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Clinical Grade Adenovirus Specific T Cells for Immunotherapy After Allogeneic Stem Cell Transplantation (CTL-ADV) (CTL-ADV)

Primary Purpose

Adenovirus Infection

Status

Completed

Phase

Phase 1

Locations

France

Study Type

Interventional

Intervention

Infusion of ADV specific T cells

About this trial

This is an interventional treatment trial for Adenovirus Infection focused on measuring Adenovirus

Eligibility Criteria

6 Months - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Study Population : adults or children
Allogeneic hematopoietic stem cell (bone marrow and peripheral blood stem cell, umbilical cord blood (UCB))
sibling or matched unrelated donors 10/10 or 9/10 ((M)MUD) or haploidentical donor in case of UCB transplantation

Within 18 months after HSCT, occurrence of:

- An adenovirus infection without clinical symptoms (except fever with unknown origin) definitively due to this infection, after treatment failure during at least 2 weeks with Cidofovir (5 mg/kg/week).

To determine ADV infection, 2 consecutive viremia performed at 4 days interval must be higher than viral threshold of 500 copies/mL (with significant increase between these 2 analysis and at least 0, 5 log when the first viremia is equal to 500 cp/mL).

Probable or definitive adenovirus infection after Cidofovir treatment failure, 5 mg/kg/week (according to Wisconsin's criteria)
and/or renal toxicity or major intolerance to anti-viral drug
and/or in case Cidofovir is not available in France
Acute or Chronic GVHD with acute form grade II or less, controlled after 2 lines of treatment at the most.

Or controlled Chronic GVHD

- Life expectancy > 1 month at the time of inclusion

Exclusion Criteria:

Graft failure
Derogatory HSCT
Acute or Chronic GVHD in acute form with grade > II, uncontrolled after 2 lines of immunosuppressive agents.
Patients with grade > III clinical or biological toxicities (according to OMS classification)
Chronic GVHD uncontrolled
Immediate life-threatening
Patients have not signed informed consent

Sites / Locations

Centre Hospitalier Universitaire de Nancy

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Infusion of ADV specific T cells

Arm Description

This one arm study consists in ADV-specific T cell infusion after HSCT from a (M)MUD or, for the first time, from a haploidentical donor for patients having undergone previous UCB transplantation, in the event of refractory ADV infection or disease. Specific anti-ADV immune reconstitution was observed in all patients, and viral load clearance in all but one.

Outcomes

Primary Outcome Measures

Graft Versus Hot Disease (GVHD) grade >2

No occurrence of acute Graft Versus Hot Disease (GVHD) grade >2 and/or extensive chronic GVHD and no reactivation or worsening of acute or chronic GVHD during the first month following infusion.

Secondary Outcome Measures

Follow-up of ADV viral load

Follow-up of ADV viral load by quantitative Polymerase Chain Reaction (PCR) : Decrease > 0.5 Log

Follow-up of anti-ADV immune response

Follow-up of anti-ADV immune response in the recipient (developing a specific immune response based on in vivo CTL expansion evaluated by IFN ELISPOT or intracellular cytokine staining).

Full Information

NCT ID

NCT02851576

First Posted

July 28, 2016

Last Updated

September 13, 2016

Sponsor

Central Hospital, Nancy, France

1. Study Identification

Unique Protocol Identification Number

NCT02851576

Brief Title

Clinical Grade Adenovirus Specific T Cells for Immunotherapy After Allogeneic Stem Cell Transplantation (CTL-ADV)

Acronym

CTL-ADV

Official Title

Generation of Clinical Grade Adenovirus Specific T Cells for Adoptive Immunotherapy After Allogeneic Stem Cell Transplantation : Clinical Trial

Study Type

Interventional

2. Study Status

Record Verification Date

September 2016

Overall Recruitment Status

Completed

Study Start Date

August 2011 (undefined)

Primary Completion Date

March 2015 (Actual)

Study Completion Date

March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Central Hospital, Nancy, France

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Fourteen patients will be included for infusion of adenovirus-specific T-cells generated by a clinical grade IFN-γ based immunomagnetic isolation from a leukapheresis from their original donor or a haploidentical donor, in case of Umbilical cord blood transplantation, in the event of refractory ADV infection or disease.

Detailed Description

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) has improved over the last decades. However, after HSCT and especially with matched unrelated, cord blood or haploidentical donors, patients often experience a deep immunodeficiency, increasing susceptibility to viral infections. Among them, adenovirus (ADV) systemic infection, often refractory to antiviral treatment, is associated with a high mortality rate up to 50% (even more in children). Viremia monitoring after HSCT has contributed to improve survival allowing the implementation of a pre-emptive anti-viral treatment before any appearance of clinical signs of ADV disease. Nevertheless, no anti-viral drug is authorized for ADV infections, although intravenous (IV) cidofovir seemed to be, up to now, the most efficient. However, nephrotoxicity, especially tubular dysfunction, is often described, requiring hydratation and uroprotection with probenecid and limiting the treatment period. Meanwhile, adoptive transfer of ADV-specific T cells, prepared with an immunomagnetic clinical grade technology, is becoming an alternative treatment that has already proved feasible, safe and helpful in viral clearance and immune reconstitution related to an in vivo expansion of ADV-specific T cells leading to clinical improvement (Feuchtinger et al, 2006, 2015; Qazim et al, 2013). Our team proposes a multicenter Phase I/II clinical trial with ADV-specific T cells where 14 patients, with refractory ADV infection or disease after unrelated Peripheral blood or umbilical cord blood HSCT, are included.

6. Conditions and Keywords

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

Adenovirus Infection

Keywords

Adenovirus

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

14 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Infusion of ADV specific T cells

Arm Type

Experimental

Arm Description

Intervention Type

Other

Intervention Name(s)

Infusion of ADV specific T cells

Intervention Description

Cell engineering

Primary Outcome Measure Information:

Title

Graft Versus Hot Disease (GVHD) grade >2

Description

No occurrence of acute Graft Versus Hot Disease (GVHD) grade >2 and/or extensive chronic GVHD and no reactivation or worsening of acute or chronic GVHD during the first month following infusion.

Time Frame

1 month

Secondary Outcome Measure Information:

Title

Follow-up of ADV viral load

Description

Follow-up of ADV viral load by quantitative Polymerase Chain Reaction (PCR) : Decrease > 0.5 Log

Time Frame

90 days

Title

Follow-up of anti-ADV immune response

Description

Follow-up of anti-ADV immune response in the recipient (developing a specific immune response based on in vivo CTL expansion evaluated by IFN ELISPOT or intracellular cytokine staining).

Time Frame

90 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

6 Months

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Study Population : adults or children Allogeneic hematopoietic stem cell (bone marrow and peripheral blood stem cell, umbilical cord blood (UCB)) sibling or matched unrelated donors 10/10 or 9/10 ((M)MUD) or haploidentical donor in case of UCB transplantation Within 18 months after HSCT, occurrence of: - An adenovirus infection without clinical symptoms (except fever with unknown origin) definitively due to this infection, after treatment failure during at least 2 weeks with Cidofovir (5 mg/kg/week). To determine ADV infection, 2 consecutive viremia performed at 4 days interval must be higher than viral threshold of 500 copies/mL (with significant increase between these 2 analysis and at least 0, 5 log when the first viremia is equal to 500 cp/mL). Probable or definitive adenovirus infection after Cidofovir treatment failure, 5 mg/kg/week (according to Wisconsin's criteria) and/or renal toxicity or major intolerance to anti-viral drug and/or in case Cidofovir is not available in France Acute or Chronic GVHD with acute form grade II or less, controlled after 2 lines of treatment at the most. Or controlled Chronic GVHD - Life expectancy > 1 month at the time of inclusion Exclusion Criteria: Graft failure Derogatory HSCT Acute or Chronic GVHD in acute form with grade > II, uncontrolled after 2 lines of immunosuppressive agents. Patients with grade > III clinical or biological toxicities (according to OMS classification) Chronic GVHD uncontrolled Immediate life-threatening Patients have not signed informed consent

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Cécile POCHON, Doctor

Organizational Affiliation

Central Hospital, Nancy, France

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Laurence CLEMENT, Doctor

Organizational Affiliation

University Hospital, Bordeaux

Official's Role

Principal Investigator

Facility Information:

Facility Name

Centre Hospitalier Universitaire de Nancy

City

Vandœuvre-Lès-Nancy

ZIP/Postal Code

54511

Country

France

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

20386465

Citation

Aissi-Rothe L, Decot V, Venard V, Jeulin H, Salmon A, Clement L, Kennel A, Mathieu C, Dalle JH, Rauser G, Cambouris C, de Carvalho M, Stoltz JF, Bordigoni P, Bensoussan D. Rapid generation of full clinical-grade human antiadenovirus cytotoxic T cells for adoptive immunotherapy. J Immunother. 2010 May;33(4):414-24. doi: 10.1097/CJI.0b013e3181cc263b.

Results Reference

background

PubMed Identifier

25617426

Citation

Feucht J, Opherk K, Lang P, Kayser S, Hartl L, Bethge W, Matthes-Martin S, Bader P, Albert MH, Maecker-Kolhoff B, Greil J, Einsele H, Schlegel PG, Schuster FR, Kremens B, Rossig C, Gruhn B, Handgretinger R, Feuchtinger T. Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT. Blood. 2015 Mar 19;125(12):1986-94. doi: 10.1182/blood-2014-06-573725. Epub 2015 Jan 23.

Results Reference

background

PubMed Identifier

16803570

Citation

Feuchtinger T, Matthes-Martin S, Richard C, Lion T, Fuhrer M, Hamprecht K, Handgretinger R, Peters C, Schuster FR, Beck R, Schumm M, Lotfi R, Jahn G, Lang P. Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation. Br J Haematol. 2006 Jul;134(1):64-76. doi: 10.1111/j.1365-2141.2006.06108.x.

Results Reference

background

PubMed Identifier

28482908

Citation

Qian C, Campidelli A, Wang Y, Cai H, Venard V, Jeulin H, Dalle JH, Pochon C, D'aveni M, Bruno B, Paillard C, Vigouroux S, Jubert C, Ceballos P, Marie-Cardine A, Galambrun C, Cholle C, Clerc Urmes I, Petitpain N, De Carvalho Bittencourt M, Decot V, Reppel L, Salmon A, Clement L, Bensoussan D. Curative or pre-emptive adenovirus-specific T cell transfer from matched unrelated or third party haploidentical donors after HSCT, including UCB transplantations: a successful phase I/II multicenter clinical trial. J Hematol Oncol. 2017 May 8;10(1):102. doi: 10.1186/s13045-017-0469-0.

Results Reference

derived

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Clinical Grade Adenovirus Specific T Cells for Immunotherapy After Allogeneic Stem Cell Transplantation (CTL-ADV)

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