Back to resultsEfficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia (TK008)
Primary Purpose
Acute Leukemia (Category)
Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
HSV-Tk
T-cell depleted or T-cell replete strategies
Sponsored by
About this trial
This is an interventional treatment trial for Acute Leukemia (Category) focused on measuring high risk acute leukemia, HSV-TK, Haploidentical HCT, GvHD, GvL, Immunoreconstitution
Eligibility Criteria
Inclusion Criteria:
- Age ≥ 18 years
Any of the following conditions:
- AML and ALL in 1st complete remission (CR1)
- AML and ALL in 2nd or subsequent CR
- secondary AML in CR
- 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)
Sites / Locations
- Northwestern University Feinberg School of Medicine
- Washington University Medical School
- John Theurer Cancer Center at Hackensack University Medical Center
- Universitair Ziekenhuis
- University Hospitals Leuven
- Centre Hospitalier Universitaire de Liège - Domaine Universitaire du Sart Tilman
- Hôpital Jean Minjoz
- Centre Hospitalier Universitaire de Clermont-Ferrand
- Centre Hospitalier Régional Universitaire de Lille
- Institut Paoli-Calmettes
- Centre Hospitalier Universitaire de Nantes
- Hôpital l'Archet
- Hôpital Saint-Antoine
- IUCT Oncopole - Institut Universitaire du Cancer de Toulouse
- Charitè; Campus Benjamin Franklin
- University Medical Center Hamburg-Eppendorf
- Medizinische Hochschule Hannover
- University of Leipzig
- Universitat Tubingen
- Medizinische Klinik und Poliklinik
- George Papanicolaou Hospital
- Chaim Sheba Medical Center
- Azienda Sanitaria Ospedaliera S.Croce e Carle
- Azienda Ospedaliero-Universitaria Policlinico-Vittorio Emanuele
- Azienda Ospedaliera Universitaria Careggi
- Azienda Ospedaliera Ospedali Riuniti Villa Sofia - Cervello
- Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Presidio Molinette
- Ospedale Santa Maria della Misericordia
- Policlinico G. B. Rossi, Azienda ospedaliera universitaria integrata di Verona
- Ospedale San Raffaele
- Azienda Ospedaliero-Universitaria Policlinico di Modena
- Santaros Klinikos
- Centro Hospitalar Lisboa Norte, E.P.E.
- Hospital de la Santa Creu i Sant Pau
- Instituto Catalán de Oncología
- Hospital de Navarra
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
A
B
Arm Description
HSV-TK engineering donor Lymphocytes
T-cell depleted or T-cell replete strategies
Outcomes
Primary Outcome Measures
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).
Secondary Outcome Measures
Overall Survival (OS)
any death without previous occurrence of a documented relapse (or progression).Patients alive or without any follow up will be censored.
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, γGT, total bilirubin, LDH.
Engraftment Rate
Defined as the persistent blood cells count above predefined level.
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
Cumulative Incidence of Chronic GvHD (cGvHD)
Diagnosed and graded according to standard NIH consensus criteria
Duration of GvHD Episodes
Diagnosed and graded according to standard NIH consensus criteria
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
Incidence and Duration of Infectious Episodes and Infectious Disease Mortality
Diagnosis, monitoring and treatment of infectious relevant events
Evaluate the Acute and Long-term Toxicity Related to the HSV-Tk Infusions
Toxicity profile of HSV-Tk infusions
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00914628
Brief Title
Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia
Acronym
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
Study Type
Interventional
2. Study Status
Record Verification Date
June 2021
Overall Recruitment Status
Terminated
Why Stopped
EMA withdrew the marketing Authorisation at the request of AGC Biologics S.p.A (formerly MolMed S.p.A), which decided to permanently discontinue the marketing of the product for commercial reasons
Study Start Date
April 12, 2010 (Actual)
Primary Completion Date
November 30, 2019 (Actual)
Study Completion Date
November 30, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AGC Biologics S.p.A.
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Leukemia (Category)
Keywords
high risk acute leukemia, HSV-TK, Haploidentical HCT, GvHD, GvL, Immunoreconstitution
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
92 (Actual)
8. Arms, Groups, and Interventions
Arm Title
A
Arm Type
Experimental
Arm Description
HSV-TK engineering donor Lymphocytes
Arm Title
B
Arm Type
Active Comparator
Arm Description
T-cell depleted or T-cell replete strategies
Intervention Type
Genetic
Intervention Name(s)
HSV-Tk
Intervention Description
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
Other
Intervention Name(s)
T-cell depleted or T-cell replete strategies
Intervention Description
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
Primary Outcome Measure Information:
Title
Disease-free Survival (DFS)
Description
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).
Time Frame
From the date of randomization, assessed up to 12 months
Secondary Outcome Measure Information:
Title
Overall Survival (OS)
Description
any death without previous occurrence of a documented relapse (or progression).Patients alive or without any follow up will be censored.
Time Frame
From the date of randomization to the date of death, assessed up to 12 months
Title
Immune Reconstitution (IR)
Description
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, γGT, total bilirubin, LDH.
Time Frame
Weekly up to IR after engraftment of HCT, monthly for 6 months from date of IR and then at month 9 and 12
Title
Engraftment Rate
Description
Defined as the persistent blood cells count above predefined level.
Time Frame
At day 15 after HCT, monthly for 6 months after HCT and then at month 9 and 12
Title
Cumulative Incidence of Grade 2, 3, or 4 Acute GvHD (aGvHD)
Description
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
Time Frame
from the date of HCT until the date of the first occurrence of aGvHD, assessed up to 6 months
Title
Cumulative Incidence of Chronic GvHD (cGvHD)
Description
Diagnosed and graded according to standard NIH consensus criteria
Time Frame
From the date of HCT until the date of the first occurrence of cGvHD, assessed up to 12 months
Title
Duration of GvHD Episodes
Description
Diagnosed and graded according to standard NIH consensus criteria
Time Frame
From the date of start until the date of resolution and duration of immunosuppressive treatments administered for controlling GvHD assessed up to 12 months
Title
Cumulative Incidence of Relapse (CIR)
Description
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
Time Frame
from the date of randomization to the date of the first occurrence of relapse, assessed up to 12 months
Title
Incidence and Duration of Infectious Episodes and Infectious Disease Mortality
Description
Diagnosis, monitoring and treatment of infectious relevant events
Time Frame
From randomization to the date of resolution, assessed up to 12 months
Title
Evaluate the Acute and Long-term Toxicity Related to the HSV-Tk Infusions
Description
Toxicity profile of HSV-Tk infusions
Time Frame
From HSV-Tk infusions to the date of resolution, assessed up to 12 months
Title
Quality of Life (QoL) and Medical Care Utilization (MCU) in Both Arms
Description
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.
Time Frame
from randomization up to 12 months
Title
Non-relapse Mortality (NRM)
Description
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.
Time Frame
From the date of randomization to the date of death, assessed up to 12 months.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age ≥ 18 years
Any of the following conditions:
AML and ALL in 1st complete remission (CR1)
AML and ALL in 2nd or subsequent CR
secondary AML in CR
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Antonio Lambiase, MD
Organizational Affiliation
AGC Biologics S.p.A.
Official's Role
Study Director
Facility Information:
Facility Name
Northwestern University Feinberg School of Medicine
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Washington University Medical School
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
John Theurer Cancer Center at Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
Universitair Ziekenhuis
City
Gent
Country
Belgium
Facility Name
University Hospitals Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Centre Hospitalier Universitaire de Liège - Domaine Universitaire du Sart Tilman
City
Liège
Country
Belgium
Facility Name
Hôpital Jean Minjoz
City
Besançon
ZIP/Postal Code
25030
Country
France
Facility Name
Centre Hospitalier Universitaire de Clermont-Ferrand
City
Clermont-Ferrand
Country
France
Facility Name
Centre Hospitalier Régional Universitaire de Lille
City
Lille
Country
France
Facility Name
Institut Paoli-Calmettes
City
Marseille
Country
France
Facility Name
Centre Hospitalier Universitaire de Nantes
City
Nantes
Country
France
Facility Name
Hôpital l'Archet
City
Nice
Country
France
Facility Name
Hôpital Saint-Antoine
City
Paris
Country
France
Facility Name
IUCT Oncopole - Institut Universitaire du Cancer de Toulouse
City
Toulouse
Country
France
Facility Name
Charitè; Campus Benjamin Franklin
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
University Medical Center Hamburg-Eppendorf
City
Hamburg
Country
Germany
Facility Name
Medizinische Hochschule Hannover
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
University of Leipzig
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
Universitat Tubingen
City
Tubingen
ZIP/Postal Code
72076
Country
Germany
Facility Name
Medizinische Klinik und Poliklinik
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Facility Name
George Papanicolaou Hospital
City
Thessaloniki
ZIP/Postal Code
57010
Country
Greece
Facility Name
Chaim Sheba Medical Center
City
Tel Hashomer
ZIP/Postal Code
52621
Country
Israel
Facility Name
Azienda Sanitaria Ospedaliera S.Croce e Carle
City
Cuneo
State/Province
CN
Country
Italy
Facility Name
Azienda Ospedaliero-Universitaria Policlinico-Vittorio Emanuele
City
Catania
State/Province
CT
Country
Italy
Facility Name
Azienda Ospedaliera Universitaria Careggi
City
Firenze
State/Province
FI
Country
Italy
Facility Name
Azienda Ospedaliera Ospedali Riuniti Villa Sofia - Cervello
City
Palermo
State/Province
PA
Country
Italy
Facility Name
Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Presidio Molinette
City
Torino
State/Province
TO
Country
Italy
Facility Name
Ospedale Santa Maria della Misericordia
City
Udine
State/Province
UD
Country
Italy
Facility Name
Policlinico G. B. Rossi, Azienda ospedaliera universitaria integrata di Verona
City
Verona
State/Province
VR
Country
Italy
Facility Name
Ospedale San Raffaele
City
Milan
Country
Italy
Facility Name
Azienda Ospedaliero-Universitaria Policlinico di Modena
City
Modena
ZIP/Postal Code
41124
Country
Italy
Facility Name
Santaros Klinikos
City
Vilnius
Country
Lithuania
Facility Name
Centro Hospitalar Lisboa Norte, E.P.E.
City
Lisboa
Country
Portugal
Facility Name
Hospital de la Santa Creu i Sant Pau
City
Barcelona
Country
Spain
Facility Name
Instituto Catalán de Oncología
City
L'Hospitalet De Llobregat
Country
Spain
Facility Name
Hospital de Navarra
City
Pamplona
ZIP/Postal Code
31008
Country
Spain
12. IPD Sharing Statement
Plan to Share IPD
No
IPD Sharing Plan Description
No, only information requested by law will be released
Learn more about this trial
Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia
We'll reach out to this number within 24 hrs