Primary ObjectivesThe primary objectives are:• The primary safety objective is to evaluate the safety and tolerability of the infusion of up to three doses of oNKord®• The primary efficacy objective is to assess the cumulative incidence of MRD…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints:
Safety and Tolerability:
To evaluate the safety and tolerability of oNKord® using the cumulative
incidence of the adverse events of special interest (AESI), including:
• Grade 3-4 infusion-related toxicity of oNKord®, as rated by the National
Cancer Institute (NCI)*s Common Terminology Criteria for Adverse Events (CTCAE)
version 5.0
• Acute graft versus host disease (GVHD) grade III and IV / Extensive chronic
GVHD
• Cytokine Release Syndrome (CRS) >= Grade 2, as rated by the American Society
for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for Cytokine
Release Syndrome
• Immune effector cell-associated neurotoxicity syndrome (ICANS) >= Grade 2, as
rated by the ASTCT Consensus Grading for Neurologic Toxicity Associated with
Immune Effector Cells
Efficacy:
To evaluate the efficacy of oNKord® using:
• The cumulative incidence of MRD response as assessed via centralized
assessment in bone marrow at 1, 2, 3, 6, 9 and 12 months post-RP2D oNKord®
infusion. Subjects with responses are defined as MRD negative (as per the
European LeukemiaNet [ELN] MRD Working Party 2021 recommendations) subjects
still in morphologic CR at any time during the follow-up period of the trial
after receiving oNKord® at RP2D.
Secondary outcome
Secondary endpoints
Safety and Tolerability:
To evaluate the safety and tolerability of the trial treatment using the
cumulative incidence of AESIs, including:
• Grade 3-4 infusion-related toxicity, as rated by CTCAE v5.0
• Acute GVHD grade III and IV / Extensive chronic GVHD
• CRS >= Grade 2, as rated by the ASTCT Consensus Grading for Cytokine Release
Syndrome
• ICANS >= Grade 2, as rated by the ASTCT Consensus Grading for Neurologic
Toxicity Associated with Immune Effector Cells
• Haemorrhagic cystitis
• Death related to the trial treatment
• Incidence and severity of viral, fungal, and bacterial infections with onset
during the first two months following trial treatment, including viral
reactivations, and Infection Related Mortality (IRM) defined as death due to
infectious disease
Efficacy:
To evaluate the efficacy of the trial treatment at the RP2D by assessing:
• EFS, defined as the time from enrolment until disease relapse (morphologic
and/or clinical relapse) after morphologic CR or death due to any cause,
whichever occurs first
• CIR, defined as the cumulative incidence of relapse throughout the course of
the trial
• Duration of MRD response, defined as duration between MRD negativity to
returning to MRD positivity, as determined by centralized assessment
• OS rate (defined as the time from enrolment until death from any cause) at 12
months
• Changes in QoL using the European Organisation for Research and Treatment of
Cancer (EORTC) QLQ-C30 and SF-36 questionnaires, assessed at 1, 3 and 12 months
post-treatment compared to baseline
Exploratory Endpoints
• Analysis of biomarkers predictive of response may include:
o Analysis of responders and non-responders, as assessed by the efficacy
primary endpoint, in relation to secondary efficacy endpoints
o Targeted DNA sequencing of commonly mutated genes in AML, performed by next
generation sequencing (NGS) on bone marrow samples, compared to diagnosis
tumour genetic profiling (if available), and associated to response/
non-response
o Assessment of oNKord® immunogenicity
o Number of oNKord® infusions and corresponding enumeration of oNKord®-derived
NK-cells in combination with relevant cytokine levels, including chimerism as
determined by genomic assays and/or flow cytometry
o MRD negativity, baseline physical and functional conditions associated to
occurrence of relapse and survival
• Determination of the biological parameters related to oNKord® derived
NK-cells may include analysis of the in-vivo lifespan (immunophenotyping),
cytolytic activity (persistence of oNKord® derived NK-cell functionality after
infusions), and extent of oNKord® derived NK-cell expansion and persistence
(chimerism) at multiple time points after oNKord® infusion(s)
• Cumulative incidence of molecular response on MRD as assessed by
error-corrected NGS at various timepoints post oNKord® infusion(s) in bone
marrow and peripheral blood
Background summary
Transfusion of allogeneic natural killer (NK)-cells is a promising therapeutic
approach for patients with acute myeloid leukaemia (AML). NK cells are major
effector cells of the innate immune system and play a key role in controlling
viral infections as well as tumour immunosurveillance. In the setting of
haplo-identical allogeneic haematopoietic stem cell transplantation (HSCT), NK
cell alloreactivity has proven to decrease relapse rates and improve survival
among AML patients. Therefore, there is an emerging interest in exploiting
adoptive NK cell transfer in the treatment of AML.
For the current trial, allogeneic NK cells are generated from umbilical cord
blood (UCB) CD34+ hematopoietic stem and progenitor cells (HSPCs) using an ex
vivo expansion and differentiation method that was developed by Glycostem
Therapeutics B.V. via oNKord®.
The approach is supported by the capability of the oNKord® NK cells to migrate
to the bone marrow (BM) and to mediate a cytotoxic effect on leukaemia cells
following adoptive transfer. In addition, efficient oNKord® cell survival in
vivo in the presence of low dose human interleukin-15 (IL-15) was observed.
Transient elevation of IL-15 plasma levels was reported in AML patients
following lymphodepletion by cyclophosphamide and fludarabine (Cy/Flu)
conditioning, which could favour the in vivo expansion and maturation of
oNKord® NK cells, as well as clinical responses to AML following oNKord®
adoptive transfer.
Measurable residual disease (MRD) is a predictive factor of relapse and
mortality in patients with AML who are in morphologic complete remission (CR).
Since BM is the primary site of AML development and encloses niches essential
for leukaemic stem cells causing relapse, BM targeting is essential for
elimination of MRD before morphologic relapse in patients having reached
morphologic CR and thus induction of optimal and persistent clinical responses
against AML during this window of opportunity before relapse. Reaching a
threshold dose of functionally active NK cells with or without repeat dosing
might be a prerequisite for NK cell therapy to be effective in this population
of patients when HSCT is not a suitable or preferred option.
In this phase I-IIa trial, oNKord® will be evaluated for its safety,
tolerability and clinical benefit in AML patients in morphologic CR (including
CR with incomplete blood recovery [CRi]) with MRD and who are currently not
proceeding to allo-HSCT.. The safety and tolerability of oNKord® intravenous
infusion (IV) of a single dose of up to 30 x 106 NK cells/kg bodyweight has
been established in a phase I trial (PMLA25 study).
Stage A of the present trial (dose-escalation stage) is designed to assess the
safety and tolerability of up to three oNKord® infusions, either on a single
day or four days apart, at a dose of 325 - 1,000 x 106 viable NK-cells per
intravenous infusion (IV) infusion, and to determine the oNKord® recommended
phase II dose (RP2D) to be used in Stage B.
Stage B of the trial (expansion stage) will evaluate the safety and
tolerability of oNKord® at the RP2D, as identified in Stage A, and efficacy on
MRD (cumulative incidence of response and duration of response), Event Free
Survival (EFS), Overall Survival (OS), and Cumulative Incidence of Relapse
(CIR).
The starting material (umbilical cord blood) for the up to three doses of
oNKord® to be infused in each individual subject is collected from the same
donor. Dosing of oNKord® by intravenous infusion is not bodyweight related.
The overall objective of the trial is to evaluate whether oNKord® therapy is
safe and if it can reduce the relapse risk and therefore mortality in AML
subjects who are in morphologic CR with MRD and who are currently not
proceeding to allo-HSCT
Study objective
Primary Objectives
The primary objectives are:
• The primary safety objective is to evaluate the safety and tolerability of
the infusion of up to three doses of oNKord®
• The primary efficacy objective is to assess the cumulative incidence of MRD
response following the infusion of oNKord® at the recommended phase 2 dose
(RP2D)
Secondary Objectives
The secondary objectives are:
• In Stage A, to determine oNKord® RP2D
• To further evaluate the safety and tolerability of the trial treatment
• To further assess the efficacy of the trial treatment on event-free survival
(EFS), duration of MRD response, cumulative incidence of relapse (CIR) and
overall survival (OS)
• To evaluate the effect of the trial treatment on quality of life (QoL)
Exploratory Objectives
The exploratory objectives are:
• To identify biomarkers predictive of response for MRD, EFS and OS
• To evaluate biological parameters related to oNKord® mechanism of action
following up to three oNKord® infusions
• To assess the cumulative incidence of molecular response on MRD following up
to three oNKord® infusions
Study design
This trial will be conducted as a multicentre, open label, phase I-IIa trial to
evaluate the safety and efficacy of oNKord® alone (all cohorts) and as part of
the overall trial treatment, consisting of the non-myeloablative conditioning
regimen (Cy/Flu) followed by up to three oNKord® infusions (for cohorts A1, A2,
A3, A5 and cohort B if applicable), in AML subjects who are in morphologic CR
(including CRi) with MRD and have no strong indication for HSCT.
The trial uses a 2-stage, single arm design in 40 subjects (Stage A with 16
subjects and Stage B with 24 subjects). The overall design is shown in Figure 1
in the Synopsis section.
The trial will start with Stage A, a dose-escalation stage, in which 3 cohorts
(A1-A3) of 3 subjects each will receive escalating repeat doses of oNKord®,
while a fourth and fifth cohorts will receive the dose of the third cohort (A3)
but will undergo either an adjusted conditioning strategy (A4) or a different
oNKord® dosing schedule (A5).
Dose cohort A4 will enroll three subjects undergoing treatment with
azacitidine-venetoclax as per standard of care who will receive the same number
of oNKord® doses as cohort A3, but without the use of Cy/Flu (the
immunosuppressive effect of the azacitidine-venetoclax treatment alleviates the
need for the Cy/Flu lymphodepleting conditioning regimen to prevent/minimize
immune rejection of the allogeneic NK cells).
Dose cohort A5 will enroll three subjects who will receive the Cy/Flu
conditioning regimen followed by the same cumulative total dose of oNKord® (3 x
325 - 1,000 x 106 viable NK cells) as cohorts A3 and A4, but as a single day
infusion on Day 0 (same day infusion of three bags of oNKord®).
Due to the acute nature of the disease, the time it takes for screening and the
attrition due to the inclusion criteria (specifically MRD positivity), an
over-enrollment of up to one more patient per dose escalation cohort will be
allowed (up to four patients total per dose cohort).
Upon completion of Stage A, the trial treatment at the RP2D to take forward to
Stage B of the trial (expansion stage) will be selected and studied in 24
additional subjects.
Eligibility criteria for participation in the trial and follow-up duration are
the same for subjects in both Stage A and Stage B.
Stage A (dose escalation stage) will investigate the safety and tolerability of
one, two, and three doses of oNKord® at 325 - 1,000 x 106 viable NK
cells/infusion in five cohorts of a minimum of three subjects each:
• Subjects within each of the five cohorts will be enrolled sequentially to
ensure a time window of at least 72 hours in between the infusion of the first
dose of oNKord® to the previous subject and the infusion of the first dose of
oNKord® to the following subject within a cohort.
• Up to four subjects in cohort A1 will receive Cy/Flu and one oNKord®
infusion on Day 0 .
• Under the condition that no dose-limiting toxicity (DLT) is observed during
the DLT observation ending at the Month 1 Follow-up Visit after oNKord®
infusion of the last subject enrolled in cohort A1, and the positive
recommendation by the IDMC, up to four subjects will be included in cohort A2
to receive Cy/Flu and two oNKord® reapeat infusions, 4 days apart (i.e., Day 0
and Day +4).
• Under the condition that no DLT is observed during the DLT observation period
ending at the Month 1 Follow-up Visit after oNKord® infusions of the last
subject enrolled in cohort A2, and with the positive recommendation by the
IDMC, up to four subjects will be included in cohort A3 to receive Cy/Flu and
three oNKord® repeat infusions, 4 days apart (i.e., Day 0, Day +4 and Day +8).
• Under the condition that no DLT is observed during the DLT observation period
ending at the Month 1 Follow-up Visit after oNKord® infusions of the first
subject enrolled in cohort A3:
o Up to four subjects will be included in cohort A4 to receive three
oNKord® repeat infusions, 4 days apart (i.e., Day 0, Day +4 and Day +8) without
the use of Cy/Flu. The removal of the Cy/Flu conditioning regimen in this
cohort is expected to further increase the safety of the experimental
treatment, and therefore cohort A4 will enroll patients in parallel with cohort
A3, after the first subject enrolled in cohort A3 has completed the DLT
observation period with no DLT. Dose cohort A4 might also enroll three
additional patients upon recommendation of the independent data monitoring
committee (IDMC) and decision by the Sponsor.
o Up to four subjects will be included in cohort A5 to receive Cy/Flu and
three back-to-back oNKord® infusions on Day 0 (same day infusion of three bags
of oNKord®). Dose cohort A5 will enroll patients in parallel with cohort A4.
If one subject develops a DLT in any of the five dose cohorts, an additional
three subjects will be enrolled into that same cohort. Development of DLTs in
more than one of all subjects treated at a specific dose level indicates that
the maximum tolerated dose (MTD) has been exceeded, and the previous dose level
is considered the RP2D. In the unlikely case that two or more DLTs occur at the
lowest dosing cohort (cohort A1 with one oNKord® infusion), a decision to stop
the trial will be taken by the Sponsor after review and recommendation by the
IDMC, the Sponsor, and the Medical Monitor.
Stage B (expansion stage) will investigate the safety, tolerability and
efficacy of oNKord® infusion(s) at the RP2D in 24 subjects: after the DLT
observation period ending at the Month 1 follow-up visit after oNKord®
infusions of the last subject enrolled in cohort A4 and/or cohort A5, and
dependent on the determination of the RP2D and positive recommendation of the
IDMC to proceed to Stage B, 24 subjects will be included in cohort B to receive
the trial treatment at the RP2D.
An interim analysis of the safety and tolerability, as well as preliminary
oNKord® efficacy signals of the trial treatment, will be conducted when 14
subjects reach three months follow-up (around 50% of subjects at the RP2D). The
IDMC will review the safety data from the interim analysis and issue an opinion
on the safety and tolerability of the trial treatment at the RP2D.
Intervention
For cohorts A1, A2, A3 and A5: Five days before the first infusion of oNKord®,
eligible subjects will receive cyclophosphamide (300 mg/m2/day IV) and
fludarabine (30 mg/m2/day IV) on Days -5, -4, and -3. The Cy/Flu regimen will
be administered in an inpatient (hospitalized) setting, as per institutional
practice.
oNKord® will be administered intravenously at a dose of 325 - 1,000 x 106
viable NK-cells per infusion:
Cohort A1: one oNKord® infusion at Day 0.
Cohort A2: two oNKord® infusions, 4 days apart (Day 0 and Day +4).
Cohort A3: three oNKord® infusions, 4 days apart (Day 0, Day +4 and Day +8).
Cohort A4: three oNKord® infusions, 4 days apart (Day 0, Day +4 and Day +8).
Cohort A5: three back-to-back oNKord® infusions on Day 0
Cohort B: RPD2, as determined in Stage A.
Study burden and risks
Known and potential risks are related both to the reduced intensity
conditioning as a prerequisite for oNKord® infusion and to oNKord® as the IMP
of the trial. Overall, the most common toxicities that might be expected from
Cy/Flu conditioning and oNKord® infusion includes fever, chills, myalgias,
malaise, lymphopenia, and neutropenia.
The most common risks for the patient are associated with the Cy/Flu
conditioning regimen. Cy/Flu conditioning can induce acute toxicity related to
the agents themselves (cyclophosphamide and fludarabine), as well as
pancytopenia requiring transfusions and increasing the probability of (severe)
infections.
See protocol for tables for commonly according adverse reactions associated
with cyclophosphamide and fludarabine.
Cohort A4 leverages the immunosuppression induced by azacitidine-venetoclax
standard of care treatment, as conditioning regimen. Azacitidine-venetoclax
standard of care treatment is not administered as part of the trial
(azacitidine-venetoclax are not non-investigational medicinal products [NIMPs]
in the WiNK trial). See Investigator's Brochure (IB) for common adverse
reactions associated with azacitidine and venetoclax.
oNKord® infusion
Potential adverse reactions after the infusion could include allergic or
hypersensitivity reactions to some of the constituents of oNKord® (e.g. the
excipient dimethyl sulfoxide [DMSO] or impurity): immediate fever or chills,
skin rash, bronchospasm, or anaphylactic shock, and delayed serum-sickness-like
reactions.
Because oNKord® contains mismatched donor NK lymphocytes, a causal relationship
between acute or chronic GVHD and oNKord® administration cannot be ruled out.
oNKord® infusion will also be closely monitored for two unique and
immunotherapy-specific toxicities: cytokine release syndrome (CRS) and
neurotoxicity, called immune effector cell-associated neurotoxicity syndrome
(ICANS).
CRS is a systemic inflammatory response that can be triggered by a variety of
factors including immunotherapy drugs like chimeric antigen receptor (CAR)-T
cell (Shimabukuro-Vornhagen et al. 2018). The early CRS manifestations are
comparable to flu-like symptoms, including high fever, malaise,
arthralgia/myalgia, nausea and headaches. Within hours, symptoms can progress
to hypotension, vascular leakage, disseminated intravascular coagulation (DIC),
and respiratory failure ultimately leading to multi-organ system failure
(Garcia Borrega et al. 2019).
ICANS is the second major side effect developing in a substantial proportion of
patients treated with CD19-targeted CAR-T cells (Santomasso et al. 2019). The
symptoms and the presentation of ICANS are heterogeneous and can progress from
headaches, fatigue, and mild aphasia to more severe and potentially
life-threatening symptoms including seizures, raised intracranial pressure with
cerebral oedema, and coma (Garcia Borrega et al. 2019).
However, the probability of occurrence of CRS and ICANS following oNKord®
infusion is reduced compared to CAR-T cell therapies. Indeed, allogeneic NK
cells have limited in vivo persistence after adoptive transfer as they do not
clonally expand, and are rapidly (within days to weeks) rejected by the immune
system (Rezvani et al. 2017; Dolstra et al. 2017).
Moreover, oNKord® manufacturing process includes a washing step allowing for
elimination of residual cytokines in the final product. Potential trace amounts
detected are more than 5-logs below what have been used in direct IL-2, IL-7
and IL-15 administration to patients with cancer or viral infections (Miller et
al. 2005; Curti et al. 2011).
oNKord® immunogenicity
The development of an immune response against oNKord® allogeneic NK cells may
trigger the apparition of anti-HLA antibodies after the oNKord® infusion(s).
The impact of these antibodies on efficacy or safety of oNKord® is still to be
evaluated.
Epstein-Barr Virus (EBV) infection
The high prevalence of EBV-positive cord blood donors implies a poor
feasibility of EBV-negative product manufacturing. In order to mitigate the
risk of infection for EBV-negative subjects, these subjects are excluded from
the WiNK trial (see Section 1.5.3).
Further information on the risks associated with oNKord® can be found in
Chapter 6.9. of the IB.
The tests used during this study may also cause complications or discomforts
for patients
ECG
The ECG procedure may cause some mild discomfort during the placement and
removal of the leads to and from the skin. Patients may also experience some
local irritation, redness, or burning in the areas where the leads are attached.
ECHO/MUGA Scan
An ECHO is generally well tolerated by patients and safe. If patients require a
multigated acquisition (MUGA) scan, they will receive a radioactive substance
through an injection in the vein. This injection may cause pain. The dose of
radioactivity is very low and it is considered safe. Your body will get rid of
the substance within about 24 hours.
CT scan/Chest X-ray
Patients will be exposed to radiation when undergoing a CT scan or chest X-ray.
The extra radiation falls within the limits set for this type of extra
radiation exposure.
For some CT scans, it is necessary that patients are injected with a contrast
agent. There is a small risk of developing an allergic reaction to the agent.
This reaction can be mild (itching, rash, nausea) or severe (difficulty
breathing or state of shock). Most allergic reactions can be controlled with
medication.
The contrast agent can also cause dehydration or damage the kidneys, which at
worst results in kidney failure. If patients are dehydrated or have poor kidney
function, the study doctor can decide to take a blood sample to check whether
your kidneys are functioning well enough, prior to performing a CT scan.
Bone marrow biopsy/Bone marrow aspiration
Patients will be given anaesthetic to numb the area and reduce the pain. This
procedure may nevertheless be very painful. However, the pain only lasts for
about 15 to 30 seconds. The bone area may be sore for a day or two. It is
possible, but not likely that patients could get an infection or have a large
amount of bleeding. In very rare cases, people might have an allergic reaction
to the numbing medicine. The allergic reaction could include rash/hive,
flushing of the face, itching, wheezing and tightness in the throat.
Blood collection
Taking blood samples can cause pain, bleeding, bruising, infection or
thrombosis (a blood clot) around the site where the needle was inserted. These
problems usually disappear naturally. You could faint while or after taking the
blood. There is a small risk of nerve damage with permanent pain. Taking blood
samples regularly can cause anaemia for which you could require a blood
transfusion. The staff who take the blood will do all they can to minimize
discomforts.
Kloosterstraat 9
Oss 5349 AB
NL
Kloosterstraat 9
Oss 5349 AB
NL
Listed location countries
Age
Inclusion criteria
To be eligible to participate in this trial, subjects must meet all of the
following eligibility criteria:
1. Male or female subjects >= 18 years old
2. Subjects with a diagnosis of AML and related precursor neoplasms according
to the World Health Organization (WHO) 2016 classification (excluding acute
promyelocytic leukaemia), including secondary AML after an antecedent
haematological disease (e.g. myelodysplastic syndrome) and therapy-related AML
3. a. For cohorts A1, A2, A3, A5 (and cohort B if applicable): Subjects who
have achieved morphologic CR, including CRi, and complete clinical remission,
with MRD documented at screening, after one or two courses of remission
induction chemotherapy and who have completed consolidation chemotherapy or who
achieved morphologic CR with documented MRD with hypomethylating agents (HMAs)
or other relevant appropriate therapies (e.g. HMAs in combination with
venetoclax)
b. For cohort A4 (and cohort B if applicable): Subjects with newly diagnosed
AML who have achieved morphologic CR, including CRi while undergoing
azacitidine-venetoclax standard of care treatment, and who are MRD-positive on
the 28th day (+/- 7 days) of at least treatment cycle 3 or later cycles (>=3)
4.Subjects who are currently (at the time of screening) not proceeding to
allo-HSCT, i.e.:
a. Subjects who have a contraindication for allo-HSCT (e.g. age > 75 years old,
diffusing capacity of the lung for carbon monoxide [DLCO] < 60%, left
ventricular ejection fraction [LVEF] < 40%, liver cirrhosis, creatinine
clearance < 30 mL/min, hematopoietic stem cell transplantation-specific
comorbidity index [HCT-CI] >= 5); or
b. Subjects who have no contraindication for allo-HSCT but do not proceed:
i. By personal choice; or
ii. Because there is no compatible donor expected to be available in a timely
manner; or
iii. Due to unfavorable patient-specific risk-benefit assessment discussed
between the treating physician and the patient and his/her close relatives.
Factors taken into consideration include the disease-related risk (risk of
relapse, toxicity or other treatment options if any), the patient-related risk
(age, comorbidities including the HCT-CI score) and the curative potential of
allo-HSCT versus toxicity (treatment intensity, graft versus leukemia effect,
non-relapse mortality risk) (Muller and Muller-Tidow 2015)
5. Life expectancy >= 6 months at screening
6. Adequate renal and hepatic functions within 14 days of trial screening,
unless clearly disease-related, as indicated by the following laboratory values:
a. Serum creatinine <= 3 times the upper limit of normal (ULN) and estimated
glomerular filtration rate (eGFR) >= 30 mL/min/1.73 m2
b. Serum total bilirubin < 2.0 mg/dL, unless due to Gilbert*s syndrome
c. Alanine transaminase (ALT) <= 2.5 x ULN
7. Karnofsky Status >= 50%
8.Seropositivity to Epstein-Barr virus (EBV)
9. Male subjects with partners who are women of childbearing potential must use
an effective contraceptive method during the trial and for a minimum of 6
months after trial treatment, or have undergone successful vasectomy at least 6
months prior to entry into the trial (confirmed by semen analysis)
10. Female subjects of childbearing potential must have a negative serum
pregnancy test at screening and agree to use an effective contraceptive method
during the trial and for a minimum of 6 months after trial treatment
11. Able to understand and willing to provide written informed consent to
participate in the trial
12. Affiliation to a national health insurance scheme (according to applicable
local requirements)
Exclusion criteria
Subjects who meet any of the following criteria at screening will be excluded
from trial entry:
1. Subjects having received prior allo- HSCT
2. Subjects with acute promyelocytic leukaemia
3. Diagnosis of any previous or concomitant malignancy is an exclusion
criterion, except when the subject completed treatment (chemotherapy and/or
surgery and/or radiotherapy) with curative intent for this malignancy at least
6 months prior to enrolment
4. Blast crisis of chronic myeloid leukaemia
5. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled
diabetes, uncontrolled infection, hypertension active or controlled infection),
including abnormal laboratory values that could compromise compliance with the
trial protocol or cause unacceptable safety risks.
6. Known allergy to any of the components of oNKord® (e.g., dimethyl sulfoxide
[DMSO]) or to any of the drugs to be administered in the preparative regimen to
oNKord® infusion
7. For cohorts A1, A2, A3, A5 (and cohort B if applicable): contraindication to
any of the drugs to be administered in the lymphodepleting conditioning
regimen. This includes Cy, Flu, and medications associated with prophylaxis of
AEs
8. Cardiac dysfunction as defined by:
a. Myocardial infarction within the last 3 months of trial entry, or
b. Reduced left ventricular function with an ejection fraction < 40% as
measured by multi-gated acquisition (MUGA) scan or echocardiogram (echo) within
28 days before screening, or
c. Unstable angina, or
d. New York Heart Association (NYHA) Class IV congestive heart failure, or
e. Unstable cardiac arrhythmiase trial
9. Pulmonary dysfunction as defined by oxygen saturation < 90% on room air.
Pulmonary function test (PFT) is required only in the case of symptomatic or
prior known impairments within 28 days before screening - with pulmonary
function < 50% corrected (DLCO) and forced expiratory volume in 1 second (FEV1)
10. Major surgery within 4 weeks prior to screening or a major wound that has
not fully healed
11. Vaccination with live, attenuated vaccines within 4 weeks prior to screening
12. Subjects must be able to be off prednisone or other immunosuppressive
medications for concomitant disease for at least 3 days prior to the:
a. Start of the Cy/Flu regimen in cohorts A1, A2, A3, A5 (and cohort B if
applicable)
b. First oNKord® infusion in cohort A4 (and cohort B if applicable)
13. History of stroke or intracranial haemorrhage within 6 months prior to
screening
14. Active infections (viral, bacterial or fungal) that requires specific
therapy. Acute anti-infectious therapy must have been completed within 14 days
prior to trial treatment
15. History of human immunodeficiency virus (HIV) or active infection with
hepatitis B virus (HBV) or hepatitis C virus (HCV)
16. a. For cohorts A1, A2, A3, A5 (and cohort B if applicable): Subjects who
are undergoing or will be undergoing chemotherapy (including HMAs), radiation
therapy, targeted therapy or immunotherapy that cannot be finished or stopped
at least 1 week prior to initiating the Cy/Flu conditioning regimen
b. For cohort A4 (and cohort B if applicable): Subjects who are undergoing or
will be undergoing chemotherapy (excluding HMAs), radiation therapy, targeted
therapy or immunotherapy that cannot be finished or stopped at least 1 week
prior to the first oNKord® infusion
17. Positive pregnancy test or breastfeeding for women of childbearing potential
18. Use of other investigational drugs/therapies within 3 weeks prior to trial
treatment (within 6 weeks in the case of drugs/therapies with long half-life)
or participation in a concomitant interventional clinical trial
19. Any serious concomitant medical condition, medication or therapy which
could, in the opinion of the Investigator, compromise participation in the trial
20. Subjects under legal protection measure (guardianship, trusteeship or
safeguard of justice) and/or inability or unwillingness to comply with the
requirements and procedures of this trial
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 | EUCTR2019-003686-17-NL |
| ClinicalTrials.gov | NCT04632316 |
| CCMO | NL73236.000.20 |