bone marrow cancer cells leukemia
Conditions
Interventions
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, an
Sponsors
Glycostem Therapeutics
Eligibility
Age
18 Years to 99 Years
Inclusion 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 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] = 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 = 30 mL/min/1.73 m2 b. Serum total bilirubin = 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 contracept
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 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 lea
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 (i | — |
Countries
Netherlands
Outcome results
None listed