. We have now demonstrated that large numbers of NK cells can be propagated ex vivo from a small volume blood draw, obviating the need for donor leukapheresis. The purpose of this trial is to determine the feasibility and maximum tolerated dose of expanded NK cells and estimate the toxicity of treating relapsed/refractory AML with fludarabine + high-dose cytarabine + G-CSF (FLAG) chemotherapy followed by haploidentical expanded natural killer (NK) cells.

The first NK cell dosing cohort will be well below the currently-established safe dose of pheresis-derived NK cells, as expanded NK cells may have increased toxicity because of their activated phenotype. In order to avoid accruing patients at suboptimal doses, a dose escalation schema based on the principles of an accelerated titration design is used in this study to allow expeditious advancement up to the current safe dose of NK cells.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Biological: NK Cells + Chemotherapy Starting Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Clinical Trial Testing the Safety and Feasibility of IL-21- Expanded Natural Killer Cells for the Induction of Relapsed/Refractory Acute Myeloid Leukemia
Actual Study Start Date : April 1, 2017
Actual Primary Completion Date : September 30, 2019
Estimated Study Completion Date : September 2020

Arm Intervention/treatment
Experimental: NK Cells + Chemotherapy Starting

Starting on Day -7, G-CSF daily by vein until post nadir of absolute neutrophil counts (ANC) are equal or over 1000. Day -6 to Day -2 Fludarabine administrated by vein at 30 mg/m^2. Four hours later Cytarabine administrated by vein at 2 g/m^2. Natural killer (NK) cell infusion Days 0 to 14 for 6 doses total. The first group of participants receive lowest dose level. Each new group receives a higher dose than the group before it, if no intolerable side effects were seen. This will continue for up to 6 dose levels or until the highest tolerable dose of NK cells is found. One (1) to 10 participants will be treated in each dose level.

NK Cell infusion on Days 0 to 14 for 6 doses total according to dose escalation schema.

Biological: NK Cells + Chemotherapy Starting

Drug: G-CSF G-CSF daily by vein starting on Day -7 until post nadir of absolute neutrophil counts (ANC) are equal or over 1000.

Other Names:

Filgrastim Neupogen Drug: Fludarabine monophosphate 30 mg/m2 by vein on Days -6, -5, -4, -3, and -2.

Other Names:

Fludarabine Phosphate Fludara Drug: Cytarabine 2 g/m^2 by vein on Days -6, -5, -4, -3, and -2.

Other Names:

Ara-C Cytosar DepoCyt Cytosine arabinosine hydrochloride Procedure: Natural Killer (NK) Cell Infusion NK Cell infusion on Days 0 to 14 for 6 doses total according to dose escalation schema.

Other Name: Natural killer cells

Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of membrane-bound interleukin 21 (mbIL21)-Expanded Haploidentical NK Cells After Induction Chemotherapy with Fludarabine, Cytarabine, and Granulocyte-colony stimulating factor (G-CSF). [ Time Frame: 28 days ]

    Maximum tolerated dose defined as highest dose studied in which 6 patients have been treated and at most 2 patients with dose-limiting toxicities (DLTs) observed.

    A dose-limiting toxicity (DLT) is defined as:

    Acute severe (grade 3 or 4) infusional allergic reaction related to the NK cells infusion.

    Prolonged cytopenia beyond D+28. If neutropenia is still present at day 28, that will trigger the designation of prolonged neutropenia as a DLT. If neutrophil counts have recovered by day 28, then no DLT will have occurred. In either case, the status of neutrophil recovery beyond day 28 will not change the designation of DLT or No DLT made at day 28.

    Acute GvHD overall grade 3 or 4. Severe (grade 3 or 4) unexpected toxicity related to the NK cell infusion.

Secondary Outcome Measures :
  1. Complete Remission (CR) Assessment Following Infusion of the NK Cells [ Time Frame: Baseline up to Day 56 ]
    Percentage of participants with complete remission (CR): Bone marrow aspiration - Less than 5% leukemic blasts. Disease assessment after neutrophil recovery and or Day 28, whichever is earlier: 1. Unilateral bone marrow biopsy and aspirate for cytology, flow cytometry, Minimal Residual Disease MRD, chimerism, cytogenetics, and fluorescent in situ hybridization (FISH) (for known tumor markers). 2. If recovery has not occurred by Day +28, then a second bone marrow will be obtained at the time of neutrophil recovery or Day +56, whichever is earlier. CR estimated with Kaplan-Meier estimator and tabulated with 95% confidence intervals.

  2. Donor NK-Cell Expansion [ Time Frame: 28 days ]
    Donor NK-cell expansion defined as an absolute circulating donor-derived NK cell count that increases above the post-infusion level. Proportion of patients with successful in vivo NK-cell expansion estimated with a 95% confidence interval. The following chimerism methods employed to determine origin and number of circulating NK cells. Chimerism may be determined by flow cytometry using haplotype-specific antibodies. Chimerism may be determined by short tandem repeat (STR) polymorphisms. When there is a sex-mismatch between the donor and the recipient, assays based on determining the frequency of sex-chromosomes may be used.

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 59 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

Obtained within 30 days prior to beginning the lymphodepleting conditioning regimen, unless otherwise specified.

  • Patients with relapsed AML, including Canadian Neurological Scale (CNS) disease or previous hematopoietic stem cell transplantation, which has failed remission to at least one cycle of standard or experimental reinduction chemotherapy, or primary refractory AML (primary AML that has failed remission to at least two cycles of induction therapy)
  • Availability of a haploidentical family peripheral blood donor selected for best possible killer cell inhibitory receptor (KIR) reactivity.
  • Patient age between 2 and 59 years, inclusive.
  • Patient must have recovered from the treatment-related toxicities of prior cytotoxic agents received in the 4 weeks prior to beginning treatment on this protocol, with the exception of cytopenias resulting from persistent disease, and alopecia.
  • "Zubrod" performance scale ≤ 2 or "Lansky" scale ≥ 60.
  • Adequate renal function defined as:

    • Serum creatinine ≤2 mg/dL for adults.
    • Serum creatinine ≤2 mg/dL or ≤2 times upper limit of normal (ULN) for age (whichever is less) for children.
    • Or, if serum creatinine does not meet above criteria, patient will be eligible if 24h creatinine clearance ≥60 mL/min/1.73m2.
  • Adequate liver function, defined as: Total bilirubin ≤2 mg/dL and serum glutamate pyruvate transaminase(SGPT) (ALT) ≤2.5 x ULN for age (unless Gilbert's disease or abnormal liver function due to primary disease).
  • Pulmonary symptoms controlled by medication and pulse oximetry ≥ 92% room air.
  • New York Heart Association classification < III
  • Negative serum test to rule out pregnancy within 2 weeks prior to registration in females of childbearing potential (non childbearing potential defined as premenarchal, greater than one year post-menopausal, or surgically sterilized).
  • Sexually active males and females of childbearing potential must agree to use a form of contraception considered effective and medically acceptable by the Investigator.
  • Negative serology for human immunodeficiency virus (HIV).

Exclusion Criteria:

  • Failed attaining remission with any previous FLAG therapy.
  • Investigational therapies in the 4 weeks prior to beginning treatment on this protocol.
  • Congestive heart failure <6 months prior to screening
  • Unstable angina pectoris <6 months prior to screening
  • Myocardial infarction <6 months prior to screening

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): NCT02809092

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Centro Terapia e Tecnologia Celular
Porto Alegre, Rio Grande Do Sul, Brazil, 90035-903
Sponsors and Collaborators
Hospital de Clinicas de Porto Alegre
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Principal Investigator: Lucia Silla, Doctor Hospital de Clinicas de Porto Alegre
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Responsible Party: Hospital de Clinicas de Porto Alegre
ClinicalTrials.gov Identifier: NCT02809092    
Other Study ID Numbers: 10-0457
First Posted: June 22, 2016    Key Record Dates
Last Update Posted: October 15, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hospital de Clinicas de Porto Alegre:
Acute Myeloid Leukemia, Natural Killer Cells
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type