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

Acute Leukemia (Category) Clinical Trial

— TK008  

Official title:

TK008: Randomized Phase III Trial of Haploidentical HCT With or Without an Add Back Strategy of HSV-Tk Donor Lymphocytes in Patients With High Risk Acute Leukemia

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00914628
• Other study ID #: TK008
• Secondary ID: 2009-012973-37
• Status: Terminated
• Phase: Phase 3
• Start date: April 12, 2010
• Est. completion date: November 30, 2019

Study information

• Verified date: June 2021
• Source: AGC Biologics S.p.A.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 92
• Est. completion date: November 30, 2019
• Est. primary completion date: November 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Exclusion criteria for HSV-Tk infusion:

• 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)

Related Conditions & MeSH terms

• Acute Disease
• Acute Leukemia (Category)
• Leukemia

Intervention

Genetic:
• 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.

Other:
• 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

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis	Gent
Belgium	University Hospitals Leuven	Leuven
Belgium	Centre Hospitalier Universitaire de Liège - Domaine Universitaire du Sart Tilman	Liège
France	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
Germany	Charitè; Campus Benjamin Franklin	Berlin
Germany	University Medical Center Hamburg-Eppendorf	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	University of Leipzig	Leipzig
Germany	Universitat Tubingen	Tubingen
Germany	Medizinische Klinik und Poliklinik	Ulm
Greece	George Papanicolaou Hospital	Thessaloniki
Israel	Chaim Sheba Medical Center	Tel Hashomer
Italy	Azienda Ospedaliero-Universitaria Policlinico-Vittorio Emanuele	Catania	CT
Italy	Azienda Sanitaria Ospedaliera S.Croce e Carle	Cuneo	CN
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze	FI
Italy	Ospedale San Raffaele	Milan
Italy	Azienda Ospedaliero-Universitaria Policlinico di Modena	Modena
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
Lithuania	Santaros Klinikos	Vilnius
Portugal	Centro Hospitalar Lisboa Norte, E.P.E.	Lisboa
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Instituto Catalán de Oncología	L'Hospitalet De Llobregat
Spain	Hospital de Navarra	Pamplona
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	Washington University Medical School	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
AGC Biologics S.p.A.

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease-free Survival (DFS)	Defined as the measure from the date of randomization until the date of relapse (or progression), or death from any cause, whichever occurs first.; Disease relapse or progression was determined by the Investigator based on the following disease examination: Morphology (bone marrow or peripheral blood); Confirmation of mixed or full chimerism (evaluation of the degree of chimerism between donor/host, according to institutional clinical practice, on bone marrow or peripheral blood); Cytogenetic and/or molecular and/or other tests, according to institutional clinical practice (bone marrow or peripheral blood).	From the date of randomization, assessed up to 12 months
Secondary	Overall Survival (OS)	any death without previous occurrence of a documented relapse (or progression).Patients alive or without any follow up will be censored.	From the date of randomization to the date of death, assessed up to 12 months
Secondary	Immune Reconstitution (IR)	Assess how many patients experience IR. For the assessment, competing risk analysis was performed considering death, relapse, and disease progression as competing events. Patients who were still alive and had no recovery (IR) nor relapse (or progression) were censored.IR is defined as achieving a level of circulating CD3+ = 100/µL for two consecutive observations. The following laboratory examinations are performed: Hematology: WBC (full and differential), RBC, platelets, Hb, Htc, MCV, MPV, serology CMV (PCR and antigenemia).; Blood chemistry: AST, ALT, ?GT, total bilirubin, LDH.	Weekly up to IR after engraftment of HCT, monthly for 6 months from date of IR and then at month 9 and 12
Secondary	Engraftment Rate	Defined as the persistent blood cells count above predefined level.	At day 15 after HCT, monthly for 6 months after HCT and then at month 9 and 12
Secondary	Cumulative Incidence of Grade 2, 3, or 4 Acute GvHD (aGvHD)	Diagnosed and graded according to standard criteria.; Grade 1: Skin: Stage 1-2: Rash on < 25% of skin or Rash on 25-50% of skin Liver: Stage 1-2: Bilirubin 2-3 mg/dl or Bilirubin 3-6 mg/dl Gastrointestinal: Stage 1-2: Diarrhoea > 500 ml/day or persistent nausea or Diarrhoea > 1000ml/day	from the date of HCT until the date of the first occurrence of aGvHD, assessed up to 6 months
Secondary	Cumulative Incidence of Chronic GvHD (cGvHD)	Diagnosed and graded according to standard NIH consensus criteria	From the date of HCT until the date of the first occurrence of cGvHD, assessed up to 12 months
Secondary	Duration of GvHD Episodes	Diagnosed and graded according to standard NIH consensus criteria	From the date of start until the date of resolution and duration of immunosuppressive treatments administered for controlling GvHD assessed up to 12 months
Secondary	Cumulative Incidence of Relapse (CIR)	Defined on the basis of morphologic evidence of leukaemia in bone marrow or other sites. Gray's test was used to compare the sub-distribution functions of relapse (or progression) events in the two treatment groups. Patients alive without relapse (or regression) will be censored	from the date of randomization to the date of the first occurrence of relapse, assessed up to 12 months
Secondary	Incidence and Duration of Infectious Episodes and Infectious Disease Mortality	Diagnosis, monitoring and treatment of infectious relevant events	From randomization to the date of resolution, assessed up to 12 months
Secondary	Evaluate the Acute and Long-term Toxicity Related to the HSV-Tk Infusions	Toxicity profile of HSV-Tk infusions	From HSV-Tk infusions to the date of resolution, assessed up to 12 months
Secondary	Quality of Life (QoL) and Medical Care Utilization (MCU) in Both Arms	Medical resource use data collected will be used in health economic analyses where it may be combined with other data from other sources such as cost data or other clinical parameters.	from randomization up to 12 months
Secondary	Non-relapse Mortality (NRM)	Defined for all patients as any death without previous occurrence of a documented relapse (or progression). Absence of relapse was determined by the Investigator based on the following disease examination: Morphology (bone marrow or peripheral blood); Confirmation of mixed or full chimerism (evaluation of the degree of chimerism between donor/host, according to institutional clinical practice, on bone marrow or peripheral blood); Cytogenetic and/or molecular and/or other tests, according to institutional clinical practice (bone marrow or peripheral blood).; Gray's test was used to compare the sub-distribution functions of the death without previous relapse (or progression) and relapse (or progression) events in the two treatment groups.	From the date of randomization to the date of death, assessed up to 12 months.