A trial to evaluate the safety and efficacy of oNKord® in participants 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

• Register: EUCTR
• Last refreshed on: 18 October 2021
• Main ID: EUCTR2019-003686-17-DE
• Date of registration: 27/04/2020
• Prospective Registration: Yes
• Primary sponsor: Glycostem Therapeutics BV
• Public title: A trial to evaluate the safety and efficacy of oNKord® in participants 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
• Scientific 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 morphologic complete remission with measurable residual disease and who are currently not proceeding to allogeneic hematopoietic stem cell transplantation.
• Date of first enrolment: 27/08/2020
• Target sample size: 33
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-003686-17
• Study type: Interventional clinical trial of medicinal product
• Study 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
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, France, Germany, Netherlands, Switzerland

Contacts

• Name: Cleo Francois
• Affiliation: CATO SMS

• Name: Cleo Francois
• Affiliation: CATO SMS

Key inclusion & exclusion criteria

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 morphologic CR, 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 morphologic CR with documented MRD with hypomethylating agents or other relevant appropriate therapies (e.g. HMAs in combination with venetoclax)
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, creatine 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 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
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)

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

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 hypertension, active or uncontrolled 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. 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
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 arrhythmias
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 diffusing capacity of the lung for carbon monoxide (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. 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
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. Subjects who are undergoing or will be undergoing chemotherapy (including HMAs), radiational therapy, targeted therapy or immunotherapy that cannot be finished or stopped at least 1 week prior to initiating the Cy/Flu conditioning regimen
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
29. Subjects under legal protection measure (guardianship, trusteeship
or safeguard of justice) and/or inability or unwillingness to com

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

acute myeloid leukaemia
MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

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

Primary Outcome(s)

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

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 / 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 (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 at 1, 2, 3, 6, 9 and 12 months post-RP2D oNKord® infusion. Subjects with responses are defined as MRD negative subjects still in morphologic CR 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-5, D-4, D-3, D0, D1, (D5, D8,) D9, D14 + each follow-up visit
Efficacy: The cumulative incidence of MRD response at 1, 2, 3, 6, 9 and 12 months post-RP2D oNKord® infusion.

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)

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Safety & tolerability: at screening, 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 1, 2, 3, 6, 9 and 12 months post-RP2D oNKord® infusion.
-CIR; throughout the course of the trial
-EFS: enrolment until disease relapse

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 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 assessed by MFC
• OS (defined as the time from enrolment until death from any cause) rate 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

Secondary ID(s)

SMS-0341

WiNK

Source(s) of Monetary Support

Glycostem Therapeutics BV

Ethics review

Status: Approved
Approval date: 31/07/2020
Contact: