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

Sponsor

Institut de Recherches Internationales Servier (Other)

Overall Status

Recruiting

CT.gov ID

NCT04742101

Collaborator

ADIR, a Servier Group company (Industry)

Enrollment

Locations

Arm

35.7

Anticipated Duration (Months)

10.1

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: S65487 and azacitidine	Phase 1/Phase 2

Detailed Description

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

81 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I / II, Open Label, Dose Escalation Part (Phase I) Followed by Noncomparative 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

Actual Study Start Date :

Mar 10, 2021

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Mar 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: S65487 with azacitidine	Drug: S65487 and azacitidine 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.

Arm

Intervention/Treatment

Experimental: S65487 with azacitidine

Drug: S65487 and azacitidine

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.

Outcome Measures

Primary Outcome Measures

Dose Limiting Toxicity (DLT) (phase I part) [From Ramp-up period (day 4 or day 3 before the first cycle) to 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: 2017 ELN recommendations from an international expert panel" (Döhner, 2017).

Secondary Outcome Measures

PharmacoKinetics - maximum Concentration at the End of the infusion (Cinf) (phase I and phase II parts) [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)]
PK parameters of S65487, azacitidine and potential metabolite(s)
PharmacoKinetics - Area Under the Curve (AUC) (phase I and phase II parts) [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)]
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
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]
Progression Free Survival

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Institut Gustave Roussy	Villejuif	France	94805
2	Seoul National University Hospital - Department of Hematology-Oncology	Seoul	Korea, Republic of	03080
3	Samsung Medical Center - Division of Hematology-Oncology	Seoul	Korea, Republic of	06351
4	Hospital 12 de Octubre Servicio de Hematología	Madrid	Spain	28041
5	C. Universidad de Navarra Servicio de Hematologia	Pamplona	Spain	31008
6	H. Universitario La Fe Servicio de Hematologia	Valencia	Spain	46026
7	Western General Hospital	Edinburgh	United Kingdom	EH4 2XU
8	University College London - Hospitals NHS Foundation Trust	London	United Kingdom	NW1 2PG