NCT01974479

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.

Trial Health

33
At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Trial recruitment is currently suspended
Enrollment
20

participants targeted

Target at P25-P50 for phase_1

Timeline
Completed

Started Sep 2013

Longer than P75 for phase_1

Geographic Reach
1 country

1 active site

Status
suspended

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

September 1, 2013

Completed
2 months until next milestone

First Submitted

Initial submission to the registry

October 20, 2013

Completed
12 days until next milestone

First Posted

Study publicly available on registry

November 1, 2013

Completed
3.3 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

February 1, 2017

Completed
3 years until next milestone

Study Completion

Last participant's last visit for all outcomes

February 1, 2020

Completed
Last Updated

April 12, 2019

Status Verified

April 1, 2019

Enrollment Period

3.4 years

First QC Date

October 20, 2013

Last Update Submit

April 10, 2019

Conditions

B-cell Acute Lymphoblastic Leukemia

Keywords

Redirected Natural Killer CellsHaploidentical Cell Therapy

Outcome Measures

Primary Outcomes (1)

  • Disease Response Criteria - Minimal Disease Residual (MRD) Monitoring

    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.

    1 Month Post NK Cell Infusion

Study Arms (1)

anti-CD19 redirected NK cells

EXPERIMENTAL

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

Interventions

anti-CD19 redirected NK cellsBIOLOGICAL

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.

Also known as: NKCARCD19
anti-CD19 redirected NK cells

Eligibility Criteria

AgeUp to 80 Years
Sexall
Healthy VolunteersNo
Age GroupsChild (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

  • NK cell RECIPIENT:
  • Age: 0 months to 80 years old.
  • 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 .
  • Shortening fraction greater than or equal to 25%.
  • Glomerular filtration rate greater than or equal to 50 ml/min/1.73 m2.
  • Pulse oximetry greater than or equal to 92% on room air.
  • Direct bilirubin less than or equal to 3.0 mg/dL (50 mmol/L).
  • Alanine aminotransferase (ALT) is no more than 2 times the upper limit of normal.
  • Aspartate transaminases (AST)is no more than 2 times the upper limit of normal.
  • Karnofsky or Lansky performance score of greater than or equal to 50.
  • No known allergy to murine products or HAMA testing results within normal limits.
  • No prior receipt of a gene-transfer agent (e.g. retroviral,adenoviral, lentiviral vector).
  • Does not have a current pleural or pericardial effusion.
  • Has a suitable adult family member donor available for NK cell donation.
  • 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.
  • +11 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Department of Paediatrics, National University Health System

Singapore, 119228, Singapore

Location

Related Publications (5)

  • Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood. 2005 Jul 1;106(1):376-83. doi: 10.1182/blood-2004-12-4797. Epub 2005 Mar 8.

    PMID: 15755898BACKGROUND

  • Shimasaki N, Fujisaki H, Cho D, Masselli M, Lockey T, Eldridge P, Leung W, Campana D. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Cytotherapy. 2012 Aug;14(7):830-40. doi: 10.3109/14653249.2012.671519. Epub 2012 Mar 29.

    PMID: 22458956BACKGROUND

  • Fujisaki H, Kakuda H, Shimasaki N, Imai C, Ma J, Lockey T, Eldridge P, Leung WH, Campana D. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res. 2009 May 1;69(9):4010-7. doi: 10.1158/0008-5472.CAN-08-3712. Epub 2009 Apr 21.

    PMID: 19383914BACKGROUND

  • Lapteva N, Durett AG, Sun J, Rollins LA, Huye LL, Fang J, Dandekar V, Mei Z, Jackson K, Vera J, Ando J, Ngo MC, Coustan-Smith E, Campana D, Szmania S, Garg T, Moreno-Bost A, Vanrhee F, Gee AP, Rooney CM. Large-scale ex vivo expansion and characterization of natural killer cells for clinical applications. Cytotherapy. 2012 Oct;14(9):1131-43. doi: 10.3109/14653249.2012.700767. Epub 2012 Aug 17.

    PMID: 22900959BACKGROUND

  • Del Zotto G, Marcenaro E, Vacca P, Sivori S, Pende D, Della Chiesa M, Moretta F, Ingegnere T, Mingari MC, Moretta A, Moretta L. Markers and function of human NK cells in normal and pathological conditions. Cytometry B Clin Cytom. 2017 Mar;92(2):100-114. doi: 10.1002/cyto.b.21508. Epub 2017 Feb 12.

    PMID: 28054442DERIVED

MeSH Terms

Conditions

Burkitt Lymphoma

Condition Hierarchy (Ancestors)

Epstein-Barr Virus InfectionsHerpesviridae InfectionsDNA Virus InfectionsVirus DiseasesInfectionsTumor Virus InfectionsLymphoma, B-CellLymphoma, Non-HodgkinLymphomaNeoplasms by Histologic TypeNeoplasmsLymphoproliferative DisordersLymphatic DiseasesHemic and Lymphatic DiseasesImmunoproliferative DisordersImmune System Diseases

Study Officials

  • Poh Lin Tan

    NUHS Singapore

    PRINCIPAL INVESTIGATOR

  • Dario Campana

    NUHS Singapore

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 1
Allocation
NA
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Model Details: 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.
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Clinical Director and Senior Consultant of Paediatric Blood and Marrow Transplantation

Study Record Dates

First Submitted

October 20, 2013

First Posted

November 1, 2013

Study Start

September 1, 2013

Primary Completion

February 1, 2017

Study Completion

February 1, 2020

Last Updated

April 12, 2019

Record last verified: 2019-04

Locations

SG(1)