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

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04742101
• Other study ID #: CL1-65487-003
• Secondary ID: 2020-003061-19
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: March 10, 2021
• Est. completion date: April 30, 2025

Study information

• Verified date: June 2024
• Source: Servier
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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. 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 57
• Est. completion date: April 30, 2025
• Est. primary completion date: September 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• S65487 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.

Locations

Country	Name	City	State
France	Institut Gustave Roussy	Villejuif
Hungary	Semmelweis Egyetem Belgyógyászati és Onkológiai Klinika Klinikai Farmakológiai Részleg	Budapest
Korea, Republic of	Samsung Medical Center - Division of Hematology-Oncology	Seoul
Korea, Republic of	Seoul National University Hospital - Department of Hematology-Oncology	Seoul
Poland	Narodowy Instytut Onkologii im. M. Sklodowskiej-Curie Klinika Transplantacji Szpiku i Onkohematologii pokoj 4.041 ul. Wybrzeze Armii Krajowej 15	Gliwice
Spain	Hospital 12 de Octubre Servicio de Hematología	Madrid
Spain	C. Universidad de Navarra Servicio de Hematologia	Pamplona
Spain	H. Universitario La Fe Servicio de Hematologia	Valencia
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	University College London - Hospitals NHS Foundation Trust	London
United Kingdom	The Christie NHS foundation Trust	Manchester

Sponsors (2)

Lead Sponsor	Collaborator
Institut de Recherches Internationales Servier	ADIR, a Servier Group company

Countries where clinical trial is conducted

France,  Hungary,  Korea, Republic of,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Limiting Toxicity (DLT) (phase I part)	DLT assessment at the end of cycle 1	Through the end of first cycle (each cycle is 28 days)
Primary	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
Primary	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: 2022 ELN recommendations from an international expert panel" (Döhner, 2022).	Through study completion, up to 3 years and 5 months
Secondary	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)	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)
Secondary	PharmacoKinetics - Area Under the Curve (AUC) (phase I and phase II parts)	PK parameters of S65487, azacitidine and potential metabolite(s)	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)
Secondary	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
Secondary	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

External Links

•   Find Results on Servier Clinical Trial Data website