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Ph1 Trial Test Safety of IL-21 NK Cells for Induction of R/R AML

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04220684
Recruitment Status : Recruiting
First Posted : January 7, 2020
Last Update Posted : February 18, 2022
Sponsor:
Information provided by (Responsible Party):
Sumithira Vasu, Ohio State University Comprehensive Cancer Center

Brief Summary:
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). 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.

Condition or disease Intervention/treatment Phase
Allogeneic Stem Cell Transplant Recipient Blasts 10 Percent or More of Bone Marrow Nucleated Cells Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Drug: Cytarabine Hydrochloride Drug: Fludarabine Biological: Membrane-bound Interleukin-21-Expanded Haploidentical Natural Killer Cells Phase 1

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 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Clinical Trial Testing the Safety of IL-21-Expanded, Off-the-shelf, Third-party Natural Killer Cells (KDS-1001) for the Induction of Relapsed/Refractory Acute Myeloid Leukemia
Actual Study Start Date : June 1, 2020
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022


Arm Intervention/treatment
Experimental: Conditioning Regimen
Fludarabine 30 mg/m2/day (day -6 to day -2) and Cytarabine 2g/ m2/day (days -6 to day -2)
Drug: Cytarabine Hydrochloride
Given IV
Other Names:
  • Ara-C HCl
  • Arabinosylcytosine Hydrochloride
  • Aracytidine Hydrochloride
  • CHX-3311
  • Cytosar Hydrochloride
  • Cytosine Arabinosine Hydrochloride
  • U-19920A

Drug: Fludarabine
Given IV
Other Name: Fluradosa

Experimental: Induction
Six doses of third-party-donor mbIL-21 expanded (KDS-1001) cells given thrice weekly for two weeks. Days may vary and KDS-1001 can be given from days 0 to 21
Biological: Membrane-bound Interleukin-21-Expanded Haploidentical Natural Killer Cells
Given via infusion
Other Names:
  • (mbIL21)-expanded Haploidentical NK Cells
  • Donor mbIL21-expanded NK Cells
  • mbIL21-expanded Haploidentical NK Cells




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) of membrane-bound interleukin-21-expanded haploidentical natural killer (NK) cells [ Time Frame: Up to 63 days ]
    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.

  2. Incidence of adverse events [ Time Frame: Up to day 28 ]
    Toxicities will be assessed by type and grade using Common Terminology Criteria for Adverse Events version 5.0 and displayed in summary form by cohort and overall. Toxicities will be summarized and reported regardless of attribution and also only those attributed to NK cells.


Secondary Outcome Measures :
  1. Complete response (CR) [ Time Frame: Up to day 56 ]
    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.

  2. CR with incomplete hematologic recovery [ Time Frame: Up to day 56 ]
    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.

  3. Morphologic leukemia-free state [ Time Frame: Up to day 56 ]
    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.

  4. Median relapse free survival [ Time Frame: Up to day 56 ]
    Will use descriptive statistics to summarize the demographic and clinical characteristics of the patients on this study.

  5. Median time to neutrophil and platelet count recovery [ Time Frame: Up to day 56 ]
    Will use descriptive statistics to summarize the demographic and clinical characteristics of the patients on this study.

  6. Median duration of remission [ Time Frame: Up to day 56 ]
    Will use descriptive statistics to summarize the demographic and clinical characteristics of the patients on this study.

  7. Incidence of infectious complications [ Time Frame: Up to day 56 ]
    Will use descriptive statistics to summarize the demographic and clinical characteristics of the patients on this study.

  8. Percentage of patients receiving the regimen who are rendered transplant-eligible [ Time Frame: Up to day 56 ]
    Will use descriptive statistics to summarize the demographic and clinical characteristics of the patients on this study.


Other Outcome Measures:
  1. Identification of In-vivo expansion of NK cells [ Time Frame: Up to day 56 ]
    Peripheral blood will be obtained before therapy, during the NK cell treatment period, and after NK cell treatment. The studies may include flow cytometry analyses and sorting and molecular studies. Donor NK-cell expansion will be defined as an absolute circulating donor-derived NK cell count that increases above the post-infusion level.

  2. Chimerism analysis to determine origin and number of circulating NK cells [ Time Frame: Up to day 56 ]
    Chimerism may be determined by flow cytometry using haplotype-specific antibodies. Chimerism may be determined by short tandem repeat 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. Testing may be altered by principal investigator or designee.

  3. Number of donor human leukocyte antigen (HLA) detection [ Time Frame: Up to day 56 ]
    Donors with distinct HLA A or B antigens that can be detected by flow cytometry will be chosen. This will enable tracking of infused cells.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patient Inclusion Criteria for Induction Phase

  • Primary Relapsed AML including
  • Relapsed AML after allogeneic stem cells
  • Isolated CNS or extramedullary disease (Note: a response monitoring plan must be developed a priori for subjects with extramedullary disease)
  • 1-3 prior lines of therapy which includes chemotherapy, hypomethylating agents, venetoclax or targeted therapy.
  • Patient weight ≥ 42 kg
  • Performance status: Karnofsky or Lansky Performance Scale (PS) greater or equal to 70, or, ECOG score 0-2.
  • Renal function: Serum creatinine ≤ 2 mg/dl and/or creatinine clearance greater or equal than 40 cc/min.
  • Pulmonary function: FEV1, FVC and DLCO ≥ 50% of expected, corrected for hemoglobin.
  • Liver function: Total bilirubin ≤ 2 mg/dl or ≤ 2.5 x ULN for age (unless Gilbert's syndrome) and SGPT (ALT) ≤ 2.5 x ULN for age.
  • Cardiac function: left ventricular ejection fraction ≥ 40%.
  • CNS: Patients with seizure disorder are 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).
  • Patients on hydrocortisone for adrenal insufficiency or on inhaled or topical steroids are eligible.

Maintenance Phase: Patients that complete induction therapy and who achieve a CR/CRi/PR within the designated follow-up period and who are ineligible, unable or unwilling to undergo HSCT; these patients will not receive fludarabine or cytarabine.

Exclusion Criteria for Induction Phase:

  • Investigational therapies in the 3 weeks prior to beginning treatment on this protocol.
  • Patients receiving any concurrent therapy including but not limited to chemotherapy, targeted therapy, radiation therapy, or immunotherapy for R/R AML.
  • Any comorbidities that in the opinion of the investigator will preclude receiving fludarabine 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 CMV, HPV, BK virus, HCV, HBV etc. is NOT considered as an exclusion criteria.
  • Uncontrolled arrhythmias or uncontrolled symptomatic cardiac disease.
  • Active GVHD
  • Prednisone dose is > 20 mg/day or >0.25mg/kg, whichever is higher will be excluded.
  • Patients with donor-specific antibodies with MFI > 5000 will be ineligible
  • Maintenance Phase: Patients must continue to meet exclusion criteria as defined in Section 4.4.

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): NCT04220684


Contacts
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Contact: The Ohio State University Comprehensive Cancer Center 1-800-293-5066 OSUCCCClinicaltrials@osumc.edu
Contact: Nicole Szuminski 614-688-9796 Nicole.Szuminski@osumc.edu

Locations
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United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Sumithira Vasu, MBBS    614-293-8197    Sumithira.Vasu@osumc.edu   
Principal Investigator: Sumithira Vasu, MBBS         
Sponsors and Collaborators
Sumithira Vasu
Investigators
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Principal Investigator: Sumithira Vasu, MBBS Ohio State University Comprehensive Cancer Center
Additional Information:
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Responsible Party: Sumithira Vasu, Principal Investigator, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT04220684    
Other Study ID Numbers: OSU-18336
NCI-2019-05150 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: January 7, 2020    Key Record Dates
Last Update Posted: February 18, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sumithira Vasu, Ohio State University Comprehensive Cancer Center:
Recurrent Acute Myeloid Leukemia
Refractory Acute Myeloid Leukemia
Myelodysplastic Syndrome
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Cytarabine
Fludarabine
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents