Primary objective:-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 HCTSecondary objectives:- To compare…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary efficacy parameter:
- Disease-Free Survival (DSF) will be measured for all patients from the date
of randomization until the date of relapse or death from any cause, whichever
occurs first
Secondary outcome
Secondary efficacy parameters:
- Overall Survival (OS) will be measured for all patients from the date of
randomization until death from any cause
- Non-relapse mortality (NRM) will be defined for all patients as any death
without previous occurence of a documented relapse
- Immune Reconstitution (IR) will be defined as the time to reach a level of
circulating CD3+ >= 100/µl
- Engraftment rate will be defined as the persistent blood cells count above a
predefined level (ANC >= 1 x 109/L per 3 consecutive days with evidence of donor
haematopoiesis; platelets >= 50 x 109/L, unsupported by transfusions, for 7 days)
- Cummulative incidence of grade 2, 3 or 4 acute GvHD, diagnosed and graded
according to standard criteria, will be computed from the transplantation
- Cummulative incidence extensive chronic GvHD, diagnosed and graded according
to standard criteria, will be computed from the transplantation
- Cummulative incidence of relapse will be defined on the basis of morphologic
evidence of leukaemia in bone marrow or other sites.
Safety and tolerability parameters:
- Adverse Events (AE) and laboratory abnormalities graded according tot the
CTCAE v 4.02
- laboratory assessments (urinalisis, hematology, blood chemistry,
immunophenotype, PCR-TK, RCR analysis), bone marrow asprirate
- physical examination and vital signs
- Serious Adverse Events (SAE)
- Suspected Unexpected Serious Adverse Reactions (SUSARs)
- Long term follow up
Quality of life: FACT-BMT to summarize and evaluate patient convenience and
satisfaction
Pharmacoeconomics on medical care utilization. To summarize and evaluate
treatment group differences.
Background summary
Many patients with high risk acute leukemia potentially curable by
tranplantation of haematopoietic cells are generally not considered for such
treatment because an HLA identical family donor is lacking. For these patients
the only curative option is represented by a transplant obtained from a
haploidentical donor (haploidentical HCT).
T-cell depletion of the allograft is usually performed to reduce the risk of
GvHD. Although this is a successfull strategy for GvHD prophylaxis, it often
results in an increased risk of delayed immune reconstitution, thus leading to
relapse and post transplant infections.
Recent clinical trials confirmed that immune recovery following haploidentical
HCT could be improved by the infusion of T lymphocytes engineered to express
the thymidine kinase of the Herpes Simplex Virus (HSV-Tk), a suicide gene
activated upon ganciclovir administration.
Study objective
Primary objective:
-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
Secondary objectives:
- To compare overall survival (OS) in the two treatment arms
- To compare the cumulative incidence of non-relapse mortality (NRM)
- To compare the time to T-cell immune reconstitution
- To compare the engraftment rate
- To compare the cumulative incidence of grade II-IV acute GvHD
- To compare the cumulative incidence of extensive chronic GvHD
- To compare the cumulative incidence of relapse (CIR)
- To compare incidence and duration of infectuous episodes and infectious
disease mortality
- To evaluate the acute and long-term toxicity related to the HSV-Tk infusion
- To assess quality of life (QoL) and Medical Care Utilization (MCU) in both
arms
Study design
This is an open label, randomized (3:1) phase III study, with a comparison of
an add back strategy of HSV-TK donor lymphocytes versus standard stategy in
high risk acute leukemia patients who underwent haploidentical HCT.
Intervention
ARM A (experimental group):
Haploidentical HCT with the infusion of CD34+ cells plus a fixed dose of T
cells (1 x 10/4/Kg), followed by:
- Infusion of approximately 1 x 10/7 HSV-Tk genetically modified CD3+ cells/Kg
between day +21 and day 49 after haploidentical HCT in the absence of
spontaneous immune reconstitution (IR has to be documented by two consecutive
findings of circulating CD3+ cells >= 100/µl) and/or development of GvHD.
In absence of immune reconstitution and GvHD further infusion will be
administered wih the following dosages and timelines:
- 30 days after 1st infusion: in the absence of GvHD and immune reconstitution
genetically modified lymfocytes will be infused at a dose of 1x 10* cells/ Kg
- 30 days after 2nd infusion: in the absence of GvHD and immune reconstitution
genetically modified lymfocytes will be infused at a dose of 1x 10* cells/ Kg
- 30 days after 3rd infusion: in the absence of GvHD and immune reconstitution
genetically modified lymfocytes will be infused at a dose of 1x 10* cells/ Kg
ARM B (control group):
Haploidentical HCT with the infusion of CD34+ cells plus a fixed dose of T
cells (1 x 10/4/Kg).
Study burden and risks
Participation in the trial may involve the risk of developing acute and/or
chronic GvHD. In a recent clinical trial carried out wit the HSV-Tk-donor
lymphocytes, GvHD presented in approximately 30% of the patients treated and
was resolved in all cases after treatment with ganciclovir. Furthermore,
approximately 13% of the patients developed fever, which quickly cured after
appropriate drug treatment.
The use of gene therapy products exposes the patient to a risk of cell
abnormality secondary to the gene manipulation itself. The safety of lymfocytes
modified with HSV-Tk gene has been documented both in the recent study (TK007)
and in more than 100 patients treated throughout the world since the 1990s.
Where necessary, the administration of ganciclovir or vanganciclovir is planned
to eliminate the transduced lymphocytes. Ganciclovir/valganciclovir is a drug
that has been used for many years to combat certain viral infections.
Ganciclovir/valganciclovir can be teratogenic. Therefore female patients of
childbearing age should have a negative pregnancy test at screening and
patients should be taking an effective contraceptive up to three months after
the last infusion. Moreover, ganciclovir/valganciclovir can be frequently
associated with serious granulocytopenia and thrombocytopenia and is less
frequently associated with severe allergic dermatitis, allergic reactions,
anaemia, fever, alteration of liver enzymes, loss of appetite, mental and mood
alterations, nausea, phlebitis, erythema, gastralgia and vomiting.
Via Olgettina 58
20132 Milaan
IT
Via Olgettina 58
20132 Milaan
IT
Listed location countries
Age
Inclusion criteria
• Age >= 18 with HCT comorbidity index < 3 (Appendix I);• 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 < 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 and donors, or independent witnesses 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 disease;• Contraindication to haploidentical HCT as defined by the Investigator;• Patients with active CNS disease;• Pregnant or lactation. Patients both males and females with reproductive potential (i.e. menopausal for less than 1 year and not surgically sterilized) must practice effective;contraceptive measures throughout the study. Women of childbearing potential must provide a negative pregnancy test (serum or urine) within 14 days prior to registration.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-012973-37-NL |
| CCMO | NL36045.000.11 |