Primary: The main objective of the study is to evaluate the feasibility, safety and tolerability of allogeneic IL15-activated NK cell infusions in children transplanted for refractory or relapsed leukemia.Secondary: To document immune reconstitution…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To document the feasibility to generate sufficient numbers of IL-15 activated
NK cells from HSCT donors in real time, i.e. the Investigational Medicinal
Product (IMP), meeting the release criteria and the safety of infusion and
tolerability of the IMP post HSCT in children transplanted for refractory/
relapsed leukemia.
Secondary outcome
1. The anti-leukemic/cytolytic reactivity and cytokine producing potential,
e.g. IFN-gamma, of NK cells ex vivo prior to and after NK infusion
(intra-individual control).
2. The immune reconstitution after NK cell infusion. Apart from detailed
investigation of T- and B-lymphocyte recovery, the focus will be on analysis of
the surface expression patterns of activating and inhibitory receptors on NK
cell subpopulations and of NK cell function. The latter will also be analysed
for NK cells present in the HSCT graft (if not CD34+ enriched), donor
leukapheresis material and the IMP.
3. Incidence of disseminated (viral) infections in children undergoing NK cell
infusions post HSCT compared to controls.
4. Incidence and severity of acute and chronic GvHD in children undergoing NK
cell infusions post HSCT compared to controls.
5. Incidence of relapses of hematological malignancies in children undergoing
NK cell infusions post HSCT compared to controls.
6. Survival in children undergoing NK cell infusions post HSCT compared to
controls.
7. To study the relevance of mismatched KIR ligands (HLA types) and KIR
genotype/phenotype of donor/recipient pairs for observed biological effects.
Control group:
Patients transplanted for leukemia with stem cells from an MMFD or UD donor
between 2005 and 2012 at our unit will be the (historical) control group.
Background summary
For many children with high risk leukemia hematopoietic stem cell
transplantation (HSCT) is the only curative option. Due to ongoing improvements
in HLA typing technology, graft manipulation and supportive care, a matched
unrelated (UD) or mismatched family donor (MMFD) is nowadays a feasible and
widely accepted alternative in children lacking a HLA identical sibling donor.
However, leukemia relapse remains the main reason for transplant failure.
Following HSCT with UD and MMFD, T cell reconstitution is delayed up to 6-12
months post transplant, and thus a potential T cell mediated graft versus
leukemia (GvL) effect may be impaired. In contrast, there is rapid recovery of
natural killer (NK) cells, which have been reported to exert an anti-leukemic
effect. Still, the functional capacity of the early regenerating NK cells seems
limited. In vitro, the functional and cytolytic properties of NK cells can be
augmented by stimulation with cytokines, e.g. interleukin 15 (IL-15). We aim
to exploit this NK-cell mediated potential by adoptive transfer of ex vivo
IL15-activated donor NK cells with the final aim to enhance immune
reconstitution and reduce residual tumor burden in the early post transplant
setting.
Study objective
Primary: The main objective of the study is to evaluate the feasibility, safety
and tolerability of allogeneic IL15-activated NK cell infusions in children
transplanted for refractory or relapsed leukemia.
Secondary: To document immune reconstitution with a focus on the phenotype and
function of NK cells, rates of acute and chronic graft versus host disease
(GvHD), (viral) infections, relapse, overall and disease free survival compared
to historical controls.
Study design
This study is an open-label, non-randomized, phase I, feasibility study,
designed to treat children and adolescents, up to 18 years of age at the time
of transplantation for refractory/ relapsed pediatric hematological
malignancies. Following standard UD/MMFD HSCT, recruited patients will receive
at 4-16 weeks after HSCT one intravenous infusion of ex vivo IL-15 activated
donor NK cells.
Intervention
Patients will receive at 4-16 weeks after HSCT one intravenous infusion of ex
vivo IL-15 activated donor NK cells (dose: 5-10 x 10e6 IL-15-activated NK cells
per kg b.w. with a maximum total dose of 200 x 10e6 NK cells; children > 40 kg
receive one dose of 200 x 10e6 NK cells)
Study burden and risks
Burden:
Extra burden consists of infusion of NK cells.
The frequency of post HSCT site visits and concomitant blood sampling is
similar to the standard post HSCT procedures.
Risk:
Based on the reported clinical experience with autologous as well as allogeneic
NK cell infusions, treatment related toxicity appears very limited.
Particularly, the risk to develop GvHD is reported to be negligible.
The possible benefit involves enhanced immune reconstitution and associated
reduction in infectious complications.
Albinusdreef 2
Leiden 2333ZA
NL
Albinusdreef 2
Leiden 2333ZA
NL
Listed location countries
Age
Inclusion criteria
1. Aged between 1-18 years at the time of HSCT;
2. Undergoing HSCT for ALL or AML according to existing indications;
3. Receiving a stem cell graft from a mismatched family (MMFD) or volunteer unrelated (MUD) donor;
4. Life expectancy > 3 months.
5. Availability of a stem cell donor willing to donate white blood cells by means of a non-mobilized leukapheresis procedure.
Exclusion criteria
1. Progressive uncontrollable malignant disease after HSCT but before or at the day of NK cell infusion, defined as overt leukemia relapse, i.e., >= 25% blasts in the marrow and/or 5% circulating blasts in the peripheral blood or progressive extra-medullary disease;
2. Lack of evidence for donor myeloid engraftment at the day of infusion (< 0.5 x 106
neutrophils/L);
3. Active acute GvHD >= grade II (overall grade);
4. Patient is receiving (or received less than 2 weeks before IMP infusion) pharmacological GvHD prophylaxis or immunosuppressive drugs used for non-GvHD indications;
5. Any medical condition, which in the opinion of the treating physician, would interfere
with the adequate evaluation of the patient (e.g. end-stage irreversible multi-system
organ failure).
6. Cord blood stem cell donor.
7. Patient received a second cellular product after the stem cell graft;Donor exclusion criteria:
1. Donor cord blood;
2. Lack of consent for leukapheresis.
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 | EUCTR2011-001514-34-NL |
| CCMO | NL38836.000.12 |
| Other | NTR 16086 |