NeuroblastomaPhase 1NCT03209869
Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Expanded Haploidentical NK Cells and Hu14.18-IL2
A Phase 1 study testing Ex vivo Expanded and Activated Haploidentical Donor NK Cells and Hu14.18-IL2 in people with Neuroblastoma and Relapsed Neuroblastoma, run by University of Wisconsin, Madison at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 7 months to 25 years
- Conditions the study is for
- Neuroblastoma, Relapsed Neuroblastoma, Recurrent Neuroblastoma
- What is being tested?
- Ex vivo Expanded and Activated Haploidentical Donor NK Cells and Hu14.18-IL2
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- 12 Mar 2018to 7 Sep 2022
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 7 months to 25 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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)
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Wisconsin Carbone Cancer Center; UW Hospital and Clinics
Madison, Wisconsin, 53792
About this study
Official title: Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Ex-Vivo Expanded and Activated Haploidentical NK Cells and Hu14.18-IL2
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.
Read the 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.
- Being tested
- Ex vivo Expanded and Activated Haploidentical Donor NK Cells, Hu14.18-IL2
- Medical subject headings
- Neuroblastoma, Osteosarcoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ex vivo Expanded and Activated Haploidentical Donor NK CellsBiological
Also called EANK cells
Haploidentical donor NK cells that are expanded and activated under current GMP conditions using K562-mbIL15-41BBL.
Hu14.18-IL2Biological
Also called Immunocytokine
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.
| Study group | Role | What they receive |
|---|---|---|
| Single arm | Experimental | All subjects will receive Ex vivo Expanded and Activated Haploidentical Donor NK Cells + hu14.18-IL2 Receives: Biological: Ex vivo Expanded and Activated Haploidentical Donor NK Cells; Biological: Hu14.18-IL2 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: up to 28 days after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
Safety: Incidence of any grade acute or chronic GVHD
Safety will be assessed by monitoring for any grade acute or chronic GVHD.
Measured: up to 21 days after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
Secondary outcomes (9)
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
Measured: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
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
Measured: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
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
Measured: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
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
Measured: 28 days
Immunocytokine (hu14.18-IL2) serum levels given as daily infusions for 7 consecutive days
Hu14.18-IL2 serum levels will be assessed using ELISA
Measured: up to 28 days after last hu14.18-IL2 infusion
Immunogenicity of hu14.18-IL2 given as daily infusions for 7 consecutive days
Measurement of anti-hu14.18-IL2 antibodies (HAHA) using ELISA
Measured: up to 28 days after last hu14.18-IL2 infusion
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.
Measured: 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
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
Measured: 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 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
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jul 2017
- Study start12 Mar 2018
- Primary completion7 Sep 2022
- Study completion7 Sep 2022
Why it stopped: resources limited due to COVID-19
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for NeuroblastomaStudies of the same condition, open and under way.
- More trials run by University of Wisconsin, MadisonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Wisconsin, Madison
- Sponsor type
- University, hospital or other
- 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
- Responsible party
- Sponsor
- Investigators
- Ken DeSantes, MD, Principal investigator, University of Wisconsin, Madison
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03209869
- Sponsor's protocol ID
- UW16009
- Other IDs
- P30CA014520, 2016-1195, A536755, SMPH/PEDIATRICS/PEDIATRICS, NCI-2017-01267, Protocol V12 01/30/2021
- Status last verified
- Sep 2022
- First submitted
- 13 Jun 2017
- Last updated
- 13 Sep 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Sep 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Ex-Vivo Expanded and Activated Haploidentical NK Cells and Hu14.18-IL2
- ClinicalTrials.gov ID
- NCT03209869
- Acronym / sponsor ID
- UW16009
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: resources limited due to COVID-19
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University of Wisconsin, MadisonUniversity, hospital or other
- 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
- Study start
- 12 Mar 2018 (actual)
- Primary completion
- 7 Sep 2022 (actual)
- Study completion
- 7 Sep 2022 (actual)
- First posted
- 6 Jul 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Single arm | Experimental | Biological: Ex vivo Expanded and Activated Haploidentical Donor NK Cells, Biological: Hu14.18-IL2All subjects will receive Ex vivo Expanded and Activated Haploidentical Donor NK Cells + hu14.18-IL2 |
Who may qualify
- Ages
- 7 months to 25 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (28 listed)
- 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
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ex vivo Expanded and Activated Haploidentical Donor NK CellsAlso: EANK cellsHaploidentical donor NK cells that are expanded and activated under current GMP conditions using K562-mbIL15-41BBL. | Biological | Single arm |
| Hu14.18-IL2Also: ImmunocytokineThe 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. | Biological | Single arm |
Primary outcome
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.
9 secondary outcomes
Efficacy: Progression free survival
Time frame: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
Efficacy: Overall survival
Time frame: up to12 months after final dose of EA-NK cells or hu14.18-IL2, whichever occurs last
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
Longevity of EA-NK cells in vivo
Time frame: 28 days
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
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
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
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
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
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Sep 2022.
- UW Carbone Cancer Center Home PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ken DeSantes, MD principal investigator
University of Wisconsin, Madison
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Ex vivo Expanded and Activated Haploidentical Donor NK Cells and Hu14.18-IL2 in people with Neuroblastoma and Relapsed Neuroblastoma, run by University of Wisconsin, Madison at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 28 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 13 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Sep 2022.