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Pilot Study of Redirected Haploidentical Natural Killer Cell Infusions for B-Lineage Acute Lymphoblastic Leukemia

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ClinicalTrials.gov Identifier: NCT01974479
Recruitment Status : Suspended (Suspended for an interim review of (CAR) CD19 research strategy for the treatment of CD19 positive ALL.)
First Posted : November 1, 2013
Last Update Posted : April 12, 2019
Sponsor:
Information provided by (Responsible Party):
Dr. Tan Poh Lin, National University Health System, Singapore

Brief Summary:

Modern therapy for patients with B-lineage acute lymphoblastic leukemia (ALL) is based on intensive administration of multiple drugs. In patients with relapsed disease, treatment response is generally poor; for most patients, particularly those who relapse while still receiving frontline therapy, the only therapeutic option is hematopoietic stem cell transplantation (HSCT). There is no proven curative therapy for patients who relapse after transplant.

Natural killer (NK) cells have powerful anti-leukemia activity. In patients undergoing allogeneic HSCT, several studies have demonstrated NK-mediated anti-leukemic activity. NK cell infusions in patients with leukemia have been shown to be well tolerated and void of graft-versus-host disease (GVHD) effects.

NK cell cytotoxicity is most powerful against acute myeloid leukemia (AML) cells, whereas their capacity to lyse ALL cells is generally low. We have developed a novel method to expand and redirect NK cells towards CD19, a molecule highly expressed on the surface of B-lineage ALL cells but not expressed on normal cells other than B-lymphocytes. In this method, donor NK cells are first expanded by co-culture with the cell line K562-mb15-41BBL and interleukin (IL)-2. Then, the expanded NK cells are transduced with a signaling receptor that binds to CD19 (anti-CD19-BB-zeta). NK cells expressing these receptors showed powerful anti-leukemic activity against CD19+ ALL cells in vitro and in an animal model of leukemia.

This study will assess the feasibility, safety and efficacy of infusing expanded, activated redirected NK cells into research participants with B-lineage ALL who have persistent disease after intensive chemotherapy . In this same cohort, we will study the in vivo lifespan and phenotype of these redirected NK cells.


Condition or disease Intervention/treatment Phase
B-cell Acute Lymphoblastic Leukemia Biological: anti-CD19 redirected NK cells Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: To determine the feasibility, safety and efficacy of anti-CD19 redirected NK cells infusion in research participants with B-Lineage Acute Lymphoblastic Leukemia (B-ALL) who have persistent disease as determined by MRD methods after intensive chemotherapy.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study of Redirected Haploidentical Natural Killer Cell Infusions for B-Lineage Acute Lymphoblastic Leukemia
Actual Study Start Date : September 2013
Actual Primary Completion Date : February 2017
Estimated Study Completion Date : February 2020


Arm Intervention/treatment
Experimental: anti-CD19 redirected NK cells
This is a single arm study. Intravenous Infusion of activated NK cells bearing anti-CD19-BB-zeta receptors at cell dose of 0.5 - 5 x 10^7 CD56+ cells/kg, and up to 1 x 10^8 CD56+ cells/Kg
Biological: anti-CD19 redirected NK cells
Haploidentical donor NK cells will be expanded and electroporated over 10 days and infused. NK cells will be infused at single dose on day 0. The patient will receive cyclophosphamide 60mg/kg on day - 7 , and Fludarabine 25 mg/m2/day will be given on day -6 to day -2 prior to the NK cell infusion. IL- 2 will be given subcutaneously for 6 doses every alternate day starting on day -1, for NK cell survival.
Other Name: NKCARCD19




Primary Outcome Measures :
  1. Disease Response Criteria - Minimal Disease Residual (MRD) Monitoring [ Time Frame: 1 Month Post NK Cell Infusion ]
    Treatment response will be measured by comparing MRD levels before and 1 month after NK cell infusion. Achievement of MRD negativity in bone marrow, i.e., < 0.01% blasts by flow cytometry or PCR, will be regarded as a complete response. Partial response will be defined as ≥ 1 log decrease in MRD levels, while < 1 log decrease in MRD levels will be regarded as no response.



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Ages Eligible for Study:   up to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • NK cell RECIPIENT:

    1. Age: 0 months to 80 years old.
    2. Patients with B-lineage ALL who have persistent disease (0.01% to less than 1% as determined by flow cytometric or molecular measurements of residual disease) despite intensive standard chemotherapy .
    3. Shortening fraction greater than or equal to 25%.
    4. Glomerular filtration rate greater than or equal to 50 ml/min/1.73 m2.
    5. Pulse oximetry greater than or equal to 92% on room air.
    6. Direct bilirubin less than or equal to 3.0 mg/dL (50 mmol/L).
    7. Alanine aminotransferase (ALT) is no more than 2 times the upper limit of normal.
    8. Aspartate transaminases (AST)is no more than 2 times the upper limit of normal.
    9. Karnofsky or Lansky performance score of greater than or equal to 50.
    10. No known allergy to murine products or HAMA testing results within normal limits.
    11. No prior receipt of a gene-transfer agent (e.g. retroviral,adenoviral, lentiviral vector).
    12. Does not have a current pleural or pericardial effusion.
    13. Has a suitable adult family member donor available for NK cell donation.
    14. Has recovered from all acute NCI Common Toxicity Criteria grade II-IV non-hematologic acute toxicities resulting from prior therapy per the judgment of the PI.
    15. At least two weeks since receipt of any biological therapy, systemic chemotherapy, and/or radiation therapy.
    16. Is not receiving more than the equivalent of prednisone 10 mg daily.
    17. Not pregnant (negative serum or urine pregnancy test to be conducted within 7 days prior to enrollment).
    18. Not lactating.
  • NK cell DONOR:

    1. First and second relative acceptable.
    2. 18 years of age or above.
    3. Not lactating.
    4. Greater than or equal to 3 of 6 HLA match to recipient.
    5. Meets eligibility and suitability criteria for hematopoietic cells donation as per institutional guidelines.
    6. Not pregnant (negative serum or urine pregnancy test to be conducted within 7 days prior to enrollment).

Exclusion Criteria:

  • Failure to meet any of the inclusion criteria.

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): NCT01974479


Locations
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Singapore
Department of Paediatrics, National University Health System
Singapore, Singapore, 119228
Sponsors and Collaborators
National University Health System, Singapore
Investigators
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Principal Investigator: Poh Lin Tan NUHS Singapore
Principal Investigator: Dario Campana NUHS Singapore
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Dr. Tan Poh Lin, Clinical Director and Senior Consultant of Paediatric Blood and Marrow Transplantation, National University Health System, Singapore
ClinicalTrials.gov Identifier: NCT01974479    
Other Study ID Numbers: NKCARCD19
First Posted: November 1, 2013    Key Record Dates
Last Update Posted: April 12, 2019
Last Verified: April 2019
Keywords provided by Dr. Tan Poh Lin, National University Health System, Singapore:
Redirected Natural Killer Cells
Haploidentical Cell Therapy
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases