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Trial record 2 of 2 for:    molmed | Phase 3

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

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ClinicalTrials.gov Identifier: NCT00914628
Recruitment Status : Recruiting
First Posted : June 5, 2009
Last Update Posted : September 14, 2018
Sponsor:
Information provided by (Responsible Party):
MolMed S.p.A.

Tracking Information
First Submitted Date  ICMJE June 3, 2009
First Posted Date  ICMJE June 5, 2009
Last Update Posted Date September 14, 2018
Actual Study Start Date  ICMJE February 2010
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 12, 2018)
Disease-free survival (DFS) [ Time Frame: from the date of randomization, assessed up to 12 months ]
measured from the date of randomization until the date of relapse (or progression), or death from any cause, whichever occurs first.
Original Primary Outcome Measures  ICMJE
 (submitted: June 4, 2009)
  • Overall Survival (OS) measured for all patients from the date of randomization until death from any cause. [ Time Frame: From randomization to death ]
  • Non-Relapse Mortality (NRM) defined for all patients as the probability of death related to transplantation and not to relapse (considered as competing event). [ Time Frame: From the date of HCT until to death ]
Change History Complete list of historical versions of study NCT00914628 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 12, 2018)
  • Overall Survival (OS) [ Time Frame: 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).
  • Chronic GvHD-free/relapse-free survival (GRFS) [ Time Frame: from the date of randomization to the date of death, assessed up to 12 months ]
    the time from the date of randomization to chronic GvHD, relapse/progression or death from any cause, whichever occurs first.
  • 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 ]
    the time to reach a level of circulating CD3+ ≥ 100/µl for two consecutive observations
  • Engraftment rate [ Time Frame: 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 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
  • 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 ]
    diagnosed and graded according to standard NIH consensus criteria
  • 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 ]
    Diagnosed and graded according to standard NIH consensus criteria
  • 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.
  • Incidence and duration of infectious episodes and infectious disease mortality [ Time Frame: from randomization to the date of resolution, assessed up to 12 months ]
    diagnosis, monitoring and treatment of infectious relevant events
  • 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 ]
    Toxicity profile of HSV-Tk infusions
  • Quality of life (QoL) and Medical Care Utilization (MCU) in both arms [ Time Frame: 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.
  • 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)
Original Secondary Outcome Measures  ICMJE
 (submitted: June 4, 2009)
  • Engraftment rate defined as the persistent blood cells count above a predefined level (ANC ≥ 1x10^9/L per 3 consecutive days with evidence of donor haematopoiesis; platelets ≥ 50x10^9/L, unsupported by transfusions, for 7 days). [ Time Frame: Weekly up to IR after HCT or up to 6 months after HCT if no IR ]
  • Cumulative incidence of grade 2, 3, or 4 acute GVHD (aGvHD), diagnosed and graded according to standard criteria, will be computed in patients who will survive. [ Time Frame: During the first 100 days after HCT ]
  • Immune reconstitution (IR) will be defined as the time to reach a level of circulating CD3+ ≥ 100/μl for two consecutive observations. [ Time Frame: Weekly after HCT ]
  • Cumulative incidence of relapse (CIR) defined on the basis of morphologic evidence of leukaemia in bone marrow or other sites (considering death without evidence of relapse as competing event). [ Time Frame: From the data of HCT until the date to the first occurrence of relapse ]
  • Disease-Free Survival (DFS) will be measured for all patients from the date of transplantation until the date of relapse or death from any cause, whichever occurs first. [ Time Frame: From the date of HCT until the date of relapse or death ]
  • Cumulative incidence of extensive chronic GvHD (cGvHD) diagnosed and graded according to standard NIH consensus criteria, will be computed in patients who will survive. [ Time Frame: For at least 100 days after transplantation ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Leukemia (Category)
Intervention  ICMJE
  • Genetic: HSV-Tk
    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.
  • 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
Study Arms  ICMJE
  • Experimental: A
    HSV-TK engineering donor Lymphocytes
    Intervention: Genetic: HSV-Tk
  • Active Comparator: B
    T-cell depleted or T-cell replete strategies
    Intervention: Other: T-cell depleted or T-cell replete strategies
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 17, 2012)
170
Original Estimated Enrollment  ICMJE
 (submitted: June 4, 2009)
152
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Fabio Ciceri, MD 0
Listed Location Countries  ICMJE Belgium,   France,   Germany,   Greece,   Israel,   Italy,   Lithuania,   Portugal,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00914628
Other Study ID Numbers  ICMJE TK008
2009-012973-37 ( Registry Identifier: EUdraCT number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: No, only information requested by law will be released
Responsible Party MolMed S.p.A.
Study Sponsor  ICMJE MolMed S.p.A.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Antonio Lambiase, MD MolMed S.p.A.
PRS Account MolMed S.p.A.
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP