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TK008: Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT00914628
Recruitment Status : Recruiting
First Posted : June 5, 2009
Last Update Posted : April 14, 2016
Information provided by (Responsible Party):
MolMed 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

Condition or disease Intervention/treatment Phase
Acute Leukemia (Category) Genetic: HSV-Tk Other: T-cell depleted or T-cell replete strategies Phase 3

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 170 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Study Start Date : February 2010
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Leukemia

Arm Intervention/treatment
Experimental: A
HSV-TK engineering donor Lymphocytes
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 further infusions up to 4 will be administered on monthly basis.

Active Comparator: B
T-cell depleted or T-cell replete strategies
Other: T-cell depleted or T-cell replete strategies
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

Primary Outcome Measures :
  1. Disease-free survival (DFS) [ Time Frame: From the date of randomization to the date of the first occurrence of relapse (or progression) or death, whichever came first, assessed up to 12 months ]

Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: From the date of randomization to the date of death, assessed up to 12 months ]
  2. Immuno 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 ]
    Defined as the time to reach a level of circulating CD3+ ≥ 100/µl for two consecutive observations

  3. Engraftment rate [ Time Frame: Weekly up to IR after HCT, monthly for 6 months after IR and then at month 9 and 12 ]
    Defined as the persistent blood cells count at a predefined level

  4. 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 ]
    Diagnosed and graded according to standard criteria

  5. Cumulative incidence of extensive chronic GvHD (cGvHD) [ Time Frame: 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

  6. 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 ]
    Defined on the basis of morphologic evidence of leukaemia in bone marrow or other sites.

  7. Incidence and duration of infectious episodes and infectious disease mortality [ Time Frame: From randomization to the end of study ]
  8. Evaluate the acute and long-term toxicity related to the HSV-Tk infusions [ Time Frame: From HSV-Tk infusions to death ]
  9. Quality of life (QoL) and Medical Care Utilization (MCU) in both arms [ Time Frame: From randomization to end of study ]
    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.

  10. Non-relapse mortality (NRM) [ Time Frame: 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)

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
    • secondary AML and ALL in 1st or 2nd relapse or primary refractory
  • 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 < 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00914628

Contact: Fabio Ciceri, MD 0

United States, Illinois
Northwestern University Feinberg School of Medicine Recruiting
Chicago, Illinois, United States, 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: Rizwan Romee, MD         
Principal Investigator: Rizwan Romee, MD         
United States, New Jersey
John Theurer Cancer Center at Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Michele Donato, MD         
Principal Investigator: Michele Donato, MD         
University Hospitals Leuven Recruiting
Leuven, Belgium, 3000
Contact: Johan Maertens, MD         
Principal Investigator: Johan Maertens, MD         
Hôpital Jean Minjoz Recruiting
Besançon, France, 25030
Contact: Eric Deconinck, MD         
Principal Investigator: Eric Deconinck, MD         
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         
George Papanicolaou Hospital Recruiting
Thessaloniki, Greece, 57010
Contact: Evangelia Yannaki, MD         
Principal Investigator: Evangelia Yannaki, MD         
Chaim Sheba Medical Center Recruiting
Tel Hashomer, Israel, 52621
Contact: Arnon Nagler, MD         
Principal Investigator: Arnon Nagler, MD         
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: Franco Narni, MD         
Principal Investigator: Franco Narni, MD         
Hospital de Navarra Recruiting
Pamplona, Spain, 31008
Contact: Mercedes Rodríguez, MD         
Principal Investigator: Mercedes Rodríguez, MD         
Sponsors and Collaborators
MolMed S.p.A.
Principal Investigator: Fabio Ciceri, MD Fondazione San Raffaele

Responsible Party: MolMed S.p.A. Identifier: NCT00914628     History of Changes
Other Study ID Numbers: TK008
2009-012973-37 ( Registry Identifier: EUdraCT number )
First Posted: June 5, 2009    Key Record Dates
Last Update Posted: April 14, 2016
Last Verified: April 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No, only information requested by law will be released

Keywords provided by MolMed S.p.A.:
high risk acute leukemia
Haploidentical HCT

Additional relevant MeSH terms:
Acute Disease
Neoplasms by Histologic Type
Disease Attributes
Pathologic Processes