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

NCT02409576 | Unknown Phase 1 DMC

• 3 other identifiers: DSRB 2014/00452CTC1400413 (NUH)CTC1400412 (KKWCH)
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Ewing Sarcoma; Rhabdomyosarcoma

Keywords

EWS; RMS

Outcome Measures

Primary Outcomes (1)

• 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.

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

Secondary Outcomes (4)

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

  1 month ( 30 days) post- NK cell infusion

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

  1 month ( 30 days) post- NK cell infusion

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

  Initiation of conditioning till 30 days post-NK cell infusion

• Acute and Chronic GVHD

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

Study Arms (1)

Expanded, activated NK Cells(NKEXPSARC)

EXPERIMENTAL

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.

Biological: Expanded , Activated NK cells

Interventions

Expanded , Activated NK cells BIOLOGICAL

1. 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 2. 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 3. 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 4. NK cells - Expanded activated haploidentical NK cells will be infused on day 0.

Expanded, activated NK Cells(NKEXPSARC)

Eligibility Criteria

• Age: Up to 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

Sponsors & Collaborators

• National University Hospital, Singapore: lead

Study Sites (1)

National University Hospital

Singapore, 119228, Singapore

RECRUITING

Related Publications (2)

• 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.

  PMID: 20542985 BACKGROUND

• 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.

  PMID: 22771496 BACKGROUND

MeSH Terms

Conditions

Sarcoma, Ewing; Rhabdomyosarcoma

Condition Hierarchy (Ancestors)

Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Myosarcoma; Neoplasms, Muscle Tissue

Study Officials

• Bernice Oh

  Department of Paediatrics, National University Hospital

  PRINCIPAL INVESTIGATOR

• Dario Campana

  Department of Paediatrics, National University of Singapore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Bernice Oh Lingzhi, MBBS

CONTACT

(65)97739114; bernice_lx_oh@nuhs.edu.sg

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 1, 2015
• First Posted: April 7, 2015
• Study Start: February 1, 2015
• Primary Completion: August 1, 2020
• Study Completion: September 1, 2020
• Last Updated: April 16, 2019

Record last verified: 2019-04

Locations

SG (1)