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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: S65487 and azacitidine

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.

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.

• Study Type: Interventional
• Enrollment (Estimated): 109
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Institut de Recherches Internationales Servier, Clinical Studies Department; Phone Number: +33 1 55 72 43 66; Email: scientificinformation@servier.com

Study Locations

• France
  • Villejuif, France, 94805
    • Recruiting
    • Institut Gustave Roussy
    • Contact: Stephane DE BOTTON; Phone Number: +33 142114079; Email: stephane.debotton@gustaveroussy.fr
• Hungary
  • Budapest, Hungary, H-1083
    • Not yet recruiting
    • Semmelweis Egyetem Belgyógyászati és Onkológiai Klinika Klinikai Farmakológiai Részleg
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Not yet recruiting
    • Seoul National University Hospital - Department of Hematology-Oncology
  • Seoul, Korea, Republic of, 06351
    • Recruiting
    • Samsung Medical Center - Division of Hematology-Oncology
    • Contact: Jun Ho JANG; Phone Number: 82 2 3410 0219; Email: smcjunhojang@gmail.com
• Poland
  • Gliwice, Poland, 44-102
    • Not yet recruiting
    • Narodowy Instytut Onkologii im. M. Sklodowskiej-Curie Klinika Transplantacji Szpiku i Onkohematologii pokoj 4.041 ul. Wybrzeze Armii Krajowej 15
• Spain
  • Barcelona, Spain, 08035
    • Withdrawn
    • Hospital Universitario Vall d´Hebron
  • Madrid, Spain, 28041
    • Recruiting
    • Hospital 12 de Octubre Servicio de Hematología
    • Contact: María CALBACHO ROBLES; Phone Number: 0034 917 792 877; Email: hematx.hdoc@salud.madrid.org
    • Contact: Email: maria.calbacho@salud.madrid.org
  • Pamplona, Spain, 31008
    • Recruiting
    • C. Universidad de Navarra Servicio de Hematologia
    • Contact: Ana Alfonso; Phone Number: 5801 0034 948 255 400; Email: aalfonso@unav.es
  • Valencia, Spain, 46026
    • Recruiting
    • H. Universitario La Fe Servicio de Hematologia
    • Contact: Pau MONTESINOS; Phone Number: 0034 961 244 864; Email: montesinos_pau@gva.es
• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XU
    • Recruiting
    • Western General Hospital
    • Contact: Victoria CAMPBELL; Phone Number: +44 (0)131 537 1000; Email: Victoria.L.Campbell@nhslothian.scot.nhs.uk
  • London, United Kingdom, NW1 2PG
    • Recruiting
    • University College London - Hospitals NHS Foundation Trust
  • Manchester, United Kingdom, M20 4BX
    • Not yet recruiting
    • The Christie Nhs Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: S65487 with azacitidine	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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)
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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)
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)

Collaborators and Investigators

• Sponsor: Institut de Recherches Internationales Servier
• Collaborators: ADIR, a Servier Group company

Publications and helpful links

Helpful Links

• Find Results on Servier Clinical Trial Data website

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2021
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): March 15, 2025

Study Registration Dates

• First Submitted: December 14, 2020
• First Submitted That Met QC Criteria: February 4, 2021
• First Posted (Actual): February 5, 2021

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; Dose escalation; Oncology; Phase I/II; Azacitidine; Combination
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: CL1-65487-003; 2020-003061-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.

In addition, access can be requested for all interventional clinical studies in patients:

• sponsored by Servier
• with a first patient enrolled as of 1 January 2004 onwards
• for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

• IPD Sharing Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
• IPD Sharing Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Study Data/Documents

1. Individual Participant Data Set
2. Study Protocol
3. Statistical Analysis Plan
4. Informed Consent Form
5. Clinical Study Report
6. Study-level clinical trial data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No