This study has been transitioned to CTIS with ID 2024-515357-16-00 check the CTIS register for the current data. The study is divided in two phases.The primary objective of phase I of the study is to evaluate the safety and toxicity of the infusion…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase 1: All patients will be evaluated extensively for toxicity using the
CTCAE toxicity criteria and graft versus host disease criteria. Based on this
dose-limiting toxicities will be scored. In case 1 patient will experience DLT
at a particular dose, the cohort will be increased to 6 patients. The maximum
tolerated IL-2 dose will be defined as the dose at which less than 2 patients
experience DLT within a cohort of 6 patients.
Phase 2: The primary endpoint of phase 2 of the study is to evaluate te effect
of NK cells following adoptive transfer in combination with sc IL-2 on disease
activity in patients with AML. Effect will be determined as a CR or PR
according to ELN criteria.
Secondary outcome
- Evaluation of the in vivo lifespan and expansion potential of the NK cells
following adoptive transfer, either with or without IL-2 administration. For
phase 2: A positive expansion rate of the infused NK cells requires an absolute
number of >= 100 donor-derived NK cells per µl blood at day +7 and/or +14.
- Exploration of the functional activity of the donor NK cells in PB and BM,
either with and without sc IL-2 administration using flow cytometry and CD107a
(LAMP-1)-based degranulation and IFNy-secretion assays
- Evaluation of IL-2 plasma levels and cytokine concentrations (IL-15, IL-7,
IFN-γ, TNFα, IL-6) pre- and post infusion of IL-2, which will be correlated
with absolute lymphocyte count and in vivo NK cells persistence and expansion
- For phase 2: amount of patients eligible for allogeneic stem cell
transplantation defined at day +28
Background summary
AML is the most common type of acute leukemia in adults and incidence increases
with age. Despite (agressive) treatment progrnosis remains poor, with at the
moment a 5 years survival of 35-40% in young and 5-15% in older AML patients.
New treatments are necessary. Allogeneic natural killer cell based
immunotherapy is a promising adjuvant treatment with less toxicity. However the
therapeutic effect can en should be improved. Our previous clinical trial
showed that administration of our NK-cel product to older AML patients is safe.
Additionally it showed that the NK cells do not have a high expansion potential
in the patient. In this study we want to combine allogeneic NK-cel therapy with
IL-2, an essential cytokine for NK cell survival and proliferation.
Study objective
This study has been transitioned to CTIS with ID 2024-515357-16-00 check the CTIS register for the current data.
The study is divided in two phases.
The primary objective of phase I of the study is to evaluate the safety and
toxicity of the infusion of ex vivo expanded RNK001 NK cells, both with and
without sc IL-2 following immunosuppressive conditioning therapy in patients
with AML. In this phase we will determine the maximum tolerable dose of IL-2.
The primary objective of phase II of the study is to evaluate the effect of
RNK001 NK cell adoptive immunotherapy in combination with sc IL-2 on disease
activity in patients with AML.
Study design
After written informed consent in- and exclusion criteria will be checked for.7
days before NK cell infusion the patiënt will be admitted to the hospital and
will receive chemotherapy for 3 days, as preparative regimen for the NK cell
infusion. NK-cell infusion will be followed by 6 times every other day a
subcutaneous injection of IL-2, starting on the day of NK-cell administration.
Patients will be admitted at least until the last IL-2 administration.
Phase 1: 3 cohorts of 3 patients receiving IL-2 in increasing dose (0, 3.0, 6.0
x 10^6 IU/dose). Dose limiting toxicities (DLT*s) will be monitored till 28
days (4 weeks) after NK cell infusion. Four weeks after NK cell infusion of the
last patient in a cohort, the next patient can be included in a new cohort.
Phase 2: phase 2 consists of 2 stages; If 3 or more of the 8 patients enrolled
in stage 1 of phase 2 show either CR or a PR according to ELN response criteria
by day +28 post NK cell infusion an additional 10 patients will be enrolled in
stage 2 to obtain a precise estimate of PR/CR. If < 3 of the 8 patients show CR
or PR the study will be stopped.
Intervention
As preparative regimen to NK-cell administration patients receive chemotherapy
for 3 days, starting one week prior to a single intravenous administration of
NK-cells. Except 3 patients, the NK cell infusion will be followed by a 6 times
every other day subcutaneous injection of IL-2. Follow up consists of
venapunctures and 3 times (possibly 4 times) a bone marrow aspiration, combined
with two times (possibly 3 times) a bone marrow biopsy.
Study burden and risks
Due to the chemotherapy patients are vulnerable for infections which might
require antibiotic treatment. In addition bloodtransfusions might be necessary.
NK-cell therapy has been shown to be a less toxic treatment in published
literature, including our own clinical trial. Patients experience less side
effects. Although is has not been seen before, a graft versus host reaction
could occur.
Administration of IL-2 subcutaneous can be accompanied by fever-like
complaints, changes in blood pressure and a rash at the injection side.
Geert Grooteplein Zuid 8
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 8
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
MDS with excess blasts, MDS/AML or AML patients (de novo and secondary)
according to ELN 2022 criteria, who have stable disease or non-rapidly
progressive disease with or without disease controlling medication, who are not
eligible for allogeneic SCT
- Age > 18 years
- WHO performance 0-2
- Life expectancy of > 4 months
- Written informed consent
- Hydrea is allowed as pre-treatment to control blast count until day -3
- Other disease controlling medication is allowed until day -7
Exclusion criteria
- Progressive disease in case of previous therapy
- Patients on immunosuppressive drugs or active GvHD
- Patients with active infections (viral, bacterial or fungal); acute
anti-infectious therapy must have been completed within 7 days prior to study
treatment
- Severe cardiovascular disease (CTCAE III-IV)
- Severe pulmonary dysfunction (CTCAE III-IV)
- Severe renal dysfunction (CTCAE III-IV)
- Severe hepatic dysfunction (CTCAE III-IV)
- Severe neurological or psychiatric dysfunction (CTCAE III-IV)
- Patients on concurrent chemotherapy or interferon-alpha treatment
- Pregnancy or breastfeeding
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
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-515357-16-00 |
| EudraCT | EUCTR2019-001929-27-NL |
| ClinicalTrials.gov | NCT04347616 |
| CCMO | NL67150.000.19 |