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

• ClinicalTrials.gov Identifier: NCT00914628
• Recruitment Status: Terminated
• First Posted: June 5, 2009
• Results First Posted: June 22, 2021
• Last Update Posted: June 22, 2021
• Sponsor: AGC Biologics S.p.A.
• Information provided by (Responsible Party): AGC Biologics S.p.A.

Tracking Information

• First Submitted Date: June 3, 2009
• First Posted Date: June 5, 2009
• Results First Submitted Date: February 12, 2021
• Results First Posted Date: June 22, 2021
• Last Update Posted Date: June 22, 2021
• Actual Study Start Date: April 12, 2010
• Actual Primary Completion Date: November 30, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 1, 2021)

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).

Original Primary Outcome Measures (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 ]

Current Secondary Outcome Measures (submitted: June 1, 2021)

• 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).Patients alive or without any follow up will be censored.
• 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 ]
  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.
• Engraftment Rate [ Time Frame: At 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. 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
• 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. 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
• 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). 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.

Original Secondary Outcome Measures (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: Efficacy Study on the Strategy of HSV-Tk Engineering Donor Lymphocytes to Treat Patients With High Risk Acute Leukemia
• 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
• 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Acute Leukemia (Category)

Intervention

• 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

• 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

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: June 1, 2021): 92
• Original Estimated Enrollment (submitted: June 4, 2009): 152
• Actual Study Completion Date: November 30, 2019
• Actual Primary Completion Date: November 30, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, France, Germany, Greece, Israel, Italy, Lithuania, Portugal, Spain, United States

Administrative Information

• NCT Number: NCT00914628
• Other Study ID Numbers: TK008; 2009-012973-37 ( Registry Identifier: EUdraCT number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: No, only information requested by law will be released

• Current Responsible Party: AGC Biologics S.p.A.
• Original Responsible Party: Molmed
• Current Study Sponsor: AGC Biologics S.p.A.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Antonio Lambiase, MD; AGC Biologics S.p.A.

• PRS Account: AGC Biologics S.p.A.
• Verification Date: June 2021