E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
A type of blood cancer with cancer cells in the bone marrow. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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
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E.2.2 | Secondary objectives of the trial |
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)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
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E.4 | Principal 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
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E.5 End points |
E.5.1 | 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
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E.5.1.1 | 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. |
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E.5.2 | 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: 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 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 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
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E.5.2.1 | 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 |
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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 | Yes |
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 |
dose-escalation stage + Expansion stage |
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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 | No |
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 | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
France |
Germany |
Netherlands |
Switzerland |
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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 end of the trial is defined as the date at which the last data point for the primary endpoint from the last subject is received.
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |