Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia

NCT ID: NCT00914628

Last Updated: 2021-06-22

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 92 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-04-12
• Study Completion Date: 2019-11-30

Brief Summary

The main objective of this randomized trial is to compare disease-free survival (DFS) in high risk leukemia patients who underwent haploidentical HCT followed by an add back strategy of HSV-Tk donor lymphocytes or standard haploidentical HCT

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 CD3+ reconstitution could take more than 10 months. The low number of lymphocytes infused with the graft, the degree of HLA (Human Leukocyte Antigen) 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 HCT (hematopoietic cell transplantation), because it remarkably may enhance both GvL (Graft versus Leukemia) 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 survival in patients receiving haplo-HCT. Finally, this therapeutic approach 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 high risk acute leukemia, who have undergone haploidentical stem cell transplantation.

Conditions

Acute Leukemia (Category)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

A

HSV-TK engineering donor Lymphocytes

Group Type: EXPERIMENTAL

HSV-Tk

Intervention Type: GENETIC

Infusion of approximately 1±0.2 x 10\^7 HSV-Tk genetically modified CD3+ cells/Kg between day +21 and day +49 after haploidentical HCT; in absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.

B

T-cell depleted or T-cell replete strategies

Group Type: ACTIVE_COMPARATOR

T-cell depleted or T-cell replete strategies

Intervention Type: OTHER

Haploidentical HCT with the infusion of CD34+ cells plus a fixed dose of T cells (1 x 10\^4/Kg) or unmanipulated haploidentical stem cell transplantation followed by high-dose cyclophosphamide as part of GvHD prophylaxis

Interventions

HSV-Tk

Infusion of approximately 1±0.2 x 10\^7 HSV-Tk genetically modified CD3+ cells/Kg between day +21 and day +49 after haploidentical HCT; in absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.

Intervention Type: GENETIC

T-cell depleted or T-cell replete strategies

Haploidentical HCT with the infusion of CD34+ cells plus a fixed dose of T cells (1 x 10\^4/Kg) or unmanipulated haploidentical stem cell transplantation followed by high-dose cyclophosphamide as part of GvHD prophylaxis

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Age ≥ 18 years
• Any of the following conditions:

1. AML and ALL in 1st complete remission (CR1)

2. AML and ALL in 2nd or subsequent CR

3. secondary AML in CR

4. AML and ALL in 1st or 2nd relapse or primary refractory

• Family donor with patient-donor number of HLA mismatches ≥ 2 (full haploidentical), or family donors sharing one HLA-haplotype with the patient
• Stable clinical conditions and life expectancy > 3 months
• PS ECOG < 2
• Serum creatinine < 1.5 x ULN
• Bilirubin < 1.5 x ULN; transaminases < 3 x ULN
• Left ventricular ejection fraction > 45%
• QTc interval < 450 ms
• DLCO > 50%
• Patients, or legal guardians, and donors must sign an informed consent indicating that they are aware this is a research study and have been told of its possible benefits and toxic side effects

Exclusion Criteria

• Patients with life-threatening condition or complication other than their basic condition
• Contraindication to haploidentical HCT as defined by the Investigator
• Patients with active CNS disease
• Pregnant or lactation.

• Infections requiring administration of ganciclovir or valganciclovir at the time of infusion
• GvHD requiring systemic immunosuppressive therapy
• Ongoing systemic immunosuppressive therapy after haploidentical HCT
• Administration of G-CSF after haploidentical HCT

HSV-Tk cells can be administered after an adequate patient wash-out period (24 hours)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AGC Biologics S.p.A.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Antonio Lambiase, MD

Role: STUDY_DIRECTOR

AGC Biologics S.p.A.

Locations

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

Washington University Medical School

St Louis, Missouri, United States

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, United States

Universitair Ziekenhuis

Ghent, , Belgium

University Hospitals Leuven

Leuven, , Belgium

Centre Hospitalier Universitaire de Liège - Domaine Universitaire du Sart Tilman

Liège, , Belgium

Hôpital Jean Minjoz

Besançon, , France

Centre Hospitalier Universitaire de Clermont-Ferrand

Clermont-Ferrand, , France

Centre Hospitalier Régional Universitaire de Lille

Lille, , France

Institut Paoli-Calmettes

Marseille, , France

Centre Hospitalier Universitaire de Nantes

Nantes, , France

Hôpital l'Archet

Nice, , France

Hôpital Saint-Antoine

Paris, , France

IUCT Oncopole - Institut Universitaire du Cancer de Toulouse

Toulouse, , France

Charitè; Campus Benjamin Franklin

Berlin, , Germany

University Medical Center Hamburg-Eppendorf

Hamburg, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

University of Leipzig

Leipzig, , Germany

Universitat Tubingen

Tübingen, , Germany

Medizinische Klinik und Poliklinik

Ulm, , Germany

George Papanicolaou Hospital

Thessaloniki, , Greece

Chaim Sheba Medical Center

Tel Litwinsky, , Israel

Azienda Sanitaria Ospedaliera S.Croce e Carle

Cuneo, CN, Italy

Azienda Ospedaliero-Universitaria Policlinico-Vittorio Emanuele

Catania, CT, Italy

Azienda Ospedaliera Universitaria Careggi

Florence, FI, Italy

Azienda Ospedaliera Ospedali Riuniti Villa Sofia - Cervello

Palermo, PA, Italy

Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Presidio Molinette

Torino, TO, Italy

Ospedale Santa Maria della Misericordia

Udine, UD, Italy

Policlinico G. B. Rossi, Azienda ospedaliera universitaria integrata di Verona

Verona, VR, Italy

Ospedale San Raffaele

Milan, , Italy

Azienda Ospedaliero-Universitaria Policlinico di Modena

Modena, , Italy

Santaros Klinikos

Vilnius, , Lithuania

Centro Hospitalar Lisboa Norte, E.P.E.

Lisbon, , Portugal

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Instituto Catalán de Oncología

L'Hospitalet de Llobregat, , Spain

Hospital de Navarra

Pamplona, , Spain

Countries

United States; Belgium; France; Germany; Greece; Israel; Italy; Lithuania; Portugal; Spain

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2009-012973-37

Identifier Type: REGISTRY

Identifier Source: secondary_id

TK008

Identifier Type: -

Identifier Source: org_study_id