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

Hematological Malignancies Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00423124
• Other study ID #: TK007
• Secondary ID: 2005-003587-34
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: January 16, 2007
• Last updated: May 29, 2014
• Start date: July 2002
• Est. completion date: November 2013

Study information

• Verified date: May 2014
• Source: MolMed S.p.A.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: National Institute of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 57
• Est. completion date: November 2013
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hematologic Neoplasms
• Hematological Malignancies
• Neoplasms

Intervention

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.

Locations

Country	Name	City	State
Germany	Medizinische Hoschule Hannover	Hannover
Greece	G. Papanicolau	Thessaloniki
Israel	Hadassah University Hospital	Jerusalem
Italy	Fondazione San Raffaele	Milan
Italy	Istituto Clinico Humanitas	Milan
Italy	Policlinico Monteluce	Perugia
Italy	Ospedale Civile	Pescara
United Kingdom	Hammersmith Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
MolMed S.p.A.

Countries where clinical trial is conducted

Germany,  Greece,  Israel,  Italy,  United Kingdom, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evaluation of clinical activity in terms of immune-reconstitution, provided by the add- back of the transduced T-cells after haplo-HCT		during the study	No
Primary	Evaluation of the "in vivo" control of GvHD after administration of ganciclovir in patients treated with HSV-TK transduced T-cells		during the study	Yes
Primary	Evaluation of GvL effect		during the study	No
Secondary	Time to relapse, time to death (evaluated by disease free survival and overall survival)		during the study	Yes
Secondary	Incidence of infectious events (measured by number of infectious events)		during the study	Yes
Secondary	Acute and long term toxicity related to the infusions (measured by incidence of adverse events)		during the study and study follow up	Yes