Clinical Trials /

Off-the-shelf Third Party Expanded NK Cells in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

NCT04220684

Description:

This phase I trial studies the side effects of donor natural killer (NK) cell therapy in treating patients with acute myeloid leukemia that has come back (recurrent) or has not responded to treatment (refractory), or myelodysplastic syndrome. Natural killer cells are a type of immune cell. Immunotherapy with genetically modified NK cells from donors may induce changes in the body?s immune system and may interfere with the ability of cancer cells to grow and spread.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Off-the-shelf Third Party Expanded NK Cells in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
  • Official Title: A Phase I Clinical Trial Testing the Safety of IL-21-Expanded, Off-the-Shelf, Third-Party Natural Killer Cells for Relapsed/Refractory Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: OSU-18336
  • SECONDARY ID: NCI-2019-05150
  • SECONDARY ID: P30CA016058
  • NCT ID: NCT04220684

Conditions

  • Allogeneic Stem Cell Transplant Recipient
  • Blasts 10 Percent or More of Bone Marrow Nucleated Cells
  • Myelodysplastic Syndrome
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-Beta-D-arabinofuranosylcytosine, 1.beta.-D-Arabinofuranosylcytosine, 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-, 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-, Alexan, Ara-C, ARA-cell, Arabine, Arabinofuranosylcytosine, Arabinosylcytosine, Aracytidine, Aracytin, Aracytine, Beta-cytosine Arabinoside, CHX-3311, Cytarabinum, Cytarbel, Cytosar, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Cohort I (fludarabine, cytarabine, NK cell therapy)
Cytarabine HydrochlorideAra-C HCl, Arabinosylcytosine Hydrochloride, Aracytidine Hydrochloride, CHX-3311, Cytosar Hydrochloride, Cytosine Arabinosine Hydrochloride, U-19920ACohort I (fludarabine, cytarabine, NK cell therapy)
Decitabine5-Aza-2''-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, DezocitidineCohort II (fludarabine, decitabine, NK cell therapy)
FludarabineFluradosaCohort I (fludarabine, cytarabine, NK cell therapy)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Cohort I (fludarabine, cytarabine, NK cell therapy)
Membrane-bound Interleukin-21-Expanded Haploidentical Natural Killer Cells(mbIL21)-expanded Haploidentical NK Cells, Donor mbIL21-expanded NK Cells, mbIL21-expanded Haploidentical NK CellsCohort I (fludarabine, cytarabine, NK cell therapy)

Purpose

This phase I trial studies the side effects of donor natural killer (NK) cell therapy in treating patients with acute myeloid leukemia that has come back (recurrent) or has not responded to treatment (refractory), or myelodysplastic syndrome. Natural killer cells are a type of immune cell. Immunotherapy with genetically modified NK cells from donors may induce changes in the body?s immune system and may interfere with the ability of cancer cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the safety of adoptive NK cell therapy using membrane-bound interleukin-21
      (mbIL21)-expanded, off-the-shelf, third-party donor-derived NK cells in patients with
      relapsed/refractory acute myeloid leukemia (AML).

      SECONDARY OBJECTIVES:

      I. Estimate the complete response (CR, CR with incomplete hematologic recovery [CRi] &
      morphologic leukemia-free state [MLFS]).

      II. Estimate the median relapse free survival. III. Estimate the median time to neutrophil
      and platelet count recovery. IV. Estimate the median duration of remission. V. Estimate the
      incidence of infectious complications. VI. Estimate percentage of patients receiving this
      regimen who are rendered transplant-eligible.

      CORRELATIVE OBJECTIVES:

      I. Determine the persistence of ex-vivo expanded, off-the-shelf, third-party NK cells.

      II. Characterize in vivo expansion of third-party NK cells and if it differs based on the
      conditioning regimen as defined by NK chimerism assay.

      III. Determine the immunophenotype and function of expanded cells. IV. Chimerism analysis in
      patients who have had post-transplant relapses.

      OUTLINE: This is a dose-escalation study of membrane-bound interleukin-21-expanded
      haploidentical natural killer cells.

      INDUCTION: Patients are assigned to 1 of 2 arms.

      COHORT I: Patients who are < 60 years old, are able to tolerate intensive chemotherapy, and
      not insensitive to cytarabine receive fludarabine intravenously (IV) and cytarabine IV on
      days -6 to -2 in the absence of disease progression or unacceptable toxicity.

      COHORT II: Patients who are >= 60 years old, unable/unwilling to tolerate intensive
      chemotherapy, or disease insensitive to cytarabine (tp53, TET2 mutations) receive fludarabine
      IV on days -5 to -2 and decitabine IV on days -6 to -2 in the absence of disease progression
      or unacceptable toxicity.

      All patients receive membrane-bound interleukin-21-expanded haploidentical natural killer
      cells via infusion on days 0, 2, 4, 7, 9, and 11.

      After completion of study treatment, patients are followed up to day 56.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort I (fludarabine, cytarabine, NK cell therapy)ExperimentalPatients who are < 60 years old, are able to tolerate intensive chemotherapy, and not insensitive to cytarabine receive fludarabine IV and cytarabine IV on days -6 to -2 in the absence of disease progression or unacceptable toxicity. All patients receive membrane-bound interleukin-21-expanded haploidentical natural killer cells via infusion on days 0, 2, 4, 7, 9, and 11.
  • Cytarabine
  • Cytarabine Hydrochloride
  • Fludarabine
  • Fludarabine Phosphate
  • Membrane-bound Interleukin-21-Expanded Haploidentical Natural Killer Cells
Cohort II (fludarabine, decitabine, NK cell therapy)ExperimentalPatients who are >= 60 years old, unable/unwilling to tolerate intensive chemotherapy, or disease insensitive to cytarabine (tp53, TET2 mutations) receive fludarabine IV on days -5 to -2 and decitabine IV on days -6 to -2 in the absence of disease progression or unacceptable toxicity. All patients receive membrane-bound interleukin-21-expanded haploidentical natural killer cells via infusion on days 0, 2, 4, 7, 9, and 11.
  • Decitabine
  • Fludarabine
  • Fludarabine Phosphate
  • Membrane-bound Interleukin-21-Expanded Haploidentical Natural Killer Cells

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with one of the following diagnoses:

               -  Relapsed or primary refractory acute myeloid leukemia (AML), including

                    -  Patients with relapsed AML after allogeneic stem cells transplantation,
                       including those who have received donor lymphocyte infusions

                    -  Isolated central nervous system (CNS) or extramedullary disease

                    -  Note: a response monitoring plan must be developed a priori for subjects
                       with extramedullary disease

               -  Myelodysplastic syndrome

                    -  >= 10% blasts, including patients who have received prior hypomethylating
                       agents

          -  Karnofsky or Lansky performance scale (PS) greater or equal to 70

          -  Serum creatinine =< 2 mg/dl or creatinine clearance greater or equal than 40 cc/min.
             Creatinine for pediatric patients =< 2 mg/dl or =< 2 times upper limit of normal for
             age (whichever is less)

          -  Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and
             diffusion capacity of the lung for carbon monoxide (DLCO) >= 50% of expected,
             corrected for hemoglobin. For pediatric patients, if unable to perform pulmonary
             function tests (most children < 7 years of age), pulse oximetry >= 92% on room air by
             pulse oximetry

          -  Total bilirubin =< 2 mg/dl or =< 2.5 x upper limit or normal (ULN) for age (unless
             Gilbert's syndrome)

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x
             ULN for age

          -  Left ventricular ejection fraction >= 40%

          -  Patients with seizure disorder may be eligible if seizures well controlled

          -  Negative serum test to rule out pregnancy within 2 weeks prior to enrollment 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

          -  Ability to understand and willingness to sign the written informed consent document

          -  Negative serology for human immunodeficiency virus (HIV)

        Exclusion Criteria:

          -  Investigational therapies in the 2 weeks prior to beginning treatment on this protocol

          -  Any comorbidities that in the opinion of the investigator will preclude receiving
             fludarabine, decitabine or cytarabine

          -  Uncontrolled infection, defined as an infection which has not resolved spontaneously
             or does not show evidence of significant resolution after initiating appropriate
             therapy. Asymptomatic viremia such as cytomegalovirus (CMV), human papillomavirus
             (HPV), BK virus, hepatitis C virus (HCV), etc. is NOT considered as an exclusion
             criteria

          -  Uncontrolled arrhythmias or uncontrolled symptomatic cardiac disease

          -  Active graft versus host disease (GVHD)

          -  Patient on corticosteroids to control GvHD
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of membrane-bound interleukin-21-expanded haploidentical natural killer (NK) cells
Time Frame:Up to 63 days
Safety Issue:
Description:The MTD will be defined as the highest safely tolerated dose where at most one patient in six experiences dose-limiting toxicity (DLT) during DLT observation period. DLT is defined as any steroid refractory acute graft versus host disease.

Secondary Outcome Measures

Measure:Complete response (CR)
Time Frame:Up to day 56
Safety Issue:
Description:Response rate with a 95% confidence interval (CI) will be reported for all evaluable patients, assuming a binomial distribution. Response rate will also be reported for those who received all 6 doses of NK cells.
Measure:CR with incomplete hematologic recovery
Time Frame:Up to day 56
Safety Issue:
Description:Response rate with a 95% CI will be reported for all evaluable patients, assuming a binomial distribution. Response rate will also be reported for those who received all 6 doses of NK cells.
Measure:Morphologic leukemia-free state
Time Frame:Up to day 56
Safety Issue:
Description:Response rate with a 95% CI will be reported for all evaluable patients, assuming a binomial distribution. Response rate will also be reported for those who received all 6 doses of NK cells.
Measure:Median relapse free survival
Time Frame:Up to day 56
Safety Issue:
Description:Will use descriptive statistics to summarize the demographic and clinical characteristics of the patients on this study.
Measure:Median time to neutrophil and platelet count recovery
Time Frame:Up to day 56
Safety Issue:
Description:Will use descriptive statistics to summarize the demographic and clinical characteristics of the patients on this study.
Measure:Median duration of remission
Time Frame:Up to day 56
Safety Issue:
Description:Will use descriptive statistics to summarize the demographic and clinical characteristics of the patients on this study.
Measure:Incidence of infectious complications
Time Frame:Up to day 56
Safety Issue:
Description:Will use descriptive statistics to summarize the demographic and clinical characteristics of the patients on this study.
Measure:Percentage of patients receiving the regimen who are rendered transplant-eligible
Time Frame:Up to day 56
Safety Issue:
Description:Will use descriptive statistics to summarize the demographic and clinical characteristics of the patients on this study.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sumithira Vasu

Trial Keywords

  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia
  • Myelodysplastic Syndrome

Last Updated

January 6, 2020