Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Ex-Vivo Expanded and Activated Haploidentical NK Cells and Hu14.18-IL2
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Neuroblastoma
- Sponsor
- University of Wisconsin, Madison
- Locations
- 1
- Primary Endpoint
- Safety: Incidence of any grade acute or chronic GVHD
- Status
- Withdrawn
- Last Updated
- 3 years ago
Overview
Brief Summary
Subjects with relapsed or refractory neuroblastoma and osteosarcoma will receive ex-vivo expanded and activated natural killer (NK) cells from a haploidentical donor in conjunction with the immunocytokine, hu14.18-IL2.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Relapsed or refractory neuroblastoma
- •Relapsed or refractory Osteosarcoma
- •Karnofsky/Lansky performance score \> 50
- •Life expectancy ≥ 4 months
- •Creatinine clearance or radioisotope GFR ≥ 60 ml/min/1.73m2 OR serum creatinine within normal limits based on age and gender
- •ANC ≥ 750/µL
- •Platelet count ≥ 50,000/µL
- •Hemoglobin ≥ 8 g/dL
- •Total bilirubin ≤ 1.5 x upper limit of normal for age
- •ALT (SCPT) ≤ 5 x upper limit of normal for age
Exclusion Criteria
- •Prior history of ventilator support related to lung injury, except for immediately following thoracotomy
- •Symptomatic pleural effusions or ascites
- •\<6 weeks from thoracotomy and \<2 weeks from other major surgery
- •History of anaphylaxis while receiving prior anti-GD2 therapy
- •HIV infection
- •Heart failure or uncontrolled cardiac rhythm disturbance
- •Active infection
- •Prior organ allograft
- •Prior allogeneic bone marrow or peripheral blood stem cell transplant
- •Significant serious intercurrent illnesses expected to interfere with the antitumor effect of treatment or to significantly increase the severity of toxicities experienced from treatment
Outcomes
Primary Outcomes
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.
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.
Secondary Outcomes
- Efficacy: Objective tumor response (SD + CR + PR)(up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last)
- Immunogenicity of hu14.18-IL2 given as daily infusions for 7 consecutive days(up to 28 days after last hu14.18-IL2 infusion)
- EANK cell survival in vivo(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)
- Efficacy: Progression free survival(up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last)
- Efficacy: Overall survival(up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last)
- Longevity of EA-NK cells in vivo(28 days)
- NK cell activity(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)
- Proportion and absolute numbers of NK and T cell subsets(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)
- Immunocytokine (hu14.18-IL2) serum levels given as daily infusions for 7 consecutive days(up to 28 days after last hu14.18-IL2 infusion)