Clinical trial NCT00914628: Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Acute Leukemia (Category)
Keywords: high risk acute leukemia
HSV-TK
Haploidentical HCT
GvHD
GvL
Immunoreconstitution
Lead sponsor: AGC Biologics S.p.A.
Sponsor class: INDUSTRY
First posted: 2009-06-05
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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)

Primary outcomes:
measure: Disease-free Survival (DFS)
timeFrame: From the date of randomization, assessed up to 12 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From the date of randomization to the date of death, assessed up to 12 months
measure: Immune Reconstitution (IR)
timeFrame: Weekly up to IR after engraftment of HCT, monthly for 6 months from date of IR and then at month 9 and 12
measure: Engraftment Rate
timeFrame: At day 15 after HCT, monthly for 6 months after HCT and then at month 9 and 12
measure: Cumulative Incidence of Grade 2, 3, or 4 Acute GvHD (aGvHD)
timeFrame: from the date of HCT until the date of the first occurrence of aGvHD, assessed up to 6 months
measure: Cumulative Incidence of Chronic GvHD (cGvHD)
timeFrame: From the date of HCT until the date of the first occurrence of cGvHD, assessed up to 12 months
measure: Duration of GvHD Episodes
timeFrame: From the date of start until the date of resolution and duration of immunosuppressive treatments administered for controlling GvHD assessed up to 12 months
measure: Cumulative Incidence of Relapse (CIR)
timeFrame: from the date of randomization to the date of the first occurrence of relapse, assessed up to 12 months
measure: Incidence and Duration of Infectious Episodes and Infectious Disease Mortality
timeFrame: From randomization to the date of resolution, assessed up to 12 months
measure: Evaluate the Acute and Long-term Toxicity Related to the HSV-Tk Infusions
timeFrame: From HSV-Tk infusions to the date of resolution, assessed up to 12 months
measure: Quality of Life (QoL) and Medical Care Utilization (MCU) in Both Arms
timeFrame: from randomization up to 12 months
measure: Non-relapse Mortality (NRM)
timeFrame: From the date of randomization to the date of death, assessed up to 12 months.
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Saint Louis
country: United States
facility: Washington University Medical School
state: Missouri
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Gent
country: Belgium
facility: Universitair Ziekenhuis
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Liège
country: Belgium
facility: Centre Hospitalier Universitaire de Liège - Domaine Universitaire du Sart Tilman
city: Besançon
country: France
facility: Hôpital Jean Minjoz
city: Clermont-Ferrand
country: France
facility: Centre Hospitalier Universitaire de Clermont-Ferrand
city: Lille
country: France
facility: Centre Hospitalier Régional Universitaire de Lille
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Nantes
country: France
facility: Centre Hospitalier Universitaire de Nantes
city: Nice
country: France
facility: Hôpital l'Archet
city: Paris
country: France
facility: Hôpital Saint-Antoine
city: Toulouse
country: France
facility: IUCT Oncopole - Institut Universitaire du Cancer de Toulouse
city: Berlin
country: Germany
facility: Charitè; Campus Benjamin Franklin
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Leipzig
country: Germany
facility: University of Leipzig
city: Tubingen
country: Germany
facility: Universitat Tubingen
city: Ulm
country: Germany
facility: Medizinische Klinik und Poliklinik
city: Thessaloniki
country: Greece
facility: George Papanicolaou Hospital
city: Tel Hashomer
country: Israel
facility: Chaim Sheba Medical Center
city: Cuneo
country: Italy
facility: Azienda Sanitaria Ospedaliera S.Croce e Carle
state: CN
city: Catania
country: Italy
facility: Azienda Ospedaliero-Universitaria Policlinico-Vittorio Emanuele
state: CT
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
state: FI
city: Palermo
country: Italy
facility: Azienda Ospedaliera Ospedali Riuniti Villa Sofia - Cervello
state: PA
city: Torino
country: Italy
facility: Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Presidio Molinette
state: TO
city: Udine
country: Italy
facility: Ospedale Santa Maria della Misericordia
state: UD
city: Verona
country: Italy
facility: Policlinico G. B. Rossi, Azienda ospedaliera universitaria integrata di Verona
state: VR
city: Milan
country: Italy
facility: Ospedale San Raffaele
city: Modena
country: Italy
facility: Azienda Ospedaliero-Universitaria Policlinico di Modena
city: Vilnius
country: Lithuania
facility: Santaros Klinikos
city: Lisboa
country: Portugal
facility: Centro Hospitalar Lisboa Norte, E.P.E.
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: L'Hospitalet De Llobregat
country: Spain
facility: Instituto Catalán de Oncología
city: Pamplona
country: Spain
facility: Hospital de Navarra
Study officials:
affiliation: AGC Biologics S.p.A.
name: Antonio Lambiase, MD
role: STUDY_DIRECTOR
References: