Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Expanded Haploidentical NK Cells and Hu14.18-IL2
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|ClinicalTrials.gov Identifier: NCT03209869|
Recruitment Status : Suspended (resources limited due to COVID-19)
First Posted : July 6, 2017
Last Update Posted : June 9, 2021
|Condition or disease||Intervention/treatment||Phase|
|Neuroblastoma Relapsed Neuroblastoma Recurrent Neuroblastoma Osteosarcoma||Biological: Ex vivo Expanded and Activated Haploidentical Donor NK Cells Biological: Hu14.18-IL2||Phase 1|
Natural Killer cells, a type of white blood cell, circulate around the body and kill abnormal cells (cells that are malignant, damaged or infected with virus). Sometimes cancer cells adapt to the body's own NK cells and are able to avoid being killed by them. This clinical trial uses two strategies to overcome the cancer cells' ability to avoid NK cell-mediated death.
The first strategy involves giving NK cells from another individual to the patient (in other words, donor- or haploidentical-NK cells). This is done because NK cells from an individual who is haploidentical (half-matched genetic make-up) are still able to effectively kill the cancer cells. Unfortunately, only a limited number of NK cells can be obtained from a donor. So, to increase the number of cancer-killing NK cells that will be given to the patient, the donor NK cells will first be grown in a sterile laboratory environment and allowed to multiply many-fold before they are infused into the patient. This growing process also activates the donor NK cells, which increases their ability to kill cancer cells.
The second strategy to overcome the cancer cells' ability to avoid NK cell-mediated death is to administer the immunocytokine, hu14.18-IL2, every day for seven days after infusion of the donor NK cells. The antibody portion (hu14.18) of the immunocytokine molecule "flags" the neuroblastoma cells for destruction by NK cells and the cytokine portion (IL2) further activates the NK cells (as well as other anti-tumor immune effector cells).
Since the donor NK cells are from a haploidentical individual, they are different enough to be recognized as foreign cells and will be killed immediately ("rejected") by the patients own immune system unless the immune system is restrained. So, to allow the donor NK cells time to kill neuroblastoma cells before they are "rejected", a chemotherapy regimen is first given to the patient to temporarily restrain the patient's own immune system. This also allows "room" for the donor NK cells to live, multiply and function.
Four courses of treatment are planned for each subject. Each course of treatment will be approximately one month long and involves a week of chemotherapy followed by infusion of donor NK cells. Beginning the day after the donor NK cell infusion, hu14.18-IL2 is infused over four hours for seven consecutive days.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||6 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Ex-Vivo Expanded and Activated Haploidentical NK Cells and Hu14.18-IL2|
|Actual Study Start Date :||March 12, 2018|
|Estimated Primary Completion Date :||September 1, 2021|
|Estimated Study Completion Date :||September 1, 2021|
Experimental: Single arm
All subjects will receive Ex vivo Expanded and Activated Haploidentical Donor NK Cells + hu14.18-IL2
Biological: Ex vivo Expanded and Activated Haploidentical Donor NK Cells
Haploidentical donor NK cells that are expanded and activated under current GMP conditions using K562-mbIL15-41BBL.
Other Name: EANK cells
The immunocytokine, hu14.18-IL2, is a fusion protein comprised of one molecule of the anti-GD2 humanized monoclonal antibody, hu14.18, fused to two molecules of the cytokine, interleukin-2.
Other Name: Immunocytokine
- Safety: Incidence of treatment-emergent adverse events of treatment with AENK cells and hu14.18-IL2 [ Time Frame: up to 28 days after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last ]Safety will be assessed by quantifying adverse events ≥ grade 3, using CTCAE (v.5), with certain pre-defined exceptions based on known, transient, reversible, clinically manageable toxicities of the chemotherapy and hu14.18-IL2.
- Safety: Incidence of any grade acute or chronic GVHD [ Time Frame: up to 21 days after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last ]Safety will be assessed by monitoring for any grade acute or chronic GVHD.
- Efficacy: Progression free survival [ Time Frame: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last ]The time elapsed from initial EANK cell infusion until disease progression or death or study censure 12 months after final dose of immunotherapy
- Efficacy: Overall survival [ Time Frame: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last ]The time from initial EANK cell infusion until death from any cause or study censure 12 months after final dose of immunotherapy
- Efficacy: Objective tumor response (SD + CR + PR) [ Time Frame: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last ]The anti-tumor effect of treatment will be assessed by quantifying the number of subjects who achieve stable disease, complete remission and partial remission
- Longevity of EA-NK cells in vivo [ Time Frame: 28 days ]Evaluating the survival of EA-NK cells in the subject using flow cytometric analysis of donor-only antigens
- Immunocytokine (hu14.18-IL2) serum levels given as daily infusions for 7 consecutive days [ Time Frame: up to 28 days after last hu14.18-IL2 infusion ]Hu14.18-IL2 serum levels will be assessed using ELISA
- Immunogenicity of hu14.18-IL2 given as daily infusions for 7 consecutive days [ Time Frame: up to 28 days after last hu14.18-IL2 infusion ]Measurement of anti-hu14.18-IL2 antibodies (HAHA) using ELISA
- Proportion and absolute numbers of NK and T cell subsets [ Time Frame: up to 22 days after the third EANK cell infusion for subjects in Cohort A and up to 22 days after the second EANK cell infusion for subjects in Cohort B ]NK and T cell subsets will be evaluated using flow cytometric assessment of cell phenotype expressed as percentages of larger cell subsets and absolute numbers.
- EANK cell survival in vivo [ Time Frame: up to 22 days after the third EANK cell infusion for subjects in Cohort A and up to 22 days after the second EANK cell infusion for subjects in Cohort B ]The longevity of EANK cells in vivo (i.e., after infusion) will be assessed by evaluating donor-specific HLA markers present on NK cells using flow cytometry
- NK cell activity [ Time Frame: up to 22 days after the third EANK cell infusion for subjects in Cohort A and up to 22 days after the second EANK cell infusion for subjects in Cohort B ]The functional status of NK cells will be measured: 1) indirectly by assessing NK activation receptor expression and NK exhaustion marker expression using flow cytometric analyses and 2) directly by measuring the ability of NK cells to kill tumor cells in vitro
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): NCT03209869
|United States, Wisconsin|
|University of Wisconsin Carbone Cancer Center; UW Hospital and Clinics|
|Madison, Wisconsin, United States, 53792|
|Principal Investigator:||Ken DeSantes, MD||University of Wisconsin, Madison|