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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00423124
Recruitment Status : Completed
First Posted : January 17, 2007
Last Update Posted : May 30, 2014
Information provided by (Responsible Party):
AGC Biologics S.p.A.

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.

Condition or disease Intervention/treatment Phase
Hematological Malignancies Genetic: HSV-TK Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 57 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : July 2002
Actual Primary Completion Date : December 2011
Actual Study Completion Date : November 2013

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: A Genetic: HSV-TK
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 Measures :
  1. 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 ]
  2. 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 ]
  3. Evaluation of GvL effect [ Time Frame: during the study ]

Secondary Outcome Measures :
  1. Time to relapse, time to death (evaluated by disease free survival and overall survival) [ Time Frame: during the study ]
  2. Incidence of infectious events (measured by number of infectious events) [ Time Frame: during the study ]
  3. Acute and long term toxicity related to the infusions (measured by incidence of adverse events) [ Time Frame: during the study and study follow up ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00423124

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Medizinische Hoschule Hannover
Hannover, Germany
G. Papanicolau
Thessaloniki, Greece
Hadassah University Hospital
Jerusalem, Israel
Fondazione San Raffaele
Milan, Italy
Istituto Clinico Humanitas
Milan, Italy
Policlinico Monteluce
Perugia, Italy
Ospedale Civile
Pescara, Italy
United Kingdom
Hammersmith Hospital
London, United Kingdom
Sponsors and Collaborators
AGC Biologics S.p.A.
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Principal Investigator: Fabio Ciceri, MD Hematology and BMT Unit, San Raffaele Scientific Institute, Milan, Italy
Publications of Results:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: AGC Biologics S.p.A. Identifier: NCT00423124    
Other Study ID Numbers: TK007
2005-003587-34 ( EudraCT Number )
First Posted: January 17, 2007    Key Record Dates
Last Update Posted: May 30, 2014
Last Verified: May 2014
Keywords provided by AGC Biologics S.p.A.:
Hematological malignancies
Haploidentical HCT
Additional relevant MeSH terms:
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Hematologic Neoplasms
Self-Injurious Behavior
Behavioral Symptoms
Neoplasms by Site
Hematologic Diseases