Neuroblastoma RecurrentPhase 1/2NKEXPGD2NCT03242603
Immunotherapy of Neuroblastoma Patients Using a Combination of Anti-GD2 and NK Cells
A Phase 1/2 study testing Anti-GD2 in combination with NK cells in people with Neuroblastoma Recurrent, run by National University Hospital, Singapore at 1 site in Singapore.
Trial summary
Neuroblastoma is a neoplasm of the sympathetic nervous system which affects mostly children younger than 5 years of age. It is a heterogeneous disease, with nearly 50% of patients presenting with a high-risk phenotype. Read more about this study
- Who is it for?
- Ages 6 months to 25 yearsHealthy volunteers can take part
- Conditions the study is for
- Neuroblastoma Recurrent
- What is being tested?
- Anti-GD2 in combination with NK cells
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 1 siteSingapore
- Study dates
- 3 Oct 2017to 15 Aug 2020
- Phase
- Phase 1/2
- 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 6 months to 25 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- -
- Inclusion criteria for activated NK cell Recipient:
- Age 6 months to 25 years old.
- Patients with high risk or relapsed neuroblastoma who have measurable residual disease (based on imaging findings with Curie scoring or MIBG or PET imaging criteria) after receiving or has refused to receive standard therapy.
- High risk will be defined as stage IV disease with poor response to chemotherapy. Residual disease after surgery or prior to autologous stem cell rescue which is part of Standard of Care. Infants with nMYC amplification will not automatically qualify for the protocol unless they have residual disease after surgery.
- Recurrence after completion of standard treatment.
Show all 27Show fewer
- Shortening fraction greater than or equal to 25% or Left ventricular ejection fraction (LVEF) greater than or equal to 40%.
- Glomerular filtration rate greater than or equal to 60 ml/min/1.73 m2.
- Pulse oximetry greater than or equal to 92% on room air.
- Direct bilirubin less than or equal to 3.0 mg/dL (50 mmol/L).
- Alanine aminotransferase (ALT) is no more than 2 times the upper limit of normal.
- Aspartate transaminases (AST) is no more than 2 times the upper limit of normal.
- Karnofsky or Lansky performance score of greater than or equal to 50.
- Does not have a current pleural or pericardial effusion.
- Has a suitable adult family member donor available for NK cell donation.
- Has recovered from all acute NCI Common Terminology Criteria for Adverse Events (CTCAE) grade II-IV non-hematologic acute toxicities resulting from prior therapy per the judgment of the PI.
- At least two weeks since receipt of any biological therapy, systemic chemotherapy, and/or radiation therapy.
- Is not receiving more than the equivalent of prednisone 10 mg daily.
- Not pregnant (negative serum or urine pregnancy test to be conducted within 7 days prior to enrollment).
- Not lactating.
- Inclusion criteria for NK cell Donor:
- First and second degree relative acceptable.
- 18 years of age or above.
- Not lactating.
- Greater than or equal to 3 of 6 HLA match to recipient.
- .Meets eligibility and suitability criteria for hematopoietic cells donation as per institutional guidelines.
- Not pregnant (negative serum or urine pregnancy test to be conducted within 7 days prior to enrollment).
Who cannot join
- Failure to meet any of the above criteria
Trial locations and contacts
1 site in 1 country.
Singapore1 site, 1 recruiting
- Recruiting
National University Hospital
Singapore, 119074
Miriam Kimpo, MD, (+65) 8494 3914, miriam_kimpo@nuhs.edu.sg
Chetan Dhamne, MBBS, MS, MD, (+65) 6772 3361, chetan_dhamne@nuhs.edu.sg
About this study
Official title: Pilot Study of Anti-GD2 and Expanded, Activated Natural Killer Cell Infusion for Neuroblastoma
Neuroblastoma is a neoplasm of the sympathetic nervous system which affects mostly children younger than 5 years of age. It is a heterogeneous disease, with nearly 50% of patients presenting with a high-risk phenotype. After standard treatment, the 2-year event-free survival (EFS) for high risk neuroblastoma (EFS) is only about 50%. Immunotherapy with anti-GD2 antibodies has been shown to improve EFS in Children's Oncology Group and SIOPEN trials.
The anti-GD2 antibody mediates neuroblastoma cell killing primarily through antibody-dependent cell-mediated cytotoxicity (ADCC). Natural killer (NK) cells are the main effectors of ADCC. We postulate that infusion of expanded activated NK cells from healthy haploidentical donors along with anti-GD2 antibody will enhance neuroblastoma killing.
Read the detailed description
Adoptive transfer of haploidentical NK cells has been shown to be safe in clinical trials at NUH. There is experience combining antibody infusion with autologous NK cells in the clinical trial with good safety data.
The proposed trial is a phase I/II study to determine the safety and efficacy of expanded activated haploidentical NK cells in combination with anti-GD2 (ch14.18/CHO). We plan to enrol patients with high risk or relapsed neuroblastoma with evidence of residual disease who are at high risk of recurrence or progression on current treatment.
In the proposed protocol , we plan to infuse NK cells at escalating dose levels to find the optimum dose tolerated by the patients in combination with anti-GD2 (ch14.18/CHO) . There are 3 NK cell dose levels :
Dose level 1 (1 x 10^6/kg) , Dose level 2 (1 x 10^7/kg) , Dose level 3 (1 x 10^8/kg)
If a partial response or stable disease is observed, further infusions of NK cells can be administered. There will be intra- and inter - patient dose escalation.
The donor will be either parent, based on the best NK cell donor as determined by the study team. The donor will be harvested and NK cells expanded prior to infusion into the patient along with anti-GD2 (ch14.18/CHO).
The study aims to study safety and efficacy of a combination of NK cells and anti-GD2 (ch14.18/CHO).
- Conditions
- Neuroblastoma Recurrent
- Being tested
- Anti-GD2 in combination with NK cells
- Keywords
- Relapsed, Refractory, Neuroblastoma, Anti-GD2, Natural Killer (NK) Cells, Immunotherapy
- Medical subject headings
- Recurrence, Neuroblastoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Anti-GD2 in combination with NK cellsBiological
Haploidentical donor NK cells will be expanded over 10 days and infused in combination with anti-GD2. Anti-GD2 will be given as daily infusion for 5 days ; D-1, 0,+1, +2 and +3. NK cells will be infused at single dose on day 0. The patient will receive cyclophosphamide 60mg/kg on day -3 and day -2 prior to the NK cell infusion. IL- 2 will be given subcutaneously for 6 doses every alternate day starting on day -1, for NK cell survival.
| Study group | Role | What they receive |
|---|---|---|
| Anti-GD2 in combination with NK cells | Experimental | This is a single arm study. Patients with high risk neuroblastoma who have residual measurable disease will receive a combination of 5 days of anti-GD2 with expanded activated NK cells. Receives: Biological: Anti-GD2 in combination with NK cells |
What is being measured
The primary outcome is the main question the study is designed to answer.
To measure tumor response after infusion of expanded activated haploidentical NK cells with anti-GD2. Response will be assessed as defined by Revised International Neuroblastoma Response Criteria 2017.
Disease status at primary and metastatic soft tissue sites will be assessed using MIBG scans or PET scan as applicable. RECIST and Curie scoring systems will be used to assess response. Metastatic bone disease will be assessed using MIBG or PET scan. Bone marrow will be assessed by histology or flow cytometry. Disease response will be defined as Complete response/remission (CR), Partial response (PR), Minor response, Stable disease (SD), or Progressive disease(PD).
Measured: 2 years
Secondary outcomes (2)
To measure the numbers of infused NK cells in peripheral blood at specific time-points after NK cell infusion
NK cells will be identified by flow cytometry in peripheral blood and their percentages and absolute numbers will be calculated.
Measured: 2 years
To measure cytokine levels in plasma at specific time-points after NK cell infusion
Cytokine panel to assess levels of IL15 serially post lymphodepletion regimen
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Aug 2017
- Study start3 Oct 2017
- Primary completion15 Aug 2019 (estimated)
- Study completion15 Aug 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Neuroblastoma RecurrentStudies of the same condition, open and under way.
- More trials run by National University Hospital, SingaporeThe 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 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- To determine the feasibility, safety and effectiveness of anti-GD2 in combination with expanded, activated NK cells in research participants with Neuroblastoma
- Masking
- None (open label)
- Enrolment
- 5 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National University Hospital, Singapore
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Miriam Kimpo, MD, Principal investigator, National University Hospital, SingaporeDario Campana, MD, PhD, Principal investigator, National University Singapore, Singapore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03242603
- Sponsor's protocol ID
- NKEXPGD2
- Acronym
- NKEXPGD2
- Status last verified
- Jun 2017
- First submitted
- 13 Jul 2017
- Last updated
- 30 Mar 2018
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: TBC
Publications
Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM; Children's Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1324-34. doi: 10.1056/NEJMoa0911123.
PubMed 20879881Cho D, Shook DR, Shimasaki N, Chang YH, Fujisaki H, Campana D. Cytotoxicity of activated natural killer cells against pediatric solid tumors. Clin Cancer Res. 2010 Aug 1;16(15):3901-9. doi: 10.1158/1078-0432.CCR-10-0735. Epub 2010 Jun 11.
PubMed 20542985Tarek N, Le Luduec JB, Gallagher MM, Zheng J, Venstrom JM, Chamberlain E, Modak S, Heller G, Dupont B, Cheung NK, Hsu KC. Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment. J Clin Invest. 2012 Sep;122(9):3260-70. doi: 10.1172/JCI62749. Epub 2012 Aug 6.
PubMed 22863621
Study at a glance
From the registry record, last updated by the sponsor on 30 Mar 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Study of Anti-GD2 and Expanded, Activated Natural Killer Cell Infusion for Neuroblastoma
- ClinicalTrials.gov ID
- NCT03242603
- Acronym / sponsor ID
- NKEXPGD2 / NKEXPGD2
- Conditions
- Neuroblastoma Recurrent
- Keywords
- Relapsed, Refractory, Neuroblastoma, Anti-GD2, Natural Killer (NK) Cells, Immunotherapy
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 5 participants (estimated)
- Lead sponsor
- National University Hospital, SingaporeUniversity, hospital or other
- Study start
- 3 Oct 2017 (actual)
- Primary completion
- 15 Aug 2019 (estimated)
- Study completion
- 15 Aug 2020 (estimated)
- First posted
- 8 Aug 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.
Neuroblastoma is a neoplasm of the sympathetic nervous system which affects mostly children younger than 5 years of age. It is a heterogeneous disease, with nearly 50% of patients presenting with a high-risk phenotype. After standard treatment, the 2-year event-free survival (EFS) for high risk neuroblastoma (EFS) is only about 50%. Immunotherapy with anti-GD2 antibodies has been shown to improve EFS in Children's Oncology Group and SIOPEN trials.
The anti-GD2 antibody mediates neuroblastoma cell killing primarily through antibody-dependent cell-mediated cytotoxicity (ADCC). Natural killer (NK) cells are the main effectors of ADCC. We postulate that infusion of expanded activated NK cells from healthy haploidentical donors along with anti-GD2 antibody will enhance neuroblastoma killing.
Detailed description
Adoptive transfer of haploidentical NK cells has been shown to be safe in clinical trials at NUH. There is experience combining antibody infusion with autologous NK cells in the clinical trial with good safety data.
The proposed trial is a phase I/II study to determine the safety and efficacy of expanded activated haploidentical NK cells in combination with anti-GD2 (ch14.18/CHO). We plan to enrol patients with high risk or relapsed neuroblastoma with evidence of residual disease who are at high risk of recurrence or progression on current treatment.
In the proposed protocol , we plan to infuse NK cells at escalating dose levels to find the optimum dose tolerated by the patients in combination with anti-GD2 (ch14.18/CHO) . There are 3 NK cell dose levels :
Dose level 1 (1 x 10^6/kg) , Dose level 2 (1 x 10^7/kg) , Dose level 3 (1 x 10^8/kg)
If a partial response or stable disease is observed, further infusions of NK cells can be administered. There will be intra- and inter - patient dose escalation.
The donor will be either parent, based on the best NK cell donor as determined by the study team. The donor will be harvested and NK cells expanded prior to infusion into the patient along with anti-GD2 (ch14.18/CHO).
The study aims to study safety and efficacy of a combination of NK cells and anti-GD2 (ch14.18/CHO).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- To determine the feasibility, safety and effectiveness of anti-GD2 in combination with expanded, activated NK cells in research participants with Neuroblastoma
| Arm | Type | Receives |
|---|---|---|
| Anti-GD2 in combination with NK cells | Experimental | Biological: Anti-GD2 in combination with NK cellsThis is a single arm study. Patients with high risk neuroblastoma who have residual measurable disease will receive a combination of 5 days of anti-GD2 with expanded activated NK cells. |
Who may qualify
- Ages
- 6 months to 25 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
Key inclusion criteria (27 listed)
- -
- Inclusion criteria for activated NK cell Recipient:
- Age 6 months to 25 years old.
- Patients with high risk or relapsed neuroblastoma who have measurable residual disease (based on imaging findings with Curie scoring or MIBG or PET imaging criteria) after receiving or has refused to receive standard therapy.
- Shortening fraction greater than or equal to 25% or Left ventricular ejection fraction (LVEF) greater than or equal to 40%.
Key exclusion criteria (1 listed)
- Failure to meet any of the above criteria
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 |
|---|---|---|
| Anti-GD2 in combination with NK cellsHaploidentical donor NK cells will be expanded over 10 days and infused in combination with anti-GD2. Anti-GD2 will be given as daily infusion for 5 days ; D-1, 0,+1, +2 and +3. NK cells will be infused at single dose on day 0. The patient will receive cyclophosphamide 60mg/kg on day -3 and day -2 prior to the NK cell infusion. IL- 2 will be given subcutaneously for 6 doses every alternate day starting on day -1, for NK cell survival. | Biological | Anti-GD2 in combination with NK cells |
Primary outcome
To measure tumor response after infusion of expanded activated haploidentical NK cells with anti-GD2. Response will be assessed as defined by Revised International Neuroblastoma Response Criteria 2017.
Time frame: 2 years
Disease status at primary and metastatic soft tissue sites will be assessed using MIBG scans or PET scan as applicable. RECIST and Curie scoring systems will be used to assess response. Metastatic bone disease will be assessed using MIBG or PET scan. Bone marrow will be assessed by histology or flow cytometry. Disease response will be defined as Complete response/remission (CR), Partial response (PR), Minor response, Stable disease (SD), or Progressive disease(PD).
2 secondary outcomes
To measure the numbers of infused NK cells in peripheral blood at specific time-points after NK cell infusion
Time frame: 2 years
To measure cytokine levels in plasma at specific time-points after NK cell infusion
Time frame: 2 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Mar 2018.
- Background: PubMed 20879881Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM; Children's Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1324-34. doi: 10.1056/NEJMoa0911123.
- Background: PubMed 20542985Cho D, Shook DR, Shimasaki N, Chang YH, Fujisaki H, Campana D. Cytotoxicity of activated natural killer cells against pediatric solid tumors. Clin Cancer Res. 2010 Aug 1;16(15):3901-9. doi: 10.1158/1078-0432.CCR-10-0735. Epub 2010 Jun 11.
- Background: PubMed 22863621Tarek N, Le Luduec JB, Gallagher MM, Zheng J, Venstrom JM, Chamberlain E, Modak S, Heller G, Dupont B, Cheung NK, Hsu KC. Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment. J Clin Invest. 2012 Sep;122(9):3260-70. doi: 10.1172/JCI62749. Epub 2012 Aug 6.
- Individual participant dataSharing planned: Undecided. TBC
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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.
Miriam Kimpo, MD principal investigator
National University Hospital, Singapore
Dario Campana, MD, PhD principal investigator
National University Singapore, Singapore
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Anti-GD2 in combination with NK cells in people with Neuroblastoma Recurrent, run by National University Hospital, Singapore at 1 site in Singapore.
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 27 inclusion and 1 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: status not confirmed, as of the sponsor's last update on 30 Mar 2018. 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 Singapore. 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 combined 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.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Miriam Kimpo, MD (+65 8494 3914, miriam_kimpo@nuhs.edu.sg), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To measure tumor response after infusion of expanded activated haploidentical NK cells with anti-GD2. Response will be assessed as defined by Revised International Neuroblastoma Response Criteria 2017. (time frame: 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03242603, which also lists 3 linked publications.
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 30 Mar 2018.