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Pilot Study of Expanded , Activated Haploidentical Natural Killer Cell Infusions for Sarcomas (NKEXPSARC)

Primary Purpose

Ewing Sarcoma, Rhabdomyosarcoma

Status

Unknown status

Phase

Phase 1

Locations

Singapore

Study Type

Interventional

Intervention

Expanded , Activated NK cells

About this trial

This is an interventional treatment trial for Ewing Sarcoma focused on measuring EWS, RMS

Eligibility Criteria

undefined - 80 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

A ) NK cell Recipient:

Age 0 months to 80 years old.
Patients with metastatic, progressive or relapsed EWS, RMS after completing standard of care therapy who are at high risk of relapse even if they do not have any evidence of residual disease.
a) For patients without residual disease at the point of study entry, response to NK cells will be measured by their incidence of relapse as indicated by their 5-year event free survival. Only patients at high risk of relapse > 70% will be enrolled if there is no evidence of residual disease.
Shortening fraction greater than or equal to 25%. 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) 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).
HIV negative. Negative results must be within 60 days prior to enrolment.

Exclusion Criteria:

Failure to meet any of the inclusion criteria.

Sites / Locations

National University HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Expanded, activated NK Cells(NKEXPSARC)

Arm Description

Intravenous infusion of expanded, activated NK Cells Donor cell will be expanded and activated in the cGMP compliant TECT lab for 10 to 12 days prior to infusion into the patient.

Outcomes

Primary Outcome Measures

Disease response after expanded activated NK cell infusion

Radiological response will be measured based on PET or MRI or CT scan whichever is appropriate imaging for the tumor type and location.

Secondary Outcome Measures

Persistence and phenotype of expanded NK cells in research participants with EWS, RMS and OS.

NK cell persistence and phenotype will be monitored weekly upto 4 weeks post infusion from peripheral blood.

Toxicity of NK cells infusion (NCI toxicity criteria CTC version 4.0)

Patients will be monitored for toxicity based on NCI toxicity criteria CTC version 4.0

Performance status will be assessed by age-dependent Performances Scores ( Lansky scale or Karnofsky performance scale)

Patients performance status will be monitored using Lansky scale for patients below 16 years of age and Karnofsky performance scale for patients more than 16 years of age.

Acute and Chronic GVHD

Patients will monitored for clinical evidence of GVHD

Full Information

NCT ID

NCT02409576

First Posted

April 1, 2015

Last Updated

April 12, 2019

Sponsor

National University Hospital, Singapore

1. Study Identification

Unique Protocol Identification Number

NCT02409576

Brief Title

Pilot Study of Expanded , Activated Haploidentical Natural Killer Cell Infusions for Sarcomas

Acronym

NKEXPSARC

Official Title

Pilot Study of Expanded , Activated Haploidentical Natural Killer Cell Infusions for Sarcomas

Study Type

Interventional

2. Study Status

Record Verification Date

April 2019

Overall Recruitment Status

Unknown status

Study Start Date

February 2015 (undefined)

Primary Completion Date

August 2020 (Anticipated)

Study Completion Date

September 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National University Hospital, Singapore

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Progress in the treatment of children with leukemia and lymphoma results in high cure rates but progress in the treatment of children and adolescents with solid tumors has been slow. Despite aggressive therapy with multimodality treatment involving surgery, radiation and chemotherapy, about two thirds of the patients with metastatic Ewing sarcoma (EWS), and intermediate and high risk rhabdomyosarcoma (RMS) will relapse. The available second line therapies for relapse are limited and often not effective. There is a dire need to look for treatment options beyond conventional means for the treatment of these patients. Infusions of allogeneic natural killer (NK) cells in leukemia patients have shown to be tolerated well without inducing graft versus host disease (GVHD). There is also mounting evidence that NK cells have activity against solid tumors. In the lab the investigators tested NK cell activity against cell lines from different paediatric solid tumors. Among paediatric solid tumors, EWS and RMS are exquisitely sensitive to killing by expanded NK cells; NK cells also have activity against OS cells. Preliminary clinical data suggest that donor NK cells may exert antitumor activity in children with solid tumors undergoing allogeneic hematopoietic stem cell transplantation. Taking into account the safety of adaptive NK cell infusion, and their efficacy against EWS, RMS and OS, NK cells could be a powerful new tool in the treatment of paediatric solid tumors. The great anti-tumor activity of expanded and activated NK cells, together with the feasibility of infusing haploidentical NK cells in a non-transplant setting form a compelling rationale for the clinical testing of these NK cells in patients with sarcoma.

Detailed Description

Adoptive transfer of allogeneic NK cells has been shown to be safe in patients with leukemia. The patients enrolled on this will receive lymphodepleting chemotherapy with cyclophosphamide (1 day) followed by fludarabine (5 days) Each patient will receive IL-2 on alternate days starting 1 day before infusion of NK cells for a total of 6 doses. Patient will undergo imaging MRI or PET or CT scan one month after the infusion to assess response to the NK cell infusion. In our study we aim to determine the feasibility, safety and efficacy of expanded, activated NK cells in patients with EWS and RMS . We will also study the persistence and phenotype of expanded NK cells in research participants with EWS and RMS . The main hypothesis to be tested in this study is that infusion of expanded, activated haploidentical NK cells can produce measurable clinical responses in patients with EWS and RMS .

6. Conditions and Keywords

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

Ewing Sarcoma, Rhabdomyosarcoma

Keywords

EWS, RMS

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Expanded, activated NK Cells(NKEXPSARC)

Arm Type

Experimental

Arm Description

Intravenous infusion of expanded, activated NK Cells Donor cell will be expanded and activated in the cGMP compliant TECT lab for 10 to 12 days prior to infusion into the patient.

Intervention Type

Biological

Intervention Name(s)

Expanded , Activated NK cells

Intervention Description

Chemotherapy - Each patient will receive immunosuppressive chemotherapy before infusion of NK cells. Day -7 Cyclophosphamide at 60mg/kg Day -6 Fludarabine at 25mg/m2 daily for 5 days Radiation - Each patient will receive radiation within 48 hr of NK cell infusion to make the tumor cells more sensitive to NK cell killing Radiation 2Gy Cytokine support - Each pateint will receive IL-2 to support NK cell activation and expansion in vivo Day -1 alternate day for a total of 6 doses NK cells - Expanded activated haploidentical NK cells will be infused on day 0.

Primary Outcome Measure Information:

Title

Disease response after expanded activated NK cell infusion

Description

Radiological response will be measured based on PET or MRI or CT scan whichever is appropriate imaging for the tumor type and location.

Time Frame

1 month post-NK cell infusion (and at regular intervals thereafter till a year post-NK cell infusion)

Secondary Outcome Measure Information:

Title

Persistence and phenotype of expanded NK cells in research participants with EWS, RMS and OS.

Description

NK cell persistence and phenotype will be monitored weekly upto 4 weeks post infusion from peripheral blood.

Time Frame

1 month ( 30 days) post- NK cell infusion

Title

Toxicity of NK cells infusion (NCI toxicity criteria CTC version 4.0)

Description

Patients will be monitored for toxicity based on NCI toxicity criteria CTC version 4.0

Time Frame

1 month ( 30 days) post- NK cell infusion

Title

Performance status will be assessed by age-dependent Performances Scores ( Lansky scale or Karnofsky performance scale)

Description

Patients performance status will be monitored using Lansky scale for patients below 16 years of age and Karnofsky performance scale for patients more than 16 years of age.

Time Frame

Initiation of conditioning till 30 days post-NK cell infusion

Title

Acute and Chronic GVHD

Description

Patients will monitored for clinical evidence of GVHD

Time Frame

Initiation of conditioning until 1 month ( 30 days) post- last dose of IL-2

10. Eligibility

Sex

All

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: A ) NK cell Recipient: Age 0 months to 80 years old. Patients with metastatic, progressive or relapsed EWS, RMS after completing standard of care therapy who are at high risk of relapse even if they do not have any evidence of residual disease. a) For patients without residual disease at the point of study entry, response to NK cells will be measured by their incidence of relapse as indicated by their 5-year event free survival. Only patients at high risk of relapse > 70% will be enrolled if there is no evidence of residual disease. Shortening fraction greater than or equal to 25%. 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) 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). HIV negative. Negative results must be within 60 days prior to enrolment. Exclusion Criteria: Failure to meet any of the inclusion criteria.

Central Contact Person:

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

Bernice Oh Lingzhi, MBBS

Phone

(65)97739114

bernice_lx_oh@nuhs.edu.sg

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bernice Oh

Organizational Affiliation

Department of Paediatrics, National University Hospital

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Dario Campana

Organizational Affiliation

Department of Paediatrics, National University of Singapore

Official's Role

Principal Investigator

Facility Information:

Facility Name

National University Hospital

City

Singapore

ZIP/Postal Code

119228

Country

Singapore

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Bernice Oh

Phone

(65) 97739114

bernice_lx_oh@nuhs.edu.sg

First Name & Middle Initial & Last Name & Degree

Clarice Chan

Phone

(65) 67726586

chan_zi_ying_clarice@nuhs.edu.sg

First Name & Middle Initial & Last Name & Degree

Bernice Oh

First Name & Middle Initial & Last Name & Degree

Dario Campana

12. IPD Sharing Statement

Citations:

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

22771496

Citation

Perez-Martinez A, de Prada Vicente I, Fernandez L, Gonzalez-Vicent M, Valentin J, Martin R, Maxwell H, Sevilla J, Vicario JL, Diaz MA. Natural killer cells can exert a graft-vs-tumor effect in haploidentical stem cell transplantation for pediatric solid tumors. Exp Hematol. 2012 Nov;40(11):882-891.e1. doi: 10.1016/j.exphem.2012.07.004. Epub 2012 Jul 4.

Results Reference

background

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Pilot Study of Expanded , Activated Haploidentical Natural Killer Cell Infusions for Sarcomas

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