E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Previously untreated Acute Myeloid Leukemia (AML) |
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E.1.1.1 | Medical condition in easily understood language |
Acute Myeloid Leukemia (AML) |
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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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase I: To determine the safety profile and tolerability of S65487 combined to azacitidine (including Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD)) To determine the Recommended Phase II Dose (RP2D) of S65487 combined to azacitidine
Phase II: To assess the efficacy of S65487 combined to azacitidine |
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E.2.2 | Secondary objectives of the trial |
Phase I: To determine the PK profile of S65487 and azacitidine administered in combination To assess the anti-leukemic activity of S65487 combined to azacitidine
Phase II: To assess anti-leukemic activity of S65487 combined to azacitidine To evaluate the depth and the duration of response Safety profile and tolerability of S65487 in combination with azacitidine To determine the PK profile of S65487 and azacitidine administered in combination |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female participant aged ≥ 18 years old according to section 5.1.2 2. Participants with cytologically confirmed and documented treatment naïve, de novo or secondary AML defined by WHO 2016 classification (Arber, 2016). Secondary AML includes: a. Previous myelodysplastic syndrome transformed b. AML due to exposure to potentially leukemogenic therapies or agents (e.g. radiation therapy, alkylating agents, topoisomerase II inhibitors) with the primary malignancy in remission for at least 3 years 3. Participants not eligible for standard induction chemotherapy a. Aged ≥ 75 years old b. Or Age ≥18 years with at least one of the following comorbidities: i. Clinically significant heart or lung comorbidities, as reflected by at least one of: - Lung diffusing capacity for carbon monoxide (DLCO) ≤65% of expected - Forced expiratory volume in 1 second (FEV1) ≤65% of expected ii. Other contraindication(s) to anthracycline therapy (must be documented) iii. Other comorbidity that the Investigator judges as incompatible with intensive remission induction chemotherapy, which must be documented 4. ECOG (Eastern Cooperative Oncology Group) performance status should be (criterion should be rechecked at inclusion visit) ECOG ≤ 2. 5. Written informed consent obtained prior any study-specific procedure as described in section 13.3 of the protocol. 6. Adequate renal and hepatic function 7. Circulating White Blood Cell Count (WBC count) < 25*109 G/L (with or without use of hydroxycarbamide/leukapheresis) 8. Serum potassium, serum calcium, serum phosphates, serum magnesium within normal limits with or without supplementation. |
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E.4 | Principal exclusion criteria |
9. Major surgery within 3 weeks prior to the first IMP administration, or participants who have not recovered from side effects of the surgery 10. Any radiotherapy within 3 weeks before the first IMP administration, 11. Allogenic stem cell transplant within 3 months before the first IMP administration and/or participants with active Graft-versus-host disease within 3 months before the first IMP administration and/or participants who still receive immunosuppressive treatment within 3 months before the first IMP administration and/or participant who receive donor lymphocyte infusion (DLI) within 3 months before the first IMP administration 12. Acute promyelocytic leukemia (APL, French-American-British M3 classification) 13. Favorable risk cytogenetics such as t(8;21), inv(16) or t(16;16) or t(15;17) as per the National Comprehensive Cancer Network (NCCN) Guidelines Version 2, 2016 for Acute Myeloid Leukemia 14. Treatment with hypomethylating agents (decitabine/azacitidine) or Venetoclax for AHD (antecedent hematologic disorders) in the 3 months prior to the first IMP intake |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase I: DLT assessment at the end of cycle 1 AE recording throughout the study evaluated according to CTCAE v5.0, dose interruptions, reductions, and intensity Vitals signs, Laboratory tests, ECG
Phase II: CR rate: Complete Remission (CR) rate. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
For phase I: PK parameters of S65487, azacitidine and potential metabolite(s) or co-administered drugs or potential endogenous substrates of enzymes or transporters of interest if applicable will be determined in plasma (e.g. Cinf, tinf, AUClast, tlast, Clast, AUC, t½, z, CL and Vss) CR rate: Complete Response (CR) rate, CR rate by initiation of cycle 2 (CR2), Overall response rate (ORR), CRi rate: Complete Response rate with incomplete blood recovery, Duration of Response (DOR), Event Free Survival (EFS), Progression Free Survival (PFS), Overall Survival (OS), time to first response Antileukemic activity assessment using blood, bone marrow aspirate and medullary biopsies if available according to ELN 2017 response criteria |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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 |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 |
Belgium |
France |
Korea, Republic of |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
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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End of Trial is defined as the date of the last follow-up of the last participant, or the date of the last contact attempt if the last participant is declared lost to follow-up. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 5 |