TK008: Efficacy Study on the Strategy of Herpes Simplex Virus Thymidine Kinase Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia
This study is currently recruiting participants.
Verified February 2013 by MolMed S.p.A.
Sponsor:
MolMed S.p.A.
Information provided by (Responsible Party):
MolMed S.p.A.
ClinicalTrials.gov Identifier:
NCT00914628
First received: June 3, 2009
Last updated: February 13, 2013
Last verified: February 2013
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Purpose
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
| Condition | Intervention | Phase |
|---|---|---|
|
High Risk Acute Leukemia |
Genetic: HSV-Tk Other: T cell repletion strategies |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| 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 |
Resource links provided by NLM:
Further study details as provided by MolMed S.p.A.:
Primary Outcome Measures:
- Disease-free survival (DFS) [ Time Frame: From the randomization date to relapse date or death ] [ Designated as safety issue: Yes ]
Secondary Outcome Measures:
- Overall Survival (OS) [ Time Frame: From randomization to death ] [ Designated as safety issue: No ]
- Immuno reconstitution (IR) [ Time Frame: Weekly after HCT ] [ Designated as safety issue: Yes ]Defined as the time to reach a level of circulating CD3+ ≥ 100/µl for two consecutive observations
- Engraftment rate [ Time Frame: Weekly up to IR after HCT or up to 6 months after HCT if no IR ] [ Designated as safety issue: Yes ]Defined as the persistent blood cells count as a predefined level
- Cumulative incidence of grade 2, 3, or 4 acute GVHD (aGvHD) [ Time Frame: From the date of HCT until the date to the first occurence of relapse ] [ Designated as safety issue: Yes ]Diagnosed and graded according to standard criteria and computed in patients who will survive during the first 100 days after the transplantation.
- Cumulative incidence of extensive chronic GvHD (cGvHD) [ Time Frame: For at least 100 days after transplantation ] [ Designated as safety issue: Yes ]Diagnosed and graded according to standard NIH consensus criteria and computed in patients who will survive for at least 100 days after transplantation.
- Cumulative incidence of relapse (CIR) [ Time Frame: From the date of HCT until the date to the first occurence of relapse or death ] [ Designated as safety issue: Yes ]Defined on the basis of morphologic evidence of leukaemia in bone marrow or other sites.
- Disease-Free Survival (DFS) [ Time Frame: From the date of randomization until the date of relapse or death ] [ Designated as safety issue: No ]
- Incidence and duration of infectious episodes and infectious disease mortality [ Time Frame: From randomization to the end of study ] [ Designated as safety issue: Yes ]
- Evaluate the acute and long-term toxicity related to the HSV-Tk infusions [ Time Frame: From HSV-Tk infusions to death ] [ Designated as safety issue: Yes ]
- Quality of life (QoL) and Medical Care Utilization (MCU) in both arms [ Time Frame: From randomization to end of study ] [ Designated as safety issue: No ]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.
- Non-relapse mortality (NRM) [ Time Frame: From the date of HCT until to death ] [ Designated as safety issue: Yes ]Defined for all patients as any death without previous occurrence of a documented relapse
| Estimated Enrollment: | 170 |
| Study Start Date: | February 2010 |
| Estimated Study Completion Date: | June 2016 |
| Estimated Primary Completion Date: | June 2016 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Experimental: A |
Genetic: HSV-Tk
Infusion of genetically modified lymphocytes 1x10^7 c/kg: first at +21-+49 days after HSCT; in absence of immune reconstitution and GvHD futher infusions up to 4 will be administered on monthly basis.
|
| Active Comparator: B |
Other: T cell repletion strategies
Haploidentical HCT with the infusion of CD34+ cells plus a fixed dose of T cells (1 x 10^4/Kg)
|
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 CD4+ reconstitution could take more than 10 months. The low number of lymphocytes infused with the graft, the degree of HLA 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, because it remarkably may enhance both GvL 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.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Age ≥ 18 years with HCT comorbidity index < 3
Any of the following conditions:
- AML and ALL in 1st complete remission (CR) at high risk of relapse based on negative prognostic factors (for the definition of high-risk of relapse see Appendix H).
- AML and ALL in 2nd or subsequent CR
- secondary AML in CR
- Absence of timely and suitable fully HLA matched or one HLA locus mismatched family or unrelated donor and, at Investigator's discretion, absence of other possible therapeutic alternatives
- Stable clinical conditions and life expectancy > 3 months
- PS ECOG < or = 2
- 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
- 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%
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, valganciclovir or acyclovir at the time of infusion: HSV-Tk cells can be administered after a 24-hour discontinuation interval of antiviral therapy
- GvHD requiring systemic immunosuppressive therapy
- Ongoing systemic immunosuppressive therapy after haploidentical HCT
- Administration of G-CSF after haploidentical HCT
- CD3+ cells ≥ 100/µl at day of planned experimental infusion after haploidentical HCT
- Any grade 3-4 adverse event related to HSV-Tk infusion or a grade 2 adverse event that does not resolve to no more than grade 1 before the next infusion
For criteria 2, 3 and 4: HSV-Tk cells can be administered after an adequate patient wash-out period
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00914628
Contacts
| Contact: Fabio Ciceri, MD | 0 |
Locations
| United States, Illinois | |
| Northwestern University Feinberg School of Medicine | Recruiting |
| Chicago, Illinois, United States, IL 60611 | |
| Contact: Jayesh Mehta, MD | |
| Principal Investigator: Jayesh Mehta, MD | |
| United States, Missouri | |
| Washington University Medical School | Recruiting |
| St. Louis, Missouri, United States, 63110 | |
| Contact: John F. Di Persio, MD | |
| Principal Investigator: John F. Di Persio, MD | |
| Belgium | |
| AZ St Jan AV | Recruiting |
| Brugge, Belgium, 8000 | |
| Contact: Dominik Selleslag, MD | |
| Principal Investigator: Dominik Selleslag, MD | |
| University Hospitals Leuven | Recruiting |
| Leuven, Belgium, 3000 | |
| Contact: Johan Maertens, MD | |
| Principal Investigator: Johan Maertens, MD | |
| France | |
| Hôpital Jean Minjoz | Recruiting |
| Besançon, France, 25030 | |
| Contact: Eric Deconinck, MD | |
| Principal Investigator: Eric Deconinck, MD | |
| Germany | |
| Charitè; Campus Benjamin Franklin | Recruiting |
| Berlin, Germany, 13353 | |
| Contact: Lutz Uharek, MD | |
| Principal Investigator: Lutz Uharek, MD | |
| Medizinische Hochschule Hannover | Recruiting |
| Hannover, Germany, 30625 | |
| Contact: Arnold Ganser, MD | |
| Contact: Eva Mischak-Weissinger, MD | |
| Principal Investigator: Arnold Ganser, MD | |
| Sub-Investigator: Eva Mischak-Weissinger, MD | |
| University of Leipzig | Recruiting |
| Leipzig, Germany, 04103 | |
| Contact: Dietger Niederwieser, MD | |
| Principal Investigator: Dietger Niederwieser, MD | |
| Universitat Tubingen | Recruiting |
| Tubingen, Germany, 72076 | |
| Contact: Wolfgang Bethge, MD | |
| Principal Investigator: Wolfgang Bethge, MD | |
| Medizinische Klinik und Poliklinik | Recruiting |
| Ulm, Germany, 89081 | |
| Contact: Donald Bunjes, MD | |
| Principal Investigator: Donald Bunjes, MD | |
| Greece | |
| George Papanicolaou Hospital | Recruiting |
| Thessaloniki, Greece, 57010 | |
| Contact: Evangelia Yannaki, MD | |
| Principal Investigator: Evangelia Yannaki, MD | |
| Italy | |
| Fondazione San Raffaele | Recruiting |
| Milan, Italy | |
| Contact: Fabio Ciceri, MD 0 | |
| Principal Investigator: Fabio Ciceri, MD | |
| Azienda Ospedaliero-Universitaria Policlinico di Modena | Recruiting |
| Modena, Italy, 41124 | |
| Contact: Mario Luppi, MD | |
| Contact: Franco Narni, MD | |
| Principal Investigator: Mario Luppi, MD | |
| Sub-Investigator: Franco Narni, MD | |
| Spain | |
| Hospital de Navarra | Recruiting |
| Pamplona, Spain, 31008 | |
| Contact: Eduardo Olavarria, MD | |
| Principal Investigator: Eduardo Olavarria, MD | |
Sponsors and Collaborators
MolMed S.p.A.
Investigators
| Principal Investigator: | Fabio Ciceri, MD | Fondazione San Raffaele |
More Information
No publications provided
| Responsible Party: | MolMed S.p.A. |
| ClinicalTrials.gov Identifier: | NCT00914628 History of Changes |
| Other Study ID Numbers: | TK008, 2009-012973-37 |
| Study First Received: | June 3, 2009 |
| Last Updated: | February 13, 2013 |
| Health Authority: | Italy: The Italian Medicines Agency United States: Food and Drug Administration Spain: Agencia Española de Medicamentos y Productos Sanitarios Greece: Ministry of Health and Social Solidarity Germany: Paul-Ehrlich-Institut Belgium: Federal Agency for Medicines and Health Products France: Agence Francaise de Securité Sanitaire des Produits de Sauté |
Keywords provided by MolMed S.p.A.:
|
high risk acute leukemia HSV-TK Haploidentical HCT |
GvHD GvL Immunoreconstitution |
Additional relevant MeSH terms:
|
Leukemia Acute Disease Neoplasms by Histologic Type |
Neoplasms Disease Attributes Pathologic Processes |
ClinicalTrials.gov processed this record on May 16, 2013