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Immunotherapy of Neuroblastoma Patients Using a Combination of Anti-GD2 and NK Cells (NKEXPGD2)

Primary Purpose

Neuroblastoma Recurrent

Status

Unknown status

Phase

Phase 1

Locations

Singapore

Study Type

Interventional

Intervention

Anti-GD2 in combination with NK cells

About this trial

This is an interventional treatment trial for Neuroblastoma Recurrent focused on measuring Relapsed, Refractory, Neuroblastoma, Anti-GD2, Natural Killer (NK) Cells, Immunotherapy

Eligibility Criteria

6 Months - 25 Years (Child, Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

A) 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.
1. 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.
2. Recurrence after completion of standard treatment.
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.

B) 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).

Exclusion Criteria:

Failure to meet any of the above criteria

Sites / Locations

National University HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Anti-GD2 in combination with NK cells

Arm Description

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.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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.

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

Full Information

NCT ID

NCT03242603

First Posted

July 13, 2017

Last Updated

March 28, 2018

Sponsor

National University Hospital, Singapore

1. Study Identification

Unique Protocol Identification Number

NCT03242603

Brief Title

Immunotherapy of Neuroblastoma Patients Using a Combination of Anti-GD2 and NK Cells

Acronym

NKEXPGD2

Official Title

Pilot Study of Anti-GD2 and Expanded, Activated Natural Killer Cell Infusion for Neuroblastoma

Study Type

Interventional

2. Study Status

Record Verification Date

June 2017

Overall Recruitment Status

Unknown status

Study Start Date

October 3, 2017 (Actual)

Primary Completion Date

August 15, 2019 (Anticipated)

Study Completion Date

August 15, 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National University Hospital, Singapore

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief 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. 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).

6. Conditions and Keywords

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

Neuroblastoma Recurrent

Keywords

Relapsed, Refractory, Neuroblastoma, Anti-GD2, Natural Killer (NK) Cells, Immunotherapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

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)

Allocation

N/A

Enrollment

5 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Anti-GD2 in combination with NK cells

Arm Type

Experimental

Arm Description

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.

Intervention Type

Biological

Intervention Name(s)

Anti-GD2 in combination with NK cells

Intervention Description

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.

Primary Outcome Measure Information:

Title

Description

Time Frame

2 years

Secondary Outcome Measure Information:

Title

To measure the numbers of infused NK cells in peripheral blood at specific time-points after NK cell infusion

Description

NK cells will be identified by flow cytometry in peripheral blood and their percentages and absolute numbers will be calculated.

Time Frame

2 years

Title

To measure cytokine levels in plasma at specific time-points after NK cell infusion

Description

Cytokine panel to assess levels of IL15 serially post lymphodepletion regimen

Time Frame

2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

6 Months

Maximum Age & Unit of Time

25 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: - A) 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. 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. B) 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). Exclusion Criteria: Failure to meet any of the above criteria

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Miriam Kimpo, MD

Phone

+65 8494 3914

miriam_kimpo@nuhs.edu.sg

First Name & Middle Initial & Last Name or Official Title & Degree

Chetan Dhamne, MBBS, MS, MD

Phone

+65 6772 3361

chetan_dhamne@nuhs.edu.sg

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Miriam Kimpo, MD

Organizational Affiliation

National University Hospital, Singapore

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Dario Campana, MD, PhD

Organizational Affiliation

National University Singapore, Singapore

Official's Role

Principal Investigator

Facility Information:

Facility Name

National University Hospital

City

Singapore

ZIP/Postal Code

119074

Country

Singapore

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Miriam Kimpo, MD

Phone

(+65) 8494 3914

miriam_kimpo@nuhs.edu.sg

First Name & Middle Initial & Last Name & Degree

Chetan Dhamne, MBBS, MS, MD

Phone

(+65) 6772 3361

chetan_dhamne@nuhs.edu.sg

First Name & Middle Initial & Last Name & Degree

Dr. Miriam Kimpo, MD

First Name & Middle Initial & Last Name & Degree

Dr.Chetan Dhamne, MBBS, MS. MD

12. IPD Sharing Statement

Plan to Share IPD

Undecided

IPD Sharing Plan Description

TBC

Citations:

PubMed Identifier

20879881

Citation

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.

Results Reference

background

PubMed Identifier

20542985

Citation

Cho 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.

Results Reference

background

PubMed Identifier

22863621

Citation

Tarek 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.

Results Reference

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Immunotherapy of Neuroblastoma Patients Using a Combination of Anti-GD2 and NK Cells

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