Acute Myeloid Leukemia
Conditions
Keywords
Acute Myeloid Leukemia, Dose escalation, Phase I/II, Azacitidine, Combination, Oncology
Brief summary
The purpose of this study is to assess the safety, tolerability and clinical activity of the combination S65487 with azacitidine in patients with acute myeloid leukaemia.
Detailed description
The study is designed in two parts: A dose escalation phase I part, and a dose expansion phase II part with an additional potential expansion cohort. During dose escalation of S65487 in combination with azacitidine, only S65487 agent dose will escalate and a DDI (Drug-Drug interaction) assessment between S65487 and posaconazole (antifungal drug) will be performed. A ramp-up dose of S65487 will be administered on the first two days of cycle 1, then the full dose of S65487 will be administered for the remainder of cycle 1. Each treatment cycle is 28 days. For the expansion phase, the dose will be the RP2D (Recommended Phase 2 Dose) determined during phase I part. An additional potential expansion cohort will be included if there is more than one promising dose/schedule candidate.
Interventions
DRUGS65487 and azacitidine
Treatment cycle of combination of S65487 and azacitidine during 4 weeks. Two administration schedules are set up. S65487 will be administered via intravenous (IV) infusion. Azacitidine will be administered via either subcutaneous (SC) or Intravenous (IV) infusion according to local practices.
Sponsors
Institut de Recherches Internationales Servier
ADIR, a Servier Group company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female participant aged ≥ 18 years old * Participants with cytologically confirmed and documented treatment naïve, de novo or secondary AML defined by WHO 2016 classification (Arber, 2016). Secondary AML includes: * Previous myelodysplastic syndrome transformed * 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 * Participants not eligible for standard induction chemotherapy * Aged ≥ 75 years old * Or Age ≥18 years with at least one of the following comorbidities: * 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 * Other contraindication(s) to anthracycline therapy (must be documented) * Other comorbidity that the Investigator judges as incompatible with intensive remission induction chemotherapy, which must be documented * ECOG (Eastern Cooperative Oncology Group) performance status should be (criterion should be rechecked at inclusion visit) ECOG ≤ 2. * Written informed consent obtained prior any study-specific procedure as described in section 13.3 of the protocol. * Adequate renal and hepatic function * Circulating White Blood Cell Count (WBC count) \< 25\*109 G/L (with or without use of hydroxycarbamide/leukapheresis) * Serum potassium, serum calcium, serum phosphates, serum magnesium within normal limits with or without supplementation.
Exclusion criteria
* Major surgery within 3 weeks prior to the first IMP administration, or participants who have not recovered from side effects of the surgery * Any radiotherapy within 3 weeks before the first IMP administration, * 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 * Acute promyelocytic leukemia (APL, French-American-British M3 classification) * 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 3, 2019 for Acute Myeloid Leukemia * Treatment with hypomethylating agents (decitabine/azacitidine) or Venetoclax for AHD (antecedent hematologic disorders) in the 3 months prior to the first IMP intake
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) (phase I part) | Through the end of first cycle (each cycle is 28 days) | DLT assessment at the end of cycle 1 |
| Adverse Event (phase I part) | Through study completion, an average of 3 years ans 5 months | AE recording throughout the study evaluated according to CTCAE v5.0, dose interruptions, reductions, and intensity |
| Complete Remission (CR) rate (phase II part) | Through study completion, up to 3 years and 5 months | CR rate is defined as the proportion of subjects who achieve complete response. Response is evaluated based on the "'Diagnosis and management of AML in adults: 2022 ELN recommendations from an international expert panel" (Döhner, 2022). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PharmacoKinetics - maximum Concentration at the End of the infusion (Cinf) (phase I and phase II parts) | Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15 (schedule 1, first two cohorts), Cycle 2 Day 8 (from Cohort 3), or Day 15 (first two cohorts)(each cycle is 28 days) | PK parameters of S65487, azacitidine and potential metabolite(s) |
| PharmacoKinetics - Area Under the Curve (AUC) (phase I and phase II parts) | Cycle 1 Day 8 to Day 9, Cycle 2 Day 8 to Day 9 (from cohort 3), or Day 15 to Day 16 (first two cohorts)(each cycle is 28 days) | PK parameters of S65487, azacitidine and potential metabolite(s) |
| Assessment of anti-leukemic activity of S65487 combined to azacitidine (phase I and phase II parts) | Through study completion, an average of 3 years and 5 months | Complete Remission rate |
Countries
France, Hungary, Poland, South Korea, Spain, United Kingdom
Outcome results
None listed