Trial Outcomes & Findings for Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia (NCT NCT00914628)

Last Updated: 2021-06-22

Results Overview

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).

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

92 participants

Primary outcome timeframe

From the date of randomization, assessed up to 12 months

Results posted on

2021-06-22

Participant Flow

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.

Planned sample size n.170; Randomized patients n. 92. Discontinued n. 70; Early termination by the Sponsor n. 22;

Participant milestones

Participant milestones
Measure	A-Experimental Arm 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	B - Control Arm 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 Study STARTED	64	28
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	64	28

Reasons for withdrawal

Reasons for withdrawal
Measure	A-Experimental Arm 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	B - Control Arm 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 Study Death	35	17
Overall Study Medical decision	4	0
Overall Study Protocol Violation	1	0
Overall Study Lack of Efficacy	1	0
Overall Study non-randomized	1	0
Overall Study Relapse	1	2
Overall Study Study terminated by Sponsor	14	8
Overall Study Patients who did not receive a single dose	7	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	A - Experimental Arm n=64 Participants 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.	B- Comparator Arm n=28 Participants 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 n=92 Participants Total of all reporting groups
Age, Continuous	45.89 years STANDARD_DEVIATION 15.29 • n=93 Participants	51.43 years STANDARD_DEVIATION 12.41 • n=4 Participants	47.58 years STANDARD_DEVIATION 14.63 • n=27 Participants
Sex: Female, Male Female	23 Participants n=93 Participants	9 Participants n=4 Participants	32 Participants n=27 Participants
Sex: Female, Male Male	41 Participants n=93 Participants	19 Participants n=4 Participants	60 Participants n=27 Participants
Race/Ethnicity, Customized Asian	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Race/Ethnicity, Customized Black	3 Participants n=93 Participants	1 Participants n=4 Participants	4 Participants n=27 Participants
Race/Ethnicity, Customized Caucasian	55 Participants n=93 Participants	24 Participants n=4 Participants	79 Participants n=27 Participants
Race/Ethnicity, Customized Other	5 Participants n=93 Participants	3 Participants n=4 Participants	8 Participants n=27 Participants

PRIMARY outcome

Timeframe: From the date of randomization, assessed up to 12 months

Population: 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.

Outcome measures

Outcome measures
Measure	A-Experimental Arm n=64 Participants 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	B - Control Arm n=28 Participants 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.
Disease-free Survival (DFS) DFS on ITT · Patients with DFS event	45 Participants	20 Participants
Disease-free Survival (DFS) DFS on ITT · Censored patients	19 Participants	8 Participants
Disease-free Survival (DFS) DFS on PP Set · Patients with DFS event	25 Participants	18 Participants
Disease-free Survival (DFS) DFS on PP Set · Censored patients	13 Participants	8 Participants
Disease-free Survival (DFS) DFS on ITT - day 21 after transplant · Patients with DFS event	38 Participants	20 Participants
Disease-free Survival (DFS) DFS on ITT - day 21 after transplant · Censored patients	17 Participants	8 Participants
Disease-free Survival (DFS) DFS on PP Set day 21 after transplant · Patients with DFS event	25 Participants	18 Participants
Disease-free Survival (DFS) DFS on PP Set day 21 after transplant · Censored patients	13 Participants	8 Participants

SECONDARY outcome

Timeframe: From the date of randomization to the date of death, assessed up to 12 months

Population: 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.

any death without previous occurrence of a documented relapse (or progression).Patients alive or without any follow up will be censored.

Outcome measures

Outcome measures
Measure	A-Experimental Arm n=64 Participants 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	B - Control Arm n=28 Participants 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 Survival (OS) OS on ITT · Censored patients	22 Participants	10 Participants
Overall Survival (OS) OS on ITT · Deaths	42 Participants	18 Participants
Overall Survival (OS) OS on PP Set · Censored patients	14 Participants	10 Participants
Overall Survival (OS) OS on PP Set · Deaths	24 Participants	16 Participants
Overall Survival (OS) OS on ITT- day 21 after transplant · Censored patients	20 Participants	10 Participants
Overall Survival (OS) OS on ITT- day 21 after transplant · Deaths	35 Participants	18 Participants
Overall Survival (OS) OS on PP Set - day 21 after transplant · Censored patients	18 Participants	10 Participants
Overall Survival (OS) OS on PP Set - day 21 after transplant · Deaths	33 Participants	18 Participants

SECONDARY outcome

Timeframe: Weekly up to IR after engraftment of HCT, monthly for 6 months from date of IR and then at month 9 and 12

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.

Outcome measures

Outcome measures
Measure	A-Experimental Arm n=58 Participants 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	B - Control Arm n=28 Participants 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.
Immune Reconstitution (IR) IR on ITT · Patients with relapse or progression without previous immune reconstitution	6 Participants	1 Participants
Immune Reconstitution (IR) IR on PP Set · Censored patients	0 Participants	0 Participants
Immune Reconstitution (IR) IR on ITT · Patients with immune reconstitution without previous relapse or progression	38 Participants	22 Participants
Immune Reconstitution (IR) IR on ITT · Deaths without previous immune reconstitution, relapse or progression	13 Participants	5 Participants
Immune Reconstitution (IR) IR on ITT · Censored patients	1 Participants	0 Participants
Immune Reconstitution (IR) IR on PP Set · Patients with immune reconstitution without previous relapse or progression	29 Participants	22 Participants
Immune Reconstitution (IR) IR on PP Set · Deaths without previous immune reconstitution, relapse or progression	4 Participants	3 Participants
Immune Reconstitution (IR) IR on PP Set · Patients with relapse or progression without previous immune reconstitution	5 Participants	1 Participants

SECONDARY outcome

Timeframe: At day 15 after HCT, monthly for 6 months after HCT and then at month 9 and 12

Population: Due to the early termination of the study, the analysis was not performed because data were not collected for this Outcome Measure

Defined as the persistent blood cells count above predefined level.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: from the date of HCT until the date of the first occurrence of aGvHD, assessed up to 6 months

Population: Due to the early termination of the study, the analysis was not performed because data were not collected for this Outcome Measure

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From the date of HCT until the date of the first occurrence of cGvHD, assessed up to 12 months

Population: Due to the early termination of the study, the analysis was not performed because data were not collected for this Outcome Measure

Diagnosed and graded according to standard NIH consensus criteria

Outcome measures

Outcome data not reported

SECONDARY outcome

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

Population: Due to the early termination of the study, the analysis was not performed.because data were not collected for this Outcome Measure

Diagnosed and graded according to standard NIH consensus criteria

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: from the date of randomization to the date of the first occurrence of relapse, assessed up to 12 months

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

Outcome measures

Outcome measures
Measure	A-Experimental Arm n=64 Participants 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	B - Control Arm n=28 Participants 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.
Cumulative Incidence of Relapse (CIR) CIR on ITT population - CIR · Patients with relapse or progression	18 Participants	11 Participants
Cumulative Incidence of Relapse (CIR) CIR on ITT population - CIR · Deaths without previous relapse or progression	27 Participants	9 Participants
Cumulative Incidence of Relapse (CIR) CIR on ITT population - CIR · Censored patients	19 Participants	8 Participants
Cumulative Incidence of Relapse (CIR) CIR on PP Set · Patients with relapse or progression	11 Participants	11 Participants
Cumulative Incidence of Relapse (CIR) CIR on PP Set · Deaths without previous relapse or progression	14 Participants	7 Participants
Cumulative Incidence of Relapse (CIR) CIR on PP Set · Censored patients	13 Participants	8 Participants

SECONDARY outcome

Timeframe: From randomization to the date of resolution, assessed up to 12 months

Population: Due to the early termination of the study, the analysis was not performed because data were not collected for this Outcome Measure

Diagnosis, monitoring and treatment of infectious relevant events

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From HSV-Tk infusions to the date of resolution, assessed up to 12 months

Population: Due to the early termination of the study, the analysis was not performed because data were not collected for this Outcome Measure

Toxicity profile of HSV-Tk infusions

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: from randomization up to 12 months

Population: Due to the early termination of the study, the analysis was not performed because data were not collected for this Outcome Measure

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From the date of randomization to the date of death, assessed up to 12 months.

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.

Outcome measures

Outcome measures
Measure	A-Experimental Arm n=64 Participants 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	B - Control Arm n=28 Participants 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.
Non-relapse Mortality (NRM) NRM on ITT population · Deaths without previous relapse or progression	27 Participants	9 Participants
Non-relapse Mortality (NRM) NRM on ITT population · Patients with relapse or progression	18 Participants	11 Participants
Non-relapse Mortality (NRM) NRM on ITT population · Censored patients	19 Participants	8 Participants
Non-relapse Mortality (NRM) NRM on PP Set · Deaths without previous relapse or progression	14 Participants	7 Participants
Non-relapse Mortality (NRM) NRM on PP Set · Patients with relapse or progression	11 Participants	11 Participants
Non-relapse Mortality (NRM) NRM on PP Set · Censored patients	13 Participants	8 Participants

Adverse Events

A-Experimental Arm

Serious events: 35 serious events

Other events: 22 other events

Deaths: 35 deaths

B - Control Arm

Serious events: 17 serious events

Other events: 0 other events

Deaths: 17 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	A-Experimental Arm n=53 participants at risk 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	B - Control Arm n=27 participants at risk 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
Investigations related to HSV-TK cells	41.5% 22/53 • From day 21 through day 180 or at least 30 days after last dose of HSV-TK. 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).	0.00% 0/27 • From day 21 through day 180 or at least 30 days after last dose of HSV-TK. 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).

Additional Information

Anna Stornaiuolo

AGC Biologics S.p.A

Phone: 00390221277440

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place