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Cyclophosphamide

T-cell depleted or T-cell replete strategies

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.

HSV-Tk

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

Antonio Lambiase, MD

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

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.

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

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

No, only information requested by law will be released

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).

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

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.

Defined as the persistent blood cells count above predefined level.

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

Diagnosed and graded according to standard NIH consensus criteria

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

Diagnosis, monitoring and treatment of infectious relevant events

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.

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.

AGC Biologics S.p.A.

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).

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

A-Experimental Arm

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

B - Control Arm

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.

A - Experimental Arm

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.

B- Comparator Arm

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

Anna Stornaiuolo

DFS- Intention-To-Treat population- from baseline to day 21

DFS- Intention-To-Treat population - day 21 after transplant

DFS- Per-Protocol Set DFS-day 21 after transplant

DFS on ITT

DFS on PP Set

DFS on ITT - day 21 after transplant

DFS on PP Set day 21 after transplant

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.

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.

Disease-free Survival (DFS)

Statistical analysis has been performed for Intention-To-Treat population.

Statistical analysis has been performed for Per-Protocol Set)

OS on ITT

OS on PP Set

OS on ITT- day 21 after transplant

OS on PP Set - day 21 after transplant

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.

Overall Survival (OS)

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

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

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

This Statistical analysis refers to Immune reconstitution and was performed by Gray's Test for Equality of Cumulative Incidence Functions for Per-Protocol Set.

IR on ITT

IR on PP Set

Immune Reconstitution (IR)

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.

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

Engraftment Rate

Cumulative Incidence of Grade 2, 3, or 4 Acute GvHD (aGvHD)

Cumulative Incidence of Chronic GvHD (cGvHD)

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.

B - Comparator Arm

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

Duration of GvHD Episodes

This Statistical Analysis refers to ITT Patients with relapse or progression and was performed with Gray's Test for Equality of Cumulative Incidence Functions

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

this Gray's Statistical Analysis refers to PPS patients with relapse or progression and was performed with Test for Equality of Cumulative Incidence Functions

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

CIR on ITT population - CIR

CIR on PP Set

Cumulative Incidence of Relapse (CIR)

Incidence and Duration of Infectious Episodes and Infectious Disease Mortality

Evaluate the Acute and Long-term Toxicity Related to the HSV-Tk Infusions

Quality of Life (QoL) and Medical Care Utilization (MCU) in Both Arms

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

This statistical test refers to Patients with relapse or progression and was performed to Gray's Test for Equality of Cumulative Incidence Functions.

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia	NCT00914628	Acute Leukemia ...	HSV-Tk T-cell depleted...	18 Years -	AGC Biologics S.p.A.
Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia	NCT00914628	Acute Leukemia ...	HSV-Tk T-cell depleted...	18 Years -	AGC Biologics S.p.A.

Spots Global Cancer Trial Database for high risk acute leukemia