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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Acute Leukemia (Category)

Intervention / Treatment
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* Genetic: HSV-Tk
* Other: T-cell depleted or T-cell replete strategies


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>HSV-TK engineering donor Lymphocytes | Genetic: HSV-Tk<br>* 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.<br>|
| Active Comparator: B<br>T-cell depleted or T-cell replete strategies | Other: T-cell depleted or T-cell replete strategies<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | From the date of randomization, assessed up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | any death without previous occurrence of a documented relapse (or progression).Patients alive or without any follow up will be censored. | From the date of randomization to the date of death, assessed up to 12 months | 
| 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. | Weekly up to IR after engraftment of HCT, monthly for 6 months from date of IR and then at month 9 and 12 | 
| Engraftment Rate | Defined as the persistent blood cells count above predefined level. | At day 15 after HCT, monthly for 6 months after HCT and then at month 9 and 12 | 
| 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 | from the date of HCT until the date of the first occurrence of aGvHD, assessed up to 6 months | 
| Cumulative Incidence of Chronic GvHD (cGvHD) | Diagnosed and graded according to standard NIH consensus criteria | From the date of HCT until the date of the first occurrence of cGvHD, assessed up to 12 months | 
| Duration of GvHD Episodes | Diagnosed and graded according to standard NIH consensus criteria | From the date of start until the date of resolution and duration of immunosuppressive treatments administered for controlling GvHD assessed up to 12 months | 
| 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 | from the date of randomization to the date of the first occurrence of relapse, assessed up to 12 months | 
| Incidence and Duration of Infectious Episodes and Infectious Disease Mortality | Diagnosis, monitoring and treatment of infectious relevant events | From randomization to the date of resolution, assessed up to 12 months | 
| Evaluate the Acute and Long-term Toxicity Related to the HSV-Tk Infusions | Toxicity profile of HSV-Tk infusions | From HSV-Tk infusions to the date of resolution, assessed up to 12 months | 
| 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. | from randomization up to 12 months | 
| 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. | From the date of randomization to the date of death, assessed up to 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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high risk acute leukemia, HSV-TK, Haploidentical HCT, GvHD, GvL, Immunoreconstitution