Acute Leukemia (Category)Phase 3TK008NCT00914628
Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia
A Phase 3 study testing HSV-Tk and T-cell depleted or T-cell replete strategies in people with Acute Leukemia (Category), run by AGC Biologics S.p.A. at 36 sites in 10 countries.
Trial 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 Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Leukemia (Category)
- What is being tested?
- HSV-Tk and T-cell depleted or T-cell replete strategies
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 92 participants
- Where
- 36 sitesin 10 countries
- Study dates
- 12 Apr 2010to 30 Nov 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 15Show fewer
- 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
Who cannot join
- 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.
- Infections requiring administration of ganciclovir or valganciclovir at the time of infusion
- GvHD requiring systemic immunosuppressive therapy
Show all 9Show fewer
- 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)
Trial locations and contacts
36 sites in 10 countries.
36 sites in 10 countries
Italy9 sites
Azienda Ospedaliero-Universitaria Policlinico-Vittorio Emanuele
Catania, CT
Azienda Sanitaria Ospedaliera S.Croce e Carle
Cuneo, CN
Azienda Ospedaliera Universitaria Careggi
Florence, FI
Ospedale San Raffaele
Milan
Azienda Ospedaliero-Universitaria Policlinico di Modena
Modena, 41124
Azienda Ospedaliera Ospedali Riuniti Villa Sofia - Cervello
Palermo, PA
Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Presidio Molinette
Torino, TO
Ospedale Santa Maria della Misericordia
Udine, UD
Policlinico G. B. Rossi, Azienda ospedaliera universitaria integrata di Verona
Verona, VR
France8 sites
Hôpital Jean Minjoz
Besançon, 25030
Centre Hospitalier Universitaire de Clermont-Ferrand
Clermont-Ferrand
Centre Hospitalier Régional Universitaire de Lille
Lille
Institut Paoli-Calmettes
Marseille
Centre Hospitalier Universitaire de Nantes
Nantes
Hôpital l'Archet
Nice
Hôpital Saint-Antoine
Paris
IUCT Oncopole - Institut Universitaire du Cancer de Toulouse
Toulouse
Germany6 sites
Charitè; Campus Benjamin Franklin
Berlin, 13353
University Medical Center Hamburg-Eppendorf
Hamburg
Medizinische Hochschule Hannover
Hanover, 30625
University of Leipzig
Leipzig, 04103
Universitat Tubingen
Tübingen, 72076
Medizinische Klinik und Poliklinik
Ulm, 89081
United States3 sites
Northwestern University Feinberg School of Medicine
Chicago, Illinois, 60611
John Theurer Cancer Center at Hackensack University Medical Center
Hackensack, New Jersey, 07601
Washington University Medical School
St Louis, Missouri, 63110
Belgium3 sites
Universitair Ziekenhuis
Ghent
University Hospitals Leuven
Leuven, 3000
Centre Hospitalier Universitaire de Liège - Domaine Universitaire du Sart Tilman
Liège
Spain3 sites
Hospital de la Santa Creu i Sant Pau
Barcelona
Instituto Catalán de Oncología
L'Hospitalet de Llobregat
Hospital de Navarra
Pamplona, 31008
About this study
Official title: 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
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
Read the 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.
- Conditions
- Acute Leukemia (Category)
- Being tested
- HSV-Tk, T-cell depleted or T-cell replete strategies
- Keywords
- high risk acute leukemia, HSV-TK, Haploidentical HCT, GvHD, GvL, Immunoreconstitution
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HSV-TkGenetic
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.
T-cell depleted or T-cell replete strategiesOther
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
| Study group | Role | What they receive |
|---|---|---|
| A | Experimental | HSV-TK engineering donor Lymphocytes Receives: Genetic: HSV-Tk |
| B | Active comparator | T-cell depleted or T-cell replete strategies Receives: Other: T-cell depleted or T-cell replete strategies |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: From the date of randomization, assessed up to 12 months
Secondary outcomes (11)
Overall Survival (OS)
any death without previous occurrence of a documented relapse (or progression).Patients alive or without any follow up will be censored.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 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.
Measured: From the date of randomization to the date of death, assessed up to 12 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Jun 2009 (estimated)
- Study start12 Apr 2010
- Primary completion30 Nov 2019
- Study completion30 Nov 2019
Why it stopped: EMA withdrew the marketing Authorisation at the request of AGC Biologics S.p.A (formerly MolMed S.p.A), which decided to permanently discontinue the marketing of the product for commercial reasons
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Acute Leukemia (Category)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 92 participants (actual)
Sponsor and investigators
- Lead sponsor
- AGC Biologics S.p.A.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Antonio Lambiase, MD, Study director, AGC Biologics S.p.A.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00914628
- Sponsor's protocol ID
- TK008
- Other IDs
- 2009-012973-37, 2009
- Acronym
- TK008
- Status last verified
- Jun 2021
- First submitted
- 3 Jun 2009
- Last updated
- 22 Jun 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No: No, only information requested by law will be released
Study at a glance
From the registry record, last updated by the sponsor on 22 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT00914628
- Acronym / sponsor ID
- TK008 / TK008
- Conditions
- Acute Leukemia (Category)
- Keywords
- high risk acute leukemia, HSV-TK, Haploidentical HCT, GvHD, GvL, Immunoreconstitution
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: EMA withdrew the marketing Authorisation at the request of AGC Biologics S.p.A (formerly MolMed S.p.A), which decided to permanently discontinue the marketing of the product for commercial reasons
- Enrolment
- 92 participants (actual)
- Lead sponsor
- AGC Biologics S.p.A.Industry (pharma, biotech, devices)
- Study start
- 12 Apr 2010 (actual)
- Primary completion
- 30 Nov 2019 (actual)
- Study completion
- 30 Nov 2019 (actual)
- First posted
- 5 Jun 2009 (estimated)
- Results
- Posted 22 Jun 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| A | Experimental | Genetic: HSV-TkHSV-TK engineering donor Lymphocytes |
| B | Active comparator | Other: T-cell depleted or T-cell replete strategiesT-cell depleted or T-cell replete strategies |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- Age ≥ 18 years
- Any of the following conditions:
- 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
Key exclusion criteria (9 listed)
- 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.
- Infections requiring administration of ganciclovir or valganciclovir at the time of infusion
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HSV-TkInfusion 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. | Genetic | A |
| T-cell depleted or T-cell replete strategiesHaploidentical 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 | Other | B |
Primary outcome
Disease-free Survival (DFS)
Time frame: 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).
11 secondary outcomes
Overall Survival (OS)
Time frame: From the date of randomization to the date of death, assessed up to 12 months
Immune Reconstitution (IR)
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: From the date of HCT until the date of the first occurrence of cGvHD, assessed up to 12 months
Duration of GvHD Episodes
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: from randomization up to 12 months
Non-relapse Mortality (NRM)
Time frame: From the date of randomization to the date of death, assessed up to 12 months.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jun 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No. No, only information requested by law will be released
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Antonio Lambiase, MD study director
AGC Biologics S.p.A.
36 sites in 10 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing HSV-Tk and T-cell depleted or T-cell replete strategies in people with Acute Leukemia (Category), run by AGC Biologics S.p.A. at 36 sites in 10 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 22 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 36 sites in Italy, France, Germany, United States, Belgium and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Jun 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Disease-free Survival (DFS) (time frame: From the date of randomization, assessed up to 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jun 2021.