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

Phase 3

Terminated

Conditions: Acute Leukemia (Category)

Registration Number: NCT00914628

Lead Sponsor: AGC Biologics S.p.A.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 92

Inclusion Criteria

Age ≥ 18 years
Any of the following conditions:
1. AML and ALL in 1st complete remission (CR1)
2. AML and ALL in 2nd or subsequent CR
3. secondary AML in CR
4. 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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Disease-free Survival (DFS)	From the date of randomization, assessed up to 12 months	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

Name	Time	Method
Engraftment Rate	At day 15 after HCT, monthly for 6 months after HCT and then at month 9 and 12	Defined as the persistent blood cells count above predefined level.
Cumulative Incidence of Relapse (CIR)	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
Quality of Life (QoL) and Medical Care Utilization (MCU) in Both Arms	from randomization up to 12 months	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.
Immune Reconstitution (IR)	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.
Cumulative Incidence of Grade 2, 3, or 4 Acute GvHD (aGvHD)	from the date of HCT until the date of the first occurrence of aGvHD, assessed up to 6 months	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)	From the date of HCT until the date of the first occurrence of cGvHD, assessed up to 12 months	Diagnosed and graded according to standard NIH consensus criteria
Evaluate the Acute and Long-term Toxicity Related to the HSV-Tk Infusions	From HSV-Tk infusions to the date of resolution, assessed up to 12 months	Toxicity profile of HSV-Tk infusions
Overall Survival (OS)	From the date of randomization to the date of death, assessed up to 12 months	any death without previous occurrence of a documented relapse (or progression).Patients alive or without any follow up will be censored.
Duration of GvHD Episodes	From the date of start until the date of resolution and duration of immunosuppressive treatments administered for controlling GvHD assessed up to 12 months	Diagnosed and graded according to standard NIH consensus criteria
Incidence and Duration of Infectious Episodes and Infectious Disease Mortality	From randomization to the date of resolution, assessed up to 12 months	Diagnosis, monitoring and treatment of infectious relevant events
Non-relapse Mortality (NRM)	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.

Trial Locations

Locations (36): Northwestern University Feinberg School of Medicine
🇺🇸
Chicago, Illinois, United States
Washington University Medical School
🇺🇸
Saint Louis, Missouri, United States
John Theurer Cancer Center at Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
Universitair Ziekenhuis
🇧🇪
Gent, Belgium
University Hospitals Leuven
🇧🇪
Leuven, Belgium
Centre Hospitalier Universitaire de Liège - Domaine Universitaire du Sart Tilman
🇧🇪
Liège, Belgium
Hôpital Jean Minjoz
🇫🇷
Besançon, France
Centre Hospitalier Universitaire de Clermont-Ferrand
🇫🇷
Clermont-Ferrand, France
Centre Hospitalier Régional Universitaire de Lille
🇫🇷
Lille, France
Institut Paoli-Calmettes
🇫🇷
Marseille, France
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Northwestern University Feinberg School of Medicine
🇺🇸Chicago, Illinois, United States