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NCT00914628: TK008

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

Terminated Phase 3 Results posted Last updated 22 June 2021
What this trial tests

Phase 3 trial testing HSV-Tk in Acute Leukemia (Category) in 92 participants. Terminated before completion.

Timeline
12 April 2010
Primary endpoint
30 November 2019
30 November 2019

Quick facts

Lead sponsorAGC Biologics S.p.A.
PhasePhase 3
StatusTerminated
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment92
Start date12 April 2010
Primary completion30 November 2019
Estimated completion30 November 2019
Sites36 locations across France, Italy, Greece, Belgium, Germany, Israel, Lithuania, Portugal

Drugs / interventions tested

Conditions studied

Sponsor

AGC Biologics S.p.A. — full company profile →

Who can join

18 and older, any sex, with Acute Leukemia (Category). Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Disease-free Survival (DFS) Primary · 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

DFS on ITT
GroupValue95% CI
A-Experimental Arm45
B - Control Arm20
A-Experimental Arm19
B - Control Arm8
DFS on PP Set
GroupValue95% CI
A-Experimental Arm25
B - Control Arm18
A-Experimental Arm13
B - Control Arm8
DFS on ITT - day 21 after transplant
GroupValue95% CI
A-Experimental Arm38
B - Control Arm20
A-Experimental Arm17
B - Control Arm8
DFS on PP Set day 21 after transplant
GroupValue95% CI
A-Experimental Arm25
B - Control Arm18
A-Experimental Arm13
B - Control Arm8
Overall Survival (OS) Secondary · 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.

OS on ITT
GroupValue95% CI
A-Experimental Arm22
B - Control Arm10
A-Experimental Arm42
B - Control Arm18
OS on PP Set
GroupValue95% CI
A-Experimental Arm14
B - Control Arm10
A-Experimental Arm24
B - Control Arm16
OS on ITT- day 21 after transplant
GroupValue95% CI
A-Experimental Arm20
B - Control Arm10
A-Experimental Arm35
B - Control Arm18
OS on PP Set - day 21 after transplant
GroupValue95% CI
A-Experimental Arm18
B - Control Arm10
A-Experimental Arm33
B - Control Arm18
Immune Reconstitution (IR) Secondary · 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.

IR on ITT
GroupValue95% CI
A-Experimental Arm38
B - Control Arm22
A-Experimental Arm13
B - Control Arm5
A-Experimental Arm6
B - Control Arm1
A-Experimental Arm1
B - Control Arm0
IR on PP Set
GroupValue95% CI
A-Experimental Arm29
B - Control Arm22
A-Experimental Arm4
B - Control Arm3
A-Experimental Arm5
B - Control Arm1
A-Experimental Arm0
B - Control Arm0
Cumulative Incidence of Relapse (CIR) Secondary · 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

CIR on ITT population - CIR
GroupValue95% CI
A-Experimental Arm18
B - Control Arm11
A-Experimental Arm27
B - Control Arm9
A-Experimental Arm19
B - Control Arm8
CIR on PP Set
GroupValue95% CI
A-Experimental Arm11
B - Control Arm11
A-Experimental Arm14
B - Control Arm7
A-Experimental Arm13
B - Control Arm8
Non-relapse Mortality (NRM) Secondary · 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

NRM on ITT population
GroupValue95% CI
A-Experimental Arm27
B - Control Arm9
A-Experimental Arm18
B - Control Arm11
A-Experimental Arm19
B - Control Arm8
NRM on PP Set
GroupValue95% CI
A-Experimental Arm14
B - Control Arm7
A-Experimental Arm11
B - Control Arm11
A-Experimental Arm13
B - Control Arm8

Adverse events — posted to ClinicalTrials.gov

Time frame: From day 21 through day 180 or at least 30 days after last dose of HSV-TK.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

A-Experimental Arm
Serious: 35/53 (66%)
Deaths: 35/53
B - Control Arm
Serious: 17/27 (63%)
Deaths: 17/27

Serious adverse events (75 terms)

ReactionSystemA-Experimental ArmB - Control Arm
Moderate Acute graft versus host diseaseImmune system disorders
Severe Acute graft versus host diseaseImmune system disorders
Moderate Chronic graft versus host diseaseImmune system disorders
Severe Chronic graft versus host diseaseImmune system disorders
Severe PneumoniaInfections and infestations
Life threatening Septic shockInfections and infestations
Life threatening leukaemia recurrentNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Severe Post transplant lymphoproliferative disorderNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Autoimmune haemolytic anaemiaBlood and lymphatic system disorders
Moderate Febrile neutropeniaBlood and lymphatic system disorders
Life threatening Febrile neutropeniaBlood and lymphatic system disorders
Life threatening PancytopeniaBlood and lymphatic system disorders
Severe Thrombotic microangiopathyBlood and lymphatic system disorders
Severe Thymic cystBlood and lymphatic system disorders
Mild Abdominal painGastrointestinal disorders
Severe ColitisGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
NauseaGastrointestinal disorders
Severe StomatitisGastrointestinal disorders
Severe VomitingGastrointestinal disorders
Moderate PyrexiaGeneral disorders
Severe PyrexiaGeneral disorders
Mild Acute graft versus host diseaseImmune system disorders
Mild Chronic graft versus host diseaseImmune system disorders
Moderate Graft versus host diseaseImmune system disorders
Other adverse events (1 terms — click to expand)

ReactionSystemA-Experimental ArmB - Control Arm
related to HSV-TK cellsInvestigations

Most-reported serious reactions: Moderate Acute graft versus host disease, Severe Acute graft versus host disease, Moderate Chronic graft versus host disease, Severe Chronic graft versus host disease, Severe Pneumonia, Life threatening Septic shock, Life threatening leukaemia recurrent, Severe Post transplant lymphoproliferative disorder.

Data from ClinicalTrials.gov NCT00914628 adverse events section.

Sponsor's own description

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

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Development and Clinical Translation of Approved Gene Therapy Products for Genetic Disorders.
    Shahryari A, Saghaeian Jazi M, Mohammadi S, Razavi Nikoo H, et al · · 2019 · cited 168× · PMID 31608113 · DOI 10.3389/fgene.2019.00868
  2. Gene-directed enzyme prodrug therapy.
    Zhang J, Kale V, Chen M. · · 2015 · cited 102× · PMID 25338741 · DOI 10.1208/s12248-014-9675-7
  3. Cell therapies in the clinic.
    Wang LL, Janes ME, Kumbhojkar N, Kapate N, et al · · 2021 · cited 99× · PMID 34027097 · DOI 10.1002/btm2.10214
  4. Improving the safety of cell therapy with the TK-suicide gene.
    Greco R, Oliveira G, Stanghellini MT, Vago L, et al · · 2015 · cited 91× · PMID 25999859 · DOI 10.3389/fphar.2015.00095
  5. Enzyme/Prodrug Systems for Cancer Gene Therapy.
    Malekshah OM, Chen X, Nomani A, Sarkar S, et al · · 2016 · cited 53× · PMID 28042530 · DOI 10.1007/s40495-016-0073-y
  6. Alpha-Herpesvirus Thymidine Kinase Genes Mediate Viral Virulence and Are Potential Therapeutic Targets.
    Xie Y, Wu L, Wang M, Cheng A, et al · · 2019 · cited 47× · PMID 31134006 · DOI 10.3389/fmicb.2019.00941
  7. Haploidentical transplantation for hematologic malignancies: where do we stand?
    Fuchs EJ. · · 2012 · cited 42× · PMID 23233586 · DOI 10.1182/asheducation-2012.1.230
  8. Prodrugs and prodrug-activated systems in gene therapy.
    Sheikh S, Ernst D, Keating A. · · 2021 · cited 39× · PMID 33831557 · DOI 10.1016/j.ymthe.2021.04.006

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