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Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia (TK008)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00914628
Recruitment Status : Terminated (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)
First Posted : June 5, 2009
Results First Posted : June 22, 2021
Last Update Posted : June 22, 2021
Sponsor:
Information provided by (Responsible Party):
AGC Biologics S.p.A.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Acute Leukemia (Category)
Interventions Genetic: HSV-Tk
Other: T-cell depleted or T-cell replete strategies
Enrollment 92
Recruitment Details

Study period:

Date of First patient enrolled: 12.04.2010; Date of Last patient completed: 30.11.2019; Date of End of study: 30.11.2019.

Pre-assignment Details Planned sample size n.170; Randomized patients n. 92. Discontinued n. 70; Early termination by the Sponsor n. 22;
Arm/Group Title A-Experimental Arm B - Control Arm
Hide Arm/Group Description

Patients received an infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) followed by the infusion of HSV-TK genetically modified CD3+ cells. In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.

HSV-TK engineering donor Lymphocytes

The physician could choose between the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or unmanipulated haploidentical transplantation (bone marrow or peripheral blood) followed by high-dose cyclophosphamide.
Period Title: Overall Study
Started 64 [1] 28 [1]
Completed 0 [2] 0 [2]
Not Completed 64 28
Reason Not Completed
Death             35             17
Medical decision             4             0
Protocol Violation             1             0
Lack of Efficacy             1             0
non-randomized             1             0
Relapse             1             2
Study terminated by Sponsor             14             8
Patients who did not receive a single dose             7             1
[1]
Referred to all randomized patient
[2]
Early termination of the Study
Arm/Group Title A - Experimental Arm B- Comparator Arm Total
Hide Arm/Group Description patients received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg), followed by the infusion of HSV-TK genetically modified CD3+ cells In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis. the physician chose whether the patient received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or an unmanipulated haploidentical bone marrow or peripheral blood transplant followed by high-dose cyclophosphamide. Total of all reporting groups
Overall Number of Baseline Participants 64 28 92
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 64 participants 28 participants 92 participants
45.89  (15.29) 51.43  (12.41) 47.58  (14.63)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 64 participants 28 participants 92 participants
Female
23
  35.9%
9
  32.1%
32
  34.8%
Male
41
  64.1%
19
  67.9%
60
  65.2%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 64 participants 28 participants 92 participants
Asian
1
   1.6%
0
   0.0%
1
   1.1%
Black
3
   4.7%
1
   3.6%
4
   4.3%
Caucasian
55
  85.9%
24
  85.7%
79
  85.9%
Other
5
   7.8%
3
  10.7%
8
   8.7%
1.Primary Outcome
Title Disease-free Survival (DFS)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis has been performed for all patients in the two treatment arms. The NRM analysis was performed on the "Intention to Treat Population" (ITT) and "Per Protocol" (PP) set populations.
Arm/Group Title A-Experimental Arm B - Control Arm
Hide Arm/Group Description:

Patients received an infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) followed by the infusion of HSV-TK genetically modified CD3+ cells. In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.

HSV-TK engineering donor Lymphocytes

The physician could choose between the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or unmanipulated haploidentical transplantation (bone marrow or peripheral blood) followed by high-dose cyclophosphamide.
Overall Number of Participants Analyzed 64 28
Measure Type: Count of Participants
Unit of Measure: Participants
DFS on ITT Number Analyzed 64 participants 28 participants
Patients with DFS event
45
  70.3%
20
  71.4%
Censored patients
19
  29.7%
8
  28.6%
DFS on PP Set Number Analyzed 38 participants 26 participants
Patients with DFS event
25
  65.8%
18
  69.2%
Censored patients
13
  34.2%
8
  30.8%
DFS on ITT - day 21 after transplant Number Analyzed 55 participants 28 participants
Patients with DFS event
38
  69.1%
20
  71.4%
Censored patients
17
  30.9%
8
  28.6%
DFS on PP Set day 21 after transplant Number Analyzed 38 participants 26 participants
Patients with DFS event
25
  65.8%
18
  69.2%
Censored patients
13
  34.2%
8
  30.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8974
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments DFS- Intention-To-Treat population- from baseline to day 21
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7612
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5995
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments DFS- Intention-To-Treat population - day 21 after transplant
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4078
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments DFS- Per-Protocol Set
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3351
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments DFS- Per-Protocol Set
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1233
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments DFS- Per-Protocol Set DFS-day 21 after transplant
Type of Statistical Test Equivalence
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5995
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments DFS- Per-Protocol Set DFS-day 21 after transplant
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4078
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
2.Secondary Outcome
Title Overall Survival (OS)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
TThe analysis has been performed for all patients in the two treatment arms. The NRM analysis was performed on the "Intention to Treat Population" (ITT) and "Per Protocol" (PP) set populations.
Arm/Group Title A-Experimental Arm B - Control Arm
Hide Arm/Group Description:

Patients received an infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) followed by the infusion of HSV-TK genetically modified CD3+ cells. In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.

HSV-TK engineering donor Lymphocytes

The physician could choose between the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or unmanipulated haploidentical transplantation (bone marrow or peripheral blood) followed by high-dose cyclophosphamide.
Overall Number of Participants Analyzed 64 28
Measure Type: Count of Participants
Unit of Measure: Participants
OS on ITT Number Analyzed 64 participants 28 participants
Censored patients
22
  34.4%
10
  35.7%
Deaths
42
  65.6%
18
  64.3%
OS on PP Set Number Analyzed 38 participants 26 participants
Censored patients
14
  36.8%
10
  38.5%
Deaths
24
  63.2%
16
  61.5%
OS on ITT- day 21 after transplant Number Analyzed 55 participants 28 participants
Censored patients
20
  36.4%
10
  35.7%
Deaths
35
  63.6%
18
  64.3%
OS on PP Set - day 21 after transplant Number Analyzed 51 participants 28 participants
Censored patients
18
  35.3%
10
  35.7%
Deaths
33
  64.7%
18
  64.3%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7660
Comments [Not Specified]
Method Log Rank
Comments Statistical analysis was performed on Intention-To-Treat population.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments Statistical analysis has been performed for Intention-To-Treat population.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6706
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments Statistical analysis has been performed for Per-Protocol Set)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7332
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments Statistical analysis has been performed for Per-Protocol Set)
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6439
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
3.Secondary Outcome
Title Immune Reconstitution (IR)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis has been performed for all patients in the two treatment arms. The NRM analysis was performed on the "Intention to Treat Population" (ITT) and "Per Protocol" (PP) set populations.
Arm/Group Title A-Experimental Arm B - Control Arm
Hide Arm/Group Description:

Patients received an infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) followed by the infusion of HSV-TK genetically modified CD3+ cells. In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.

HSV-TK engineering donor Lymphocytes

The physician could choose between the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or unmanipulated haploidentical transplantation (bone marrow or peripheral blood) followed by high-dose cyclophosphamide.
Overall Number of Participants Analyzed 58 28
Measure Type: Count of Participants
Unit of Measure: Participants
IR on ITT Number Analyzed 58 participants 28 participants
Patients with immune reconstitution without previous relapse or progression
38
  65.5%
22
  78.6%
Deaths without previous immune reconstitution, relapse or progression
13
  22.4%
5
  17.9%
Patients with relapse or progression without previous immune reconstitution
6
  10.3%
1
   3.6%
Censored patients
1
   1.7%
0
   0.0%
IR on PP Set Number Analyzed 38 participants 26 participants
Patients with immune reconstitution without previous relapse or progression
29
  76.3%
22
  84.6%
Deaths without previous immune reconstitution, relapse or progression
4
  10.5%
3
  11.5%
Patients with relapse or progression without previous immune reconstitution
5
  13.2%
1
   3.8%
Censored patients
0
   0.0%
0
   0.0%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments This Statistical analysis refers to Immune reconstitution and was performed by Gray's Test for Equality of Cumulative Incidence Functions for intention-To-Treat population
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1735
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments This Statistical analysis refers to deaths without previous immune reconstitution, relapse or progression and was performed by Gray's Test for Equality of Cumulative Incidence Functions for intention-To-Treat population
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5958
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments This Statistical Analysis refers to patients with relapse or progression without previous immune reconstitution and was performed Gray's Test for Equality of Cumulative Incidence Functions
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2889
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments This Statistical analysis refers to Immune reconstitution and was performed by Gray's Test for Equality of Cumulative Incidence Functions for Per-Protocol Set.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1642
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments This Statistical analysis refers to deaths without previous immune reconstitution, relapse or progression and was performed by Gray's Test for Equality of Cumulative Incidence Functions for intention-To-Treat population
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8739
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments This Statistical Analysis refers to patients with relapse or progression without previous immune reconstitution and was performed Gray's Test for Equality of Cumulative Incidence Functions
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2304
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
4.Secondary Outcome
Title Engraftment Rate
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Due to the early termination of the study, the analysis was not performed because data were not collected for this Outcome Measure
Arm/Group Title A - Experimental Arm B- Comparator Arm
Hide Arm/Group Description:
Patients received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg), followed by the infusion of HSV-TK genetically modified CD3+ cells In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.
the physician chose whether the patient received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or an unmanipulated haploidentical bone marrow or peripheral blood transplant followed by high-dose cyclophosphamide.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
5.Secondary Outcome
Title Cumulative Incidence of Grade 2, 3, or 4 Acute GvHD (aGvHD)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Due to the early termination of the study, the analysis was not performed because data were not collected for this Outcome Measure
Arm/Group Title A - Experimental Arm B- Comparator Arm
Hide Arm/Group Description:
patients received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg), followed by the infusion of HSV-TK genetically modified CD3+ cells In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.
the physician chose whether the patient received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or an unmanipulated haploidentical bone marrow or peripheral blood transplant followed by high-dose cyclophosphamide.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
6.Secondary Outcome
Title Cumulative Incidence of Chronic GvHD (cGvHD)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Due to the early termination of the study, the analysis was not performed because data were not collected for this Outcome Measure
Arm/Group Title A - Experimental Arm B- Comparator Arm
Hide Arm/Group Description:
patients received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg), followed by the infusion of HSV-TK genetically modified CD3+ cells In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.
the physician chose whether the patient received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or an unmanipulated haploidentical bone marrow or peripheral blood transplant followed by high-dose cyclophosphamide.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
7.Secondary Outcome
Title Duration of GvHD Episodes
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Due to the early termination of the study, the analysis was not performed.because data were not collected for this Outcome Measure
Arm/Group Title A - Experimental Arm B - Comparator Arm
Hide Arm/Group Description:
patients received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg), followed by the infusion of HSV-TK genetically modified CD3+ cells In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.
The physician chose whether the patient received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or an unmanipulated haploidentical bone marrow or peripheral blood transplant followed by high-dose cyclophosphamide.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
8.Secondary Outcome
Title Cumulative Incidence of Relapse (CIR)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis has been performed for all patients in the two treatment arms. The NRM analysis was performed on the "Intention to Treat Population" (ITT) and "Per Protocol" (PP) set populations.
Arm/Group Title A-Experimental Arm B - Control Arm
Hide Arm/Group Description:

Patients received an infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) followed by the infusion of HSV-TK genetically modified CD3+ cells. In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.

HSV-TK engineering donor Lymphocytes

The physician could choose between the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or unmanipulated haploidentical transplantation (bone marrow or peripheral blood) followed by high-dose cyclophosphamide.
Overall Number of Participants Analyzed 64 28
Measure Type: Count of Participants
Unit of Measure: Participants
CIR on ITT population - CIR Number Analyzed 64 participants 28 participants
Patients with relapse or progression
18
  28.1%
11
  39.3%
Deaths without previous relapse or progression
27
  42.2%
9
  32.1%
Censored patients
19
  29.7%
8
  28.6%
CIR on PP Set Number Analyzed 38 participants 26 participants
Patients with relapse or progression
11
  28.9%
11
  42.3%
Deaths without previous relapse or progression
14
  36.8%
7
  26.9%
Censored patients
13
  34.2%
8
  30.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments This Statistical Analysis refers to ITT Patients with relapse or progression and was performed with Gray's Test for Equality of Cumulative Incidence Functions
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3526
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments this Gray's Statistical Analysis refers to ITT Deaths patients without previous relapse or progression and was performed with Test for Equality of Cumulative Incidence Functions
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4035
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments this Gray's Statistical Analysis refers to PPS patients with relapse or progression and was performed with Test for Equality of Cumulative Incidence Functions
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2607
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments this Gray's Statistical Analysis refers to PPS Deaths patients without previous relapse or progression and was performed with Test for Equality of Cumulative Incidence Function
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5929
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
9.Secondary Outcome
Title Incidence and Duration of Infectious Episodes and Infectious Disease Mortality
Hide Description Diagnosis, monitoring and treatment of infectious relevant events
Time Frame From randomization to the date of resolution, assessed up to 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Due to the early termination of the study, the analysis was not performed because data were not collected for this Outcome Measure
Arm/Group Title A - Experimental Arm B- Comparator Arm
Hide Arm/Group Description:
patients received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg), followed by the infusion of HSV-TK genetically modified CD3+ cells In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.
the physician chose whether the patient received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or an unmanipulated haploidentical bone marrow or peripheral blood transplant followed by high-dose cyclophosphamide.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
10.Secondary Outcome
Title Evaluate the Acute and Long-term Toxicity Related to the HSV-Tk Infusions
Hide Description Toxicity profile of HSV-Tk infusions
Time Frame From HSV-Tk infusions to the date of resolution, assessed up to 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Due to the early termination of the study, the analysis was not performed because data were not collected for this Outcome Measure
Arm/Group Title A - Experimental Arm B- Comparator Arm
Hide Arm/Group Description:
patients received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg), followed by the infusion of HSV-TK genetically modified CD3+ cells In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.
the physician chose whether the patient received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or an unmanipulated haploidentical bone marrow or peripheral blood transplant followed by high-dose cyclophosphamide.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
11.Secondary Outcome
Title Quality of Life (QoL) and Medical Care Utilization (MCU) in Both Arms
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Due to the early termination of the study, the analysis was not performed because data were not collected for this Outcome Measure
Arm/Group Title A - Experimental Arm B- Comparator Arm
Hide Arm/Group Description:
patients received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg), followed by the infusion of HSV-TK genetically modified CD3+ cells In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.
the physician chose whether the patient received the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or an unmanipulated haploidentical bone marrow or peripheral blood transplant followed by high-dose cyclophosphamide.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
12.Secondary Outcome
Title Non-relapse Mortality (NRM)
Hide 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.
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Hide Analysis Population Description
The analysis has been performed for all patients in the two treatment arms. The NRM analysis was performed on the "Intention to Treat Population" (ITT) and "Per Protocol" (PP) set populations.
Arm/Group Title A-Experimental Arm B - Control Arm
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Patients received an infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) followed by the infusion of HSV-TK genetically modified CD3+ cells. In absence of immune reconstitution and GvHD further infusions up to 4 will be administered on monthly basis.

HSV-TK engineering donor Lymphocytes

The physician could choose between the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or unmanipulated haploidentical transplantation (bone marrow or peripheral blood) followed by high-dose cyclophosphamide.
Overall Number of Participants Analyzed 64 28
Measure Type: Count of Participants
Unit of Measure: Participants
NRM on ITT population Number Analyzed 64 participants 28 participants
Deaths without previous relapse or progression
27
  42.2%
9
  32.1%
Patients with relapse or progression
18
  28.1%
11
  39.3%
Censored patients
19
  29.7%
8
  28.6%
NRM on PP Set Number Analyzed 38 participants 26 participants
Deaths without previous relapse or progression
14
  36.8%
7
  26.9%
Patients with relapse or progression
11
  28.9%
11
  42.3%
Censored patients
13
  34.2%
8
  30.8%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments This Statistical Analysis refers to ITT Deaths without previous relapse or progression and was performed with Gray's Test for Equality of Cumulative Incidence Functions
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4035
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments This statistical test refers to Patients with relapse or progression and was performed to Gray's Test for Equality of Cumulative Incidence Functions.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3526
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments This Statistical Analysis refers to PPS Deaths without previous relapse or progression and was performed with Gray's Test for Equality of Cumulative Incidence Functions
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5929
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection A-Experimental Arm, B - Control Arm
Comments This statistical test refers to Patients with relapse or progression and was performed to Gray's Test for Equality of Cumulative Incidence Functions.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2607
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Time Frame From day 21 through day 180 or at least 30 days after last dose of HSV-TK.
Adverse Event Reporting Description Safety analyses, Serious Adverse Events and all cause of mortality evaluations were performed on the STDP. STDP is defined as all randomized patients who received at least one haploidentical HCT (80 total patients).
 
Arm/Group Title A-Experimental Arm B - Control Arm
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Analysis performed only on Standard Population so, all randomized patients who received at least an infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) followed by the infusion of HSV-TK genetically modified CD3.

A total of 53/80 were included in the analysis

Analysis performed only on Standard Population. The physician could choose between the infusion of CD34+ cells plus a dose of T cells (approximately 1 x 104/Kg) or unmanipulated haploidentical transplantation (bone marrow or peripheral blood) followed by high-dose cyclophosphamide.

A total of 27/80 were included in the analysis

All-Cause Mortality
A-Experimental Arm B - Control Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   35/53 (66.04%)   17/27 (62.96%) 
Hide Serious Adverse Events
A-Experimental Arm B - Control Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   35/53 (66.04%)   17/27 (62.96%) 
Blood and lymphatic system disorders     
Autoimmune haemolytic anaemia   0/53 (0.00%)  1/27 (3.70%) 
Moderate Febrile neutropenia   0/53 (0.00%)  1/27 (3.70%) 
Life threatening Febrile neutropenia   1/53 (1.89%)  0/27 (0.00%) 
Life threatening Pancytopenia   1/53 (1.89%)  0/27 (0.00%) 
Severe Thrombotic microangiopathy   1/53 (1.89%)  0/27 (0.00%) 
Severe Thymic cyst   0/53 (0.00%)  1/27 (3.70%) 
Gastrointestinal disorders     
Mild Abdominal pain   1/53 (1.89%)  0/27 (0.00%) 
Severe Colitis   0/53 (0.00%)  1/27 (3.70%) 
Diarrhoea   1/53 (1.89%)  1/27 (3.70%) 
Nausea   0/53 (0.00%)  1/27 (3.70%) 
Severe Stomatitis   0/53 (0.00%)  1/27 (3.70%) 
Severe Vomiting   1/53 (1.89%)  1/27 (3.70%) 
General disorders     
Moderate Pyrexia   1/53 (1.89%)  0/27 (0.00%) 
Severe Pyrexia   1/53 (1.89%)  0/27 (0.00%) 
Immune system disorders     
Mild Acute graft versus host disease   1/53 (1.89%)  0/27 (0.00%) 
Moderate Acute graft versus host disease   5/53 (9.43%)  3/27 (11.11%) 
Severe Acute graft versus host disease   3/53 (5.66%)  1/27 (3.70%) 
Mild Chronic graft versus host disease   0/53 (0.00%)  1/27 (3.70%) 
Moderate Chronic graft versus host disease   3/53 (5.66%)  0/27 (0.00%) 
Severe Chronic graft versus host disease   3/53 (5.66%)  1/27 (3.70%) 
Moderate Graft versus host disease   0/53 (0.00%)  1/27 (3.70%) 
Severe Graft versus host disease   1/53 (1.89%)  0/27 (0.00%) 
Infections and infestations     
Severe Anal abscess   1/53 (1.89%)  0/27 (0.00%) 
Severe Bronchopulmonary aspergillosis   1/53 (1.89%)  0/27 (0.00%) 
Severe Cystitis klebsiella   1/53 (1.89%)  0/27 (0.00%) 
Moderate Cystitis viral   1/53 (1.89%)  1/27 (3.70%) 
Severe Cytomegalovirus colitis   1/53 (1.89%)  0/27 (0.00%) 
Cytomegalovirus colitis Cytomegalovirus colitis   1/53 (1.89%)  0/27 (0.00%) 
Severe Cytomegalovirus infection   1/53 (1.89%)  1/27 (3.70%) 
Severe Cytomegalovirus viraemia   1/53 (1.89%)  0/27 (0.00%) 
Moderate Device related infection   1/53 (1.89%)  0/27 (0.00%) 
Severe Device related infection   0/53 (0.00%)  1/27 (3.70%) 
Moderate Epstein-Barr virus infection   1/53 (1.89%)  1/27 (3.70%) 
Severe Epstein-Barr virus infection   1/53 (1.89%)  0/27 (0.00%) 
Moderate Gastroenteritis   0/53 (0.00%)  1/27 (3.70%) 
Moderate Herpes zoster infection neurological   1/53 (1.89%)  0/27 (0.00%) 
Severe Lung infection pseudomonal   0/53 (0.00%)  1/27 (3.70%) 
Moderate Otitis media acute   1/53 (1.89%)  0/27 (0.00%) 
Severe Pneumocystis jirovecii pneumonia   1/53 (1.89%)  0/27 (0.00%) 
Moderate Pneumonia   1/53 (1.89%)  1/27 (3.70%) 
Severe Pneumonia   3/53 (5.66%)  0/27 (0.00%) 
Life threatening pneumonia   0/53 (0.00%)  1/27 (3.70%) 
Severe Pneumonia cytomegaloviral   1/53 (1.89%)  0/27 (0.00%) 
Moderate Pneumonia klebsiella   1/53 (1.89%)  0/27 (0.00%) 
Severe Pneumonia klebsiella   0/53 (0.00%)  1/27 (3.70%) 
moderate Pneumonia pseudomonal   0/53 (0.00%)  1/27 (3.70%) 
Severe Salmonellosis   1/53 (1.89%)  0/27 (0.00%) 
Life threatening Sepsis   0/53 (0.00%)  1/27 (3.70%) 
Life threatening Septic shock   0/53 (0.00%)  2/27 (7.41%) 
Severe Skin infection   1/53 (1.89%)  0/27 (0.00%) 
Severe Soft tissue infection   0/53 (0.00%)  1/27 (3.70%) 
Moderate Staphylococcal infection   0/53 (0.00%)  1/27 (3.70%) 
Severe Systemic candida   1/53 (1.89%)  0/27 (0.00%) 
Life threatening Toxoplasmosis   0/53 (0.00%)  1/27 (3.70%) 
Investigations     
Severe Transaminases abnormal   0/53 (0.00%)  1/27 (3.70%) 
Metabolism and nutrition disorders     
Severe Cachexia   1/53 (1.89%)  0/27 (0.00%) 
Life threatening Decreased appetite   0/53 (0.00%)  1/27 (3.70%) 
Severe Dehydration   1/53 (1.89%)  0/27 (0.00%) 
Severe Hyponatraemia   1/53 (1.89%)  0/27 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Life threatening Acute lymphocytic leukaemia   0/53 (0.00%)  1/27 (3.70%) 
Severe Acute myeloid leukaemia   1/53 (1.89%)  0/27 (0.00%) 
Severe Epstein-Barr virus associated lymphoproliferative disorder   1/53 (1.89%)  0/27 (0.00%) 
Severe Leukaemia recurrent   0/53 (0.00%)  1/27 (3.70%) 
Life threatening leukaemia recurrent   1/53 (1.89%)  2/27 (7.41%) 
Severe Post transplant lymphoproliferative disorder   2/53 (3.77%)  0/27 (0.00%) 
Nervous system disorders     
moderate Dizziness   1/53 (1.89%)  0/27 (0.00%) 
severe Epilepsy   0/53 (0.00%)  1/27 (3.70%) 
moderate Neuropathy peripheral   1/53 (1.89%)  0/27 (0.00%) 
Renal and urinary disorders     
Mild Haematuria   0/53 (0.00%)  1/27 (3.70%) 
Respiratory, thoracic and mediastinal disorders     
Life threatening Dyspnoea   0/53 (0.00%)  1/27 (3.70%) 
Severe Hypoxia   1/53 (1.89%)  0/27 (0.00%) 
Severe Interstitial lung disease   1/53 (1.89%)  0/27 (0.00%) 
Severe Pneumonitis   1/53 (1.89%)  0/27 (0.00%) 
Skin and subcutaneous tissue disorders     
Mild Rash   1/53 (1.89%)  0/27 (0.00%) 
Vascular disorders     
Life threatening Shock   1/53 (1.89%)  0/27 (0.00%) 
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
A-Experimental Arm B - Control Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   22/53 (41.51%)   0/27 (0.00%) 
Investigations     
related to HSV-TK cells   22/53 (41.51%)  0/27 (0.00%) 
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
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Name/Title: Anna Stornaiuolo
Organization: AGC Biologics S.p.A
Phone: 00390221277440
EMail: astornaiuolo@agcbio.com
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Responsible Party: AGC Biologics S.p.A.
ClinicalTrials.gov Identifier: NCT00914628    
Other Study ID Numbers: TK008
2009-012973-37 ( Registry Identifier: EUdraCT number )
First Submitted: June 3, 2009
First Posted: June 5, 2009
Results First Submitted: February 12, 2021
Results First Posted: June 22, 2021
Last Update Posted: June 22, 2021