Clinical trial NCT03209869: Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Expanded Haploidentical NK Cells and Hu14.18-IL2
Official title: Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Ex-Vivo Expanded and Activated Haploidentical NK Cells and Hu14.18-IL2
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Neuroblastoma
Relapsed Neuroblastoma
Recurrent Neuroblastoma
Osteosarcoma
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: Solving Kids' Cancer
name: Midwest Athletes Against Childhood Cancer, Inc. (MACC Fund)
name: Wade's Army
name: The Catherine Elizabeth Blair Memorial Foundation / GWCF
First posted: 2017-07-06
Enrollment: 0
Sex: ALL
Minimum age (years): 7
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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
* Shortening fraction of ≥ 27% by echocardiogram OR Ejection fraction of ≥55% by MUGA
* No evidence of dyspnea at rest
* Pulse oximetry \> 94% on room air
* If PFTs performed, FEV1/FVC must be \> 60%
* All Osteosarcoma patients must have PFTs performed
* CNS toxicity ≤ Grade 2
* Patients with seizure disorders may be enrolled if seizures are well controlled on anticonvulsant therapy
* \> 100 days after autologous stem cell infusion following myeloablative therapy
* ≥ 2 weeks since chemotherapy
* ≥ 7 days since anti-neoplastic, non-myelosuppressive biologic agent (or extended for agents known to have adverse events beyond the 7- day period)
* ≥ 2 weeks for local palliative XRT
* ≥ 6 months if prior craniospinal axis XRT (\> 50%)
* ≥ 6 months if \> 50% radiation of pelvis
* ≥ 6 weeks after therapeutic 131I-MIBG
* ≥ 6 weeks since thoracotomy
* Informed consent obtained (patient or legal representative)
* Women of reproductive potential must have negative pregnancy test and be willing to use effective birth control method
* Suitable haploidentical donor must be available

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
* Pregnant
* 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
* Any mental or physical condition, in the opinion of the PI (or PI designee), which could interfere with the ability of the subject (or the only parent or legal guardian available to care for the subject) to understand or adhere to the requirements of the study.
* Enrollment in any other treatment study from screening up to 28 days after the last treatment on this study (unless PI judges such enrollment would not interfere with endpoints of this study)

Primary outcomes:
measure: Safety: Incidence of treatment-emergent adverse events of treatment with AENK cells and hu14.18-IL2
timeFrame: up to 28 days after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
measure: Safety: Incidence of any grade acute or chronic GVHD
timeFrame: up to 21 days after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
Secondary outcomes:
measure: Efficacy: Progression free survival
timeFrame: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
measure: Efficacy: Overall survival
timeFrame: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
measure: Efficacy: Objective tumor response (SD + CR + PR)
timeFrame: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
measure: Longevity of EA-NK cells in vivo
timeFrame: 28 days
measure: Immunocytokine (hu14.18-IL2) serum levels given as daily infusions for 7 consecutive days
timeFrame: up to 28 days after last hu14.18-IL2 infusion
measure: Immunogenicity of hu14.18-IL2 given as daily infusions for 7 consecutive days
timeFrame: up to 28 days after last hu14.18-IL2 infusion
measure: Proportion and absolute numbers of NK and T cell subsets
timeFrame: 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
measure: EANK cell survival in vivo
timeFrame: 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
measure: NK cell activity
timeFrame: 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
Other outcomes:
Locations:
city: Madison
country: United States
facility: University of Wisconsin Carbone Cancer Center; UW Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: Ken DeSantes, MD
role: PRINCIPAL_INVESTIGATOR
References: