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Infusion of Donor Lymphocytes Transduced With the Suicide Gene HSV TK in Patients With Haematological Malignancies

Primary Purpose

Hematological Malignancies

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
HSV-TK
Sponsored by
AGC Biologics S.p.A.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hematological Malignancies focused on measuring Hematological malignancies, HSV-TK, Haploidentical HCT, GvHD, GvL

Eligibility Criteria

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

Inclusion Criteria:

  • Patients >=18 years old affected by hematological malignancies at high risk of relapse based on disease progression or presence of negative prognostic factors, who have received a HCT from donor HLA mismatched (haploidentical) for 2 or 3 loci
  • Engraftment documented by >500 neutrophils/µl for three consecutive days in the absence of growth factors
  • Mixed chimerism or full donor chimerism confirmed
  • AML in 1st or 2nd relapse or primary refractory
  • High-risk AML in 1st or subsequent remission
  • RAEB and RAEB-T
  • CML in 2nd chronic phase, blast crisis or accelerated phase
  • Poor prognosis ALL in 1st or subsequent remission
  • High grade lymphomas in 3rd or subsequent remission
  • Multiple myeloma in advanced stage relapsing or progressing after high dose chemotherapy
  • Absence of fully HLA matched or one HLA locus mismatched family donor
  • Stable clinical conditions and life expectancy >3 months
  • PS Karnofsky >70
  • Written donor/patient informed consent

Exclusion Criteria:

  • Infection with cytomegalovirus being treated with ganciclovir
  • Presence of GvHD grade > I that requires systemic immunosuppressive therapy (at baseline)
  • Ongoing systemic immunosuppressive therapy
  • Ongoing acyclovir administration
  • Administration after haplo-HCT of G-CSF and cyclosporine A
  • CD3+ lymphocytes >100/µl before day +42 after haplo-HCT
  • Life-threatening condition or complication other than their basic disease
  • CNS disease
  • Pregnant or lactating women

Sites / Locations

  • Medizinische Hoschule Hannover
  • G. Papanicolau
  • Hadassah University Hospital
  • Fondazione San Raffaele
  • Istituto Clinico Humanitas
  • Policlinico Monteluce
  • Ospedale Civile
  • Hammersmith Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

A

Arm Description

Outcomes

Primary Outcome Measures

Evaluation of clinical activity in terms of immune-reconstitution, provided by the add- back of the transduced T-cells after haplo-HCT
Evaluation of the "in vivo" control of GvHD after administration of ganciclovir in patients treated with HSV-TK transduced T-cells
Evaluation of GvL effect

Secondary Outcome Measures

Time to relapse, time to death (evaluated by disease free survival and overall survival)
Incidence of infectious events (measured by number of infectious events)
Acute and long term toxicity related to the infusions (measured by incidence of adverse events)

Full Information

First Posted
January 16, 2007
Last Updated
May 29, 2014
Sponsor
AGC Biologics S.p.A.
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1. Study Identification

Unique Protocol Identification Number
NCT00423124
Brief Title
Infusion of Donor Lymphocytes Transduced With the Suicide Gene HSV TK in Patients With Haematological Malignancies
Official Title
A Phase I-II Study: Infusion of Donor Lymphocytes Transduced With the Suicide Gene HSV TK, After Transplantation of Allogeneic T-depleted Stem Cells From a Haploidentical Donor in Patients With Haematological Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
May 2014
Overall Recruitment Status
Completed
Study Start Date
July 2002 (undefined)
Primary Completion Date
December 2011 (Actual)
Study Completion Date
November 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AGC Biologics S.p.A.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The aim of the study is to obtain immune reconsitutuion as well as reduction of infective episodes and disease relapse in patient with haematological malignancies who underwent SCT(and subsequent T lymphocytes infusions) and selectively controlling GvHD.
Detailed Description
Delayed immune-reconstitution remains one of the main limitation of haploidentical stem cell transplantation. The risk of severe infections remains high for several months and CD4+ reconstitution could take more than 10 months. The low number of lymphocytes infused with the graft, the degree of HLA disparity, and a reduced thymic function in adults and differences in host/donor antigen presenting cells are contributing causes. The infusions of HSV-TK engineered lymphocytes may represent a significant therapeutic improvement in haploidentical haplo-HCT, because it remarkably may enhance both GvL activity, thus reducing the occurrence of disease relapse, and post-transplant immune reconstitution in the absence of chronic immune suppression, thus decreasing the rate of both post-transplant opportunistic infections and transplant-related mortality. Furthermore, the efficient control of GvHD achieved via the suicide mechanism allows also the multiple infusion of HSV-TK-treated donor lymphocytes, when needed, that might further improve post-transplant host immune reconstitution, and, eventually, survival in patients receiving haplo-HCT. Finally, this therapeutic approach, which allows the safe infusion of escalating doses of donor lymphocytes, can become a valuable option for all candidates, including patients with advanced disease and older age. The proposed clinical trial represents an innovative therapeutic treatment for patients affected by hematological malignancies, who have undergone haploidentical stem cell transplantation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hematological Malignancies
Keywords
Hematological malignancies, HSV-TK, Haploidentical HCT, GvHD, GvL

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
57 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A
Arm Type
Experimental
Intervention Type
Genetic
Intervention Name(s)
HSV-TK
Intervention Description
Infusion of genetically modified lymphocytes (1x10^6-1x10^7 c/kg): first at +21-+49 days after HSCT; in absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.
Primary Outcome Measure Information:
Title
Evaluation of clinical activity in terms of immune-reconstitution, provided by the add- back of the transduced T-cells after haplo-HCT
Time Frame
during the study
Title
Evaluation of the "in vivo" control of GvHD after administration of ganciclovir in patients treated with HSV-TK transduced T-cells
Time Frame
during the study
Title
Evaluation of GvL effect
Time Frame
during the study
Secondary Outcome Measure Information:
Title
Time to relapse, time to death (evaluated by disease free survival and overall survival)
Time Frame
during the study
Title
Incidence of infectious events (measured by number of infectious events)
Time Frame
during the study
Title
Acute and long term toxicity related to the infusions (measured by incidence of adverse events)
Time Frame
during the study and study follow up

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients >=18 years old affected by hematological malignancies at high risk of relapse based on disease progression or presence of negative prognostic factors, who have received a HCT from donor HLA mismatched (haploidentical) for 2 or 3 loci Engraftment documented by >500 neutrophils/µl for three consecutive days in the absence of growth factors Mixed chimerism or full donor chimerism confirmed AML in 1st or 2nd relapse or primary refractory High-risk AML in 1st or subsequent remission RAEB and RAEB-T CML in 2nd chronic phase, blast crisis or accelerated phase Poor prognosis ALL in 1st or subsequent remission High grade lymphomas in 3rd or subsequent remission Multiple myeloma in advanced stage relapsing or progressing after high dose chemotherapy Absence of fully HLA matched or one HLA locus mismatched family donor Stable clinical conditions and life expectancy >3 months PS Karnofsky >70 Written donor/patient informed consent Exclusion Criteria: Infection with cytomegalovirus being treated with ganciclovir Presence of GvHD grade > I that requires systemic immunosuppressive therapy (at baseline) Ongoing systemic immunosuppressive therapy Ongoing acyclovir administration Administration after haplo-HCT of G-CSF and cyclosporine A CD3+ lymphocytes >100/µl before day +42 after haplo-HCT Life-threatening condition or complication other than their basic disease CNS disease Pregnant or lactating women
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Fabio Ciceri, MD
Organizational Affiliation
Hematology and BMT Unit, San Raffaele Scientific Institute, Milan, Italy
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medizinische Hoschule Hannover
City
Hannover
Country
Germany
Facility Name
G. Papanicolau
City
Thessaloniki
Country
Greece
Facility Name
Hadassah University Hospital
City
Jerusalem
Country
Israel
Facility Name
Fondazione San Raffaele
City
Milan
Country
Italy
Facility Name
Istituto Clinico Humanitas
City
Milan
Country
Italy
Facility Name
Policlinico Monteluce
City
Perugia
Country
Italy
Facility Name
Ospedale Civile
City
Pescara
Country
Italy
Facility Name
Hammersmith Hospital
City
London
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
19345145
Citation
Ciceri F, Bonini C, Stanghellini MT, Bondanza A, Traversari C, Salomoni M, Turchetto L, Colombi S, Bernardi M, Peccatori J, Pescarollo A, Servida P, Magnani Z, Perna SK, Valtolina V, Crippa F, Callegaro L, Spoldi E, Crocchiolo R, Fleischhauer K, Ponzoni M, Vago L, Rossini S, Santoro A, Todisco E, Apperley J, Olavarria E, Slavin S, Weissinger EM, Ganser A, Stadler M, Yannaki E, Fassas A, Anagnostopoulos A, Bregni M, Stampino CG, Bruzzi P, Bordignon C. Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study. Lancet Oncol. 2009 May;10(5):489-500. doi: 10.1016/S1470-2045(09)70074-9. Epub 2009 Apr 1.
Results Reference
result
PubMed Identifier
33554732
Citation
Stornaiuolo A, Valentinis B, Sirini C, Scavullo C, Asperti C, Zhou D, Martinez De La Torre Y, Corna S, Casucci M, Porcellini S, Traversari C. Characterization and Functional Analysis of CD44v6.CAR T Cells Endowed with a New Low-Affinity Nerve Growth Factor Receptor-Based Spacer. Hum Gene Ther. 2021 Jul;32(13-14):744-760. doi: 10.1089/hum.2020.216. Epub 2021 May 5.
Results Reference
derived

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Infusion of Donor Lymphocytes Transduced With the Suicide Gene HSV TK in Patients With Haematological Malignancies

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