Phase I / II, Open Label, Dose Escalation Part (Phase I) Followed by Non-comparative Expansion Part (Phase II), Multi-centre Study, Evaluating Safety, Pharmacokinetics and Efficacy of S65487, a Bcl2 Inhibitor Combined With Azacitidine in Adult Patients With Previously Untreated Acute Myeloid Leukemia Not Eligible for Intensive Treatment
Overview
- Phase
- Phase 1
- Intervention
- S65487 and azacitidine
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- Institut de Recherches Internationales Servier
- Enrollment
- 57
- Locations
- 11
- Primary Endpoint
- Adverse Event (phase I part)
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
S65487 with azacitidine
Intervention: S65487 and azacitidine
Outcomes
Primary Outcomes
Adverse Event (phase I part)
Time Frame: 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
Dose Limiting Toxicity (DLT) (phase I part)
Time Frame: Through the end of first cycle (each cycle is 28 days)
DLT assessment at the end of cycle 1
Complete Remission (CR) rate (phase II part)
Time Frame: 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 Outcomes
- 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))
- 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))
- 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)