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Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Expanded Haploidentical NK Cells and Hu14.18-IL2

Primary Purpose

Neuroblastoma, Relapsed Neuroblastoma, Recurrent Neuroblastoma

Status

Withdrawn

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Ex vivo Expanded and Activated Haploidentical Donor NK Cells

Hu14.18-IL2

About this trial

This is an interventional treatment trial for Neuroblastoma

Eligibility Criteria

7 Months - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

University of Wisconsin Carbone Cancer Center; UW Hospital and Clinics

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single arm

Arm Description

All subjects will receive Ex vivo Expanded and Activated Haploidentical Donor NK Cells + hu14.18-IL2

Outcomes

Primary Outcome Measures

Safety: Incidence of treatment-emergent adverse events of treatment with AENK cells and hu14.18-IL2

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

Safety will be assessed by monitoring for any grade acute or chronic GVHD.

Secondary Outcome Measures

Efficacy: Progression free survival

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

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)

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

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

Hu14.18-IL2 serum levels will be assessed using ELISA

Immunogenicity of hu14.18-IL2 given as daily infusions for 7 consecutive days

Measurement of anti-hu14.18-IL2 antibodies (HAHA) using ELISA

Proportion and absolute numbers of NK and T cell subsets

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

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

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

Full Information

NCT ID

NCT03209869

First Posted

June 13, 2017

Last Updated

September 12, 2022

Sponsor

University of Wisconsin, Madison

Collaborators

National Cancer Institute (NCI), Solving Kids' Cancer, Midwest Athletes Against Childhood Cancer, Inc. (MACC Fund), Wade's Army, The Catherine Elizabeth Blair Memorial Foundation / GWCF

1. Study Identification

Unique Protocol Identification Number

NCT03209869

Brief Title

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

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Withdrawn

Why Stopped

resources limited due to COVID-19

Study Start Date

March 12, 2018 (Actual)

Primary Completion Date

September 7, 2022 (Actual)

Study Completion Date

September 7, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Wisconsin, Madison

Collaborators

National Cancer Institute (NCI), Solving Kids' Cancer, Midwest Athletes Against Childhood Cancer, Inc. (MACC Fund), Wade's Army, The Catherine Elizabeth Blair Memorial Foundation / GWCF

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Neuroblastoma, Relapsed Neuroblastoma, Recurrent Neuroblastoma, Osteosarcoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Single arm

Arm Type

Experimental

Arm Description

All subjects will receive Ex vivo Expanded and Activated Haploidentical Donor NK Cells + hu14.18-IL2

Intervention Type

Biological

Intervention Name(s)

Ex vivo Expanded and Activated Haploidentical Donor NK Cells

Other Intervention Name(s)

EANK cells

Intervention Description

Haploidentical donor NK cells that are expanded and activated under current GMP conditions using K562-mbIL15-41BBL.

Intervention Type

Biological

Intervention Name(s)

Hu14.18-IL2

Other Intervention Name(s)

Immunocytokine

Intervention Description

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.

Primary Outcome Measure Information:

Title

Safety: Incidence of treatment-emergent adverse events of treatment with AENK cells and hu14.18-IL2

Description

Time Frame

up to 28 days after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last

Title

Safety: Incidence of any grade acute or chronic GVHD

Description

Safety will be assessed by monitoring for 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

Secondary Outcome Measure Information:

Title

Efficacy: Progression free survival

Description

The time elapsed from initial EANK cell infusion until disease progression or death or study censure 12 months after final dose of immunotherapy

Time Frame

up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last

Title

Efficacy: Overall survival

Description

The time from initial EANK cell infusion until death from any cause or study censure 12 months after final dose of immunotherapy

Time Frame

up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last

Title

Efficacy: Objective tumor response (SD + CR + PR)

Description

The anti-tumor effect of treatment will be assessed by quantifying the number of subjects who achieve stable disease, complete remission and partial remission

Time Frame

up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last

Title

Longevity of EA-NK cells in vivo

Description

Evaluating the survival of EA-NK cells in the subject using flow cytometric analysis of donor-only antigens

Time Frame

28 days

Title

Immunocytokine (hu14.18-IL2) serum levels given as daily infusions for 7 consecutive days

Description

Hu14.18-IL2 serum levels will be assessed using ELISA

Time Frame

up to 28 days after last hu14.18-IL2 infusion

Title

Immunogenicity of hu14.18-IL2 given as daily infusions for 7 consecutive days

Description

Measurement of anti-hu14.18-IL2 antibodies (HAHA) using ELISA

Time Frame

up to 28 days after last hu14.18-IL2 infusion

Title

Proportion and absolute numbers of NK and T cell subsets

Description

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.

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

Title

EANK cell survival in vivo

Description

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

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

Title

NK cell activity

Description

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

7 Months

Maximum Age & Unit of Time

25 Years

Accepts Healthy Volunteers

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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ken DeSantes, MD

Organizational Affiliation

University of Wisconsin, Madison

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Wisconsin Carbone Cancer Center; UW Hospital and Clinics

City

Madison

State/Province

Wisconsin

ZIP/Postal Code

53792

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Links:

URL

http://www.uwhealth.org/uw-carbone-cancer-center/cancer/10252

Description

UW Carbone Cancer Center Home Page

Learn more about this trial

Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Expanded Haploidentical NK Cells and Hu14.18-IL2

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