Phase I/II Trial of S65487 Plus Azacitidine in Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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
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The study is designed in two parts: A single arm dose escalation phase I part and dose expansion phase II part. 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. For the expansion phase, Ramp up dose and full dose will be the RP2D (Recommended Phase 2 Dose) determined during phase I part

Official Title
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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

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: S65487 and azacitidine


Participation Criteria
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Eligibility Criteria
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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 2, 2016 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: S65487 with azacitidine<br> | Drug: S65487 and azacitidine<br>* Treatment cycle of combination of S65487 and azacitidine during 4 weeks preceded by ramp-up doses. 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity (DLT) (phase I part) | DLT assessment at the end of cycle 1 | From Ramp-up period (day 4 or day 3 before the first cycle) to the end of first cycle (each cycle is 28 days) | 
| Adverse Event (phase I part) | AE recording throughout the study evaluated according to CTCAE v5.0, dose interruptions, reductions, and intensity | Through study completion, an average of 3 years ans 5 months | 
| Complete Remission (CR) rate (phase II part) | 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: 2017 ELN recommendations from an international expert panel (Döhner, 2017). | Through study completion, up to 3 years and 5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PharmacoKinetics - maximum Concentration at the End of the infusion (Cinf) (phase I and phase II parts) | PK parameters of S65487, azacitidine and potential metabolite(s) | Ramp-up (day 4 or day 3 before the first cycle), Cycle 1 Day 1, Cycle 1 Day 3 (schedule 2), Cycle 1 Day 5 (schedule 2), Cycle 1 Day 8, Cycle 1 Day 9 (schedule 1), each Day 15 (schedule 1) or Day 8 (schedule 2) for following cycles (each cycle is 28 day) | 
| PharmacoKinetics - Area Under the Curve (AUC) (phase I and phase II parts) | PK parameters of S65487, azacitidine and potential metabolite(s) | Ramp-up (day 4 or day 3 before the first cycle), Cycle 1 Day 1, Cycle 1 Day 3 (schedule 2), Cycle 1 Day 5 (schedule 2), Cycle 1 Day 8, Cycle 1 Day 9 (schedule 1), each Day 15 (schedule 1) or Day 8 (schedule 2) for following cycles (each cycle is 28 day) | 
| Assessment of anti-leukemic activity of S65487 combined to azacitidine (phase I and phase II parts) | Complete Remission rate | Through study completion, an average of 3 years and 5 months | 
| Assessment of anti-leukemic activity of S65487 combined to azacitidine (phase I and phase II parts) | Progression Free Survival | Through study completion, an average of 3 years and 5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Dose escalation, Phase I/II, Azacitidine, Combination, Oncology