A study to evaluate the safety and efficacy of oNKord® in patients with acute myeloid leukemia with residual cancer cells, for whom stem cell transplantation is currently not an option
Summary description of the study
The study investigates oNKord®, a new form of therapy for individuals with acute myeloid leukemia (AML) who have already been treated for AML but still have cancer cells and are currently not undergoing stem cell transplantation. oNKord® may represent an effective option to eliminate the remaining cancer cells in individuals with AML who do not receive a stem cell transplant. This study aims to assess the safety of oNKord® when administered in 1, 2, or 3 doses.
(BASEC)
Intervention under investigation
This Phase I-IIa study is designed to evaluate the safety, tolerability, and efficacy of oNKord® in adult AML patients (≥ 18 years old) in morphological CR with MRD, who are currently not undergoing HSCT. oNKord® represents the active ingredient and the investigational medicinal product (IMP). oNKord® is a serially manufactured cryopreserved product made from ex vivo cultured allogeneic NK cells for adoptive immunotherapy, which does not require matching of human leukocyte antigens (HLA). The dosing regimen of oNKord® after a preceding non-myeloablative conditioning was established in the Phase I study PMLA25 with oNKord® single infusions at doses of 3 to 30 x 10^6 NK cells/kg. In a total of 4 cohorts in the dose escalation part of the study, it is planned to infuse up to three doses either within one day or as repeated administration at intervals of four days, resulting in a maximum cumulative dose of 3 x 325 – 1,000 x 10^6 viable NK cells. In cohorts A1, A2, A3, and A5 of the dose escalation part, the treatment includes a lymphodepleting, non-myeloablative conditioning consisting of Cyclophosphamide (Cy) and Fludarabine (Flu), which will be given prior to the up to three infusions of oNKord®. This investigational treatment will be part of the safety assessment in this study. At the time of writing this protocol amendment, a total of 106 participants have been treated (N=3 in cohort A1; N=3 in cohort A2 and N=4 in cohort A3) and 52 serious adverse events (SAEs) have been reported so far: one three related to Cy/Flu (one grade 3 neutropenia on day 4, with an initially higher dose of Cy/Flu) and, one grade 3 Legionella pneumonia on day 11 and one grade 3 vaginal bleeding on day 20) and two not related to Cy/Flu (one grade 3 enterocolitis after 12 months, both events unrelated and one grade 3 acute kidney injury after 2 months). None of these 5 SAEs were related to oNKord®. Although the reduced dosing of Cy/Flu (Cy: 300 mg/m2/day and Flu: 30 mg/m2/day) appears to be well tolerated, it would still be beneficial for older, frail patients who cannot receive intensive induction chemotherapy if they could receive oNKord® without Cy/Flu. Since the start of the WiNK study, the European Medicines Agency (EMA) has approved in 2021 the combination of Azacitidine, a hypomethylating agent (HMA), and Venetoclax, a B Cell Lymphoma 2 (BCL2) inhibitor, for the treatment of older patients with newly diagnosed AML who cannot receive intensive chemotherapy. The approval was based on the results of the VIALE-A study, a randomized, double-blind, placebo-controlled multicenter phase 3 study that evaluated the efficacy and safety of Venetoclax in combination with Azacitidine (N=286) compared to Azacitidine with placebo (N=145), in patients with newly diagnosed AML who were not eligible for standard induction therapy. This study achieved both its primary endpoint (OS) and its secondary endpoints (response rate, duration of response (DoR)). Notably, Venetoclax in combination with Azacitidine was more effective, based on a higher rate of CR/CRi and MRD negativity (e.g., MRD <0.1%, measured by multiparametric flow cytometry): 23.4% vs 7.6% (p<0.001). However, among the 164 patients in CR/CRi included in the MRD analysis of the Azacitidine/Venetoclax arm, 59% (N=97) remained MRD positive. Importantly, 41% of patients (N=67) who achieved MRD negativity had longer overall survival (OS), event-free survival, and longer duration of response (DoR) than patients who remained MRD positive. The data further show that MRD negativity was associated with a benefit in overall survival, regardless of the timing of the MRD response. Another study by Maiti et al., 2021, on 83 patients with CR/CRi after Decitabine and Venetoclax showed that 52 patients became MRD negative, with a median of 2 months and an interquartile range of 0.9 to 3.1 months, meaning that 75% of MRD negativity was achieved after 3 months, with subsequently deteriorating EFS and OS values. Patients who achieved CR or CRi after 2 months had longer event-free survival (EFS; median EFS was not reached in MRD negative patients, in MRD positive patients it was 5.8 months). Very importantly, OS was improved with 25.1 months for MRD negative patients compared to 7.1 months for MRD positive patients when MRD was measured after 2 months. The size of the EFS and OS benefits in MRD negative status was similar at the 4 month time point compared to the 2 month time point. Therefore, achieving MRD negativity, which is associated with improved overall survival, remains an unmet medical need in AML patients undergoing treatment with HMAs in combination with Venetoclax. Furthermore, treatment with Azacitidine has shown both in vivo and in vitro that it can inhibit T cell proliferation, activation, and secretion of pro-inflammatory cytokines, which may mitigate the risk of graft-versus-host disease (GVHD) in the context of allogeneic transplantation. This immunosuppressive effect on the T cell axis could therefore also prevent or minimize the rejection of infused allogeneic NK cells. For cohort A4 of the dose escalation, the treatment in the study will consist of 3 infusions of oNKord®, spaced 4 days apart, without the use of Cy/Flu. Participants in this cohort will receive the standard treatment of Azacitidine-Venetoclax, and its immunosuppressive effect makes the use of Cy/Flu unnecessary to prevent or minimize the rejection of infused allogeneic NK cells. As a result, adoptive NK cell transfer without the use of Cy/Flu in this older patient population, who are unfit for intensive chemotherapy, could provide added value for safety while maintaining the potential anti-leukemic effect of the infused allogeneic NK cells. Cohort B of the expansion phase will evaluate the study treatment under the RP2D established in Stage A. A sustained exposure to the NK cells contained in oNKord® in the target population may have a therapeutic effect on the MRD, a surrogate endpoint for assessing survival. The target population consists of AML patients in morphological CR with MRD, for whom allogeneic allo-HSCT is not a suitable or preferred option. In patients in this group, there is a significant medical need, as their risk of relapse is high and an allo-HSCT is currently not planned, being the only available curative treatment for AML. An adoptive transfer using serially manufactured effector immune cells, such as NK cells, is a promising approach in AML, as it allows for an expansion of options for cellular immunotherapy beyond HSCT.
(BASEC)
Disease under investigation
Patients with acute myeloid leukemia in morphologically complete remission with measurable residual disease, who are currently not undergoing stem cell transplantation
(BASEC)
Patients 1. For cohorts A1, A2, A3, A5 (and cohort B, if applicable): with diagnosed acute myeloid leukemia (AML) who have achieved a complete morphological remission after one or two cycles of remission induction chemotherapy, with documentation of measurable residual disease at screening. For cohort A4 (and cohort B, if applicable): patients with newly diagnosed AML, who have achieved a morphological CR, including CRi, under standard Azacitidine-Venetoclax therapy and who remain MRD positive after several cycles. 2. be older than 18 years and have a life expectancy of at least 6 months 3. have functioning kidneys and a functioning liver 4. Patients who are not planned for an allo-HSCT (at the time of screening) (BASEC)
Exclusion criteria
1. Patients who have already received an allo-HSCT. 2. Patients with acute promyelocytic leukemia. (BASEC)
Trial sites
Basel
(BASEC)
Sponsor
Glycostem Therapeutics
(BASEC)
Contact
Name of the authorising ethics committee (for multicentre studies, only the lead committee)
Ethics Committee northwest/central Switzerland EKNZ
(BASEC)
Date of authorisation
15.06.2020
(BASEC)
ICTRP Trial ID
EUCTR2019-003686-17 (ICTRP)
Official title (approved by ethics committee)
A prospective Phase I/IIa, open-label, multicentre trial to evaluate the safety and efficacy of oNKord®, an off-the-shelf, ex vivo-cultured allogeneic NK cell preparation, in subjects with acute myeloid leukaemia who are in morphologic complete remission with measurable residual disease and who are currently not proceeding to allogeneic hematopoietic stem cell transplantation. (BASEC)
Academic title
A prospective phase I/IIa, open-label, multicentre trial to evaluate the safety and efficacy of oNKord?, an off-the-shelf, ex vivo-cultured allogeneic NK cell preparation, in subjects with acute myeloid leukaemia who are in complete morphologic remission with measurable residual disease and without a strong indication for stem cell transplantation. (ICTRP)
Public title
A trial to evaluate the safety and efficacy of oNKord? in participants with acute myeloid leukaemia who are in complete morphologic remission with measurable residual disease and without a strong indication for stem cell transplantation. (ICTRP)
Disease under investigation
acute myeloid leukaemia;Therapeutic area: Diseases [C] - Cancer [C04] (ICTRP)
Intervention under investigation
Product Name: oNKord?
Pharmaceutical Form: Infusion
INN or Proposed INN: ALLOGENEIC EX VIVO-GENERATED NATURAL KILLER CELLS FROM CD34+ UMBILICAL CORD BLOOD PROGENITOR CELLS
Other descriptive name: ALLOGENEIC EX VIVO-GENERATED NATURAL KILLER CELLS FROM CD34+ UMBILICAL CORD BLOOD PROGENITOR CELLS
Concentration unit: Other
Concentration type: range
Concentration number: 325000000-1000000000
(ICTRP)
Type of trial
Interventional clinical trial of medicinal product (ICTRP)
Trial design
Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1 (ICTRP)
Inclusion/Exclusion criteria
Gender:
Female: yes
Male: yes
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 WHO 2016 classification (excluding acute promyelocytic leukaemia), including secondary AML after an antecedent haematological disease (e.g. myelodysplastic syndrome) and therapy-related AML
3.Subjects who have achieved CMR, including CRi and complete clinical remission, with MRD documented at screening, as assessed by centralized MFC, after one or two courses of remission induction chemotherapy and who have completed consolidation chemotherapy or who achieved CMR with documented MRD with hypomethylating agents or other relevant appropriate therapies
4.Life expectancy = 6 months at screening
5.Adequate renal and hepatic functions within 14 days of study 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/1.73m2
b.Serum total bilirubin < 2.0 mg/dl, unless due to Gilbert?s syndrome
c.Alanine transaminase (ALT) = 2.5 x ULN
6.Karnofsky Status = 50%
7.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).
8.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.
9.Able and willing to provide written informed consent and comply with the study protocol and procedures
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 17
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 16
(ICTRP)
Exclusion criteria:
Subjects who meet any of the following criteria at screening will be excluded from trial entry:
1.Subjects proceeding to allogeneic HSCT, i.e. subject is a suitable candidate for allogeneic HSCT and donor is expected to be available in a timely manner
2.Subjects having received prior allogeneic HSCT
3.Subjects with acute promyelocytic leukaemia
4.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
5.Blast crisis of chronic myeloid leukaemia
6.Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etc.)
7.Antibodies against HLA (anti-HLA) present
8.Seronegativity for Epstein-Barr Virus (EBV)
9.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
10.Contraindication to any of the drugs to be administered in the conditioning regimen or oNKord? infusion. This includes Cy, Flu, and medications associated with prophylaxis of AEs
11.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 arrhythmias
12.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 diffusing capacity of the lung for carbon monoxide (DLCO) and forced expiratory volume in 1 second (FEV1)
13.Major surgery within 4 weeks prior to screening or a major wound that has not fully healed
14.Vaccination with live, attenuated vaccines within 4 weeks prior to screening
15.Immunosuppressive drugs for concomitant disease. Subject must be able to be off prednisone or other immunosuppressive medications for at least 3 days prior to the start of Cy/Flu regimen
16.History of stroke or intracranial haemorrhage within 6 months prior to screening
17.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
18.History of human immunodeficiency virus (HIV) or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
19.Current concomitant chemotherapy, radiation therapy, or immunotherapy
20.Positive pregnancy test or breastfeeding for women of childbearing potential
21.Participation in another interventional clinical trial within 4 weeks prior to trial enrolment or participation in a concomitant interventional clinical trial
22.Any serious concomitant medical condition, medication or therapy which could, in the opinion of the Investigator, compromise participation in the trial
Primary and secondary end points
Main Objective: The primary objectives are:
?The primary safety objective is to evaluate the safety and tolerability of up to three infusions of oNKord?
?The primary efficacy objective is to assess the cumulative incidence of MRD response, following the infusion of oNKord? at the RP2D
;Secondary Objective: The secondary objectives are:
?In Stage A, to determine the RP2D of oNKord?
?To evaluate the safety and tolerability of the overall trial treatment (combination of the Cy/Flu conditioning regimen and up to three oNKord? infusions)
?To further assess the efficacy of the overall trial treatment (combination of the Cy/Flu conditioning regimen and oNKord? at RP2D) on EFS, duration of MRD response, CIR and OS
?To evaluate the effect of the overall trial treatment (combination of the Cy/Flu conditioning regimen and oNKord? at RP2D) on quality of life (QoL)
;Primary end point(s): 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-to 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 GVHD grade III and IV
?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 (see Appendix C)
Efficacy:
To evaluate the efficacy of oNKord? using:
?The cumulative incidence of MRD response as assessed by multiparameter flow cytometry (MFC) in bone marrow on Day +14 and at 1, 2, 3, 6, 9 and 12 months post-RP2D oNKord? infusion. Subjects with responses are defined as MRD negative subjects still in CMR at any time during the follow-up period of the trial after receiving oNKord? at RP2D
;Timepoint(s) of evaluation of this end point: Safety & tolerability: at screening, D-6 D-5, D-4, D-3, D0, D1, (D5, D8,) D9, D14 + each follow-up visit
Efficacy: The cumulative incidence of MRD response at Day +14 and at 1, 2, 3, 6, 9 and 12 months post-RP2D oNKord? infusion. (ICTRP)
Secondary end point(s): Safety and Tolerability:
To evaluate the safety and tolerability of the overall trial treatment (Cy/Flu in combination with up to three oNKord? infusions) using the cumulative incidence of AESIs, including:
?Grade 3-to 4 infusion-related toxicity of the overall trial treatment, 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 overall trial treatment
?Incidence and severity of viral, fungal, and bacterial infections with onset during the first two months following conditioning initiation, including viral reactivations, and Infection Related Mortality (IRM) defined as death due to infectious disease
Efficacy:
To evaluate the efficacy of the overall trial treatment (Cy/Flu in combination with oNKord? at RP2D) by assessing:
?EFS, defined as the time from enrolment until disease relapse (morphologic and/or clinical relapse) after CMR 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 assessed by MFC
?OS, defined as the time from enrolment until death from any cause
?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:
oAnalysis of responders and non-responders, as assessed by the efficacy primary endpoint, in relation to secondary efficacy endpoints
oTargeted 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
oAssessment of oNKord? immunogenicity
oNumber of oNKord? infusions and corresponding enumeration of oNKord?-derived NK-cells in combination with relevant cytokine levels
oMRD 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 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
;Timepoint(s) of evaluation of this end point: Safety & tolerability: at screening, D-6 D-5, D-4, D-3, D0, D1, (D5, D8,) D9, D14 + each follow-up visit
Efficacy:
- QOL: assessed at 1, 3 and 12 months post-treatment compared to baseline
-OS: until death
-Duration MRD response at Day +14 and at 1, 2, 3, 6, 9 and 12 months post-RP2D oNKord? infusion.
-CIR; throughout the course of the trial
-EFS: enrolment until disease relapse (ICTRP)
Registration date
05.08.2020 (ICTRP)
Incorporation of the first participant
16.06.2022 (ICTRP)
Secondary sponsors
not available
Additional contacts
Pavlina Topalova, regulatory@sms-oncology.com, 00310204350580, SMS-oncology (ICTRP)
Secondary trial IDs
WiNK, SMS-0341, 2019-003686-17-BE (ICTRP)
Results-Individual Participant Data (IPD)
not available
Further information on the trial
https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-003686-17 (ICTRP)
Results of the trial
Results summary
not available
Link to the results in the primary register
not available