| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 further evaluate the safety and tolerability of the trial treatment
• To further assess the efficacy of the trial treatment on EFS, duration of MRD response, CIR and OS
• To evaluate the effect of the trial treatment 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. 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 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 (≥)
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 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) |
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| E.4 | Principal exclusion criteria |
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 leukemia
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 enrollment
4. Blast crisis of chronic myeloid leukemia
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. 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 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 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 hemorrhage within 6 months prior to screenin
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), radiational 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
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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, 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 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.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety & tolerability:
Cohort A1, A2, A3: at screening, D-5, D-4, D-3, D0, D+1, (D+4, D+5, D+8,) D+9, D+14 + each follow-up visit
Cohort A4: at screening, D0, D+1, D+4, D+5, D+8, D+9, D+14 and each follow up visit.
Cohort A5: at screening, D-5, D-4, D-3, D0, D+1, D+7, D+14 and each follow up visit.
Efficacy: The cumulative incidence of MRD response 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 trial treatment using the cumulative incidence of AESIs, including:
• Grade 3-to 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 2 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
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety & tolerability:
Cohort A1, A2, A3: at screening, D-5, D-4, D-3, D0, D+1, (D+4, D+5, D+8,) D+9, D+14 + each follow-up visit
Cohort A4: at screening, D0, D+1, D+4, D+5, D+8, D+9, D+14 and each follow up visit.
Cohort A5: at screening, D-5, D-4, D-3, D0, D+1, D+7, D+14 and 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 |
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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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| France |
| Netherlands |
| Switzerland |
| Germany |
| Belgium |
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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 of the last trial visit of the last subject enrolled in the trial.
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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