E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Children with high-risk and recurrent acute leukemia are eligible for allogeneic hematopoietic stem cell transplantation (HSCT). However, leukemia relapse and viral infections after HSCT remain main reasons for treatment failure. |
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E.1.1.1 | Medical condition in easily understood language |
Stem cell transplantation is a accepted treatment for children with high-risk acute leukemia. However, leukemia relapse and viral infections remain main reasons for treatment failure. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10023685 |
E.1.2 | Term | LAK cell therapy |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The aim of the present study is to administer purified and ex vivo IL-15 activated donor-derived NK cells early after alloHSCT in children transplanted for high-risk acute leukemia.
Primary objective:
To document the feasibility to generate sufficient numbers of IL-15 activated NK cells from HSCT donors in the actual donorpatient combination of the alloHSCT setting, i.e. the Investigational Medicinal Product (IMP), meeting the release criteria, the safety of infusion and tolerability of the IMP post SCT in children transplanted because of refractory/ relapsed acute leukemia. |
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E.2.2 | Secondary objectives of the trial |
To study and document in children receiving the IMP:
1. Anti-leukemic/cytolytic reactivity and cytokine producing potential, e.g. IFN-γ, of NK cells ex vivo prior to and after NK infusion (intra-individual control).
2. Reconstitution of lymphocyte populations with focus on analysis of activating and inhibitory receptors on NK cell subpopulations and investigation of NK cell function ex vivo. The latter will also be analyzed for NK cells present in donor leukapheresis material and the IMP.
3. Disseminated (viral) infections after HSCT.
4. Incidence and severity of acute and chronic GvHD
5. Relapse of leukemia after HSCT
6. Survival adter HSCT
7. The relevance of mismatched KIR ligands (HLA types) and KIR
genotype/phenotype of donor/recipient pairs for observed biological effects.
Historical acute leukemia patients transplanted with unrelated or mismatched family donors in our unit between 2005-2012 will be used as controls.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patient inclusion criteria:
1. Aged between 1-18 years at the time of HSCT;
2. Undergoing HSCT for ALL or AML according to existing indications as defined in
protocols/guidelines Dutch Childhood Oncolgy Group;
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.
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E.4 | Principal exclusion criteria |
Patient exclusion criteria:
1. Progressive leukemia 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;
4. Administration of steroids >1 mg/kg/day for any indication at the day of infusion;
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 as stem cells donor |
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E.5 End points |
E.5.1 | Primary end point(s) |
In addition to the standard evaluation following HSCT of children treated for leukemia, the following investigations will be performed in the context of the investigational NK cell infusion:
- Feasibility of obtaining donor leukapheresis material, isolating required numbers of viable NK cells, generating IL-15 activated NK cells with adequate activation status and purity.
- Tolerability and safety of IL-15 activated NK cell infusion. Registration of
post infusion status of the patient, fever, nausea, chills, rash, erythema, and all
serious adverse events, potentially linked to infusion.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Patients will be included during a two year period.
An interim report on the primary objective will be provided 6-8 weeks after treatment of the first five patients or 12 months after start of the study. The report will be made by the principle and coordinating investigators. |
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E.5.2 | Secondary end point(s) |
1. To document anti-leukemic/cytolytic reactivity and cytokine producing potential,
e.g. IFN-γ, of NK cells ex vivo prior to and after NK infusion (intra-individual
control).
2. To document 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. The latter will also be investigated on NK cells present in the
donor HSCT graft (if not CD34+ enriched), donor leukapheresis material and the
IMP.
Historical acute leukemia patients transplanted with unrelated or mismatched family donors in our unit between 2005-2011 will be used as controls for the functional and phenotypical studies indicated above.
3. To document disseminated (viral) infections in children undergoing NK cell
infusions post HSCT compared to aforementioned controls
4. To document occurrence and severity of acute and chronic GvHD in NK cell
recipients compared to aforementioned controls
5. To document relapse of hematological malignancies in children undergoing NK
cell infusions post HSCT compared to controls.
6. To document survival in children undergoing NK cell infusions post HSCT
compared to controls.
7. To study the relevance of mismatching KIR ligands (HLA types) and KIR
genotype/phenotype of donor/recipient pairs for observed biological effects.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Patients will be included during a two year period.
An interim report on the primary objective will be provided 6-8 weeks after treatment of the first five patients or 12 months after start of the study. The report will be made by the principle and coordinating investigators. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
First feasibility study with IL-15 activated allogeneic NK cells infusion in children |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
historical leukemia patients transplanted with unrelated or mismatched family donor |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The trial will end 1 year after inclusion of the final patient; i.e. all patients will be followed at least one year. All patients will be followed thereafter for regular follow-up in the out-patient SCT clinic of the department of Pediatrics. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |