Phase I Study of S64315 Administred Intravenously in Patients With Acute Myeloid Leukaemia or Myelodysplastic Syndrome

Myelodysplastic Syndrome (MDS) Clinical Trial

Official title:

Phase I, International, Multicentre, Open-label, Non-randomised, Non-comparative Study of Intravenously Administered S64315, a Mcl-1 Inhibitor, in Patients With Acute Myeloid Leukaemia (AML) or Myelodysplastic Syndrome (MDS)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02979366
• Other study ID #: CL1-64315-001
• Secondary ID: 2016-003768-3813
• Status: Completed
• Phase: Phase 1
• Start date: March 15, 2017
• Est. completion date: May 11, 2020

Study information

• Verified date: March 2021
• Source: Servier
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The CL1-64315-001 study is a phase I, international, multicentre, open-label, non-randomised, non-comparative study. This study is designed in two parts: one part for dose escalation, one part for dose expansion.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 38
• Est. completion date: May 11, 2020
• Est. primary completion date: May 11, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or female aged = 18 years;

• Patients with cytologically confirmed and documented de novo, secondary or therapy-related AML, excluding acute promyelocytic leukaemia (APL, French-American British M3 classification):

• with relapsed or refractory disease without established alternative therapy or

• secondary to MDS treated at least by hypomethylating agent or

• > 65 years not previously treated for AML and who are not candidates for intensive chemotherapy nor candidates for established alternative chemotherapy Or Patients with cytologically confirmed and documented MDS), in relapse or refractory after previous treatment line including at least one hypomethylating agent and have =10% bone marrow blasts;

• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2

• Circulating white blood cells < 10^9 /L (with or without use of hydroxycarbamide).

• Adequate renal function defined as:

• Serum creatinine = 1.5 x ULN (upper normal limit) or calculated creatinine clearance (determined by MDRD) > 50 mL/min/1.73m2.

• LDH < 2 x ULN

• Adequate hepatic function defined as:

• AST and ALT = 1.5 x ULN

• Total bilirubin level = 1.5 x ULN, except for patients with known Gilbert's syndrome (confirmed by the UGT1A1 polymorphism analysis), who are excluded if total bilirubin>3.0 x ULN or direct bilirubin > 1.5 x ULN

• Serum CK/CPK =2.5 x ULN.

Exclusion Criteria:

• Unlikely to cooperate in the study.

• Participant already enrolled in the study who has received at least one S64315 infusion.

• Pregnancy, breastfeeding or possibility of becoming pregnant during the study.

• Participation in another interventional study requiring investigational treatment intake within 2 weeks or at least 5 half-lives (whichever is longer) prior to first dose of S64315 (participation in non-interventional registries or epidemiological studies is allowed).

• Presence of = CTCAE grade 2 toxicity (except alopecia of any grade) due to prior cancer therapy, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.03)

• Unresolved = CTCAE grade 2 diarrhoea or medical conditions associated with chronic diarrhoea (such as irritable bowel syndrome, inflammatory bowel disease)

• Known carriers of HIV antibodies

• Known history of significant liver disease

• Uncontrolled hepatitis B or C infection

• Known active or chronic pancreatitis

• History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment.

Related Conditions & MeSH terms

• Acute Myeloid Leukaemia (AML)
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome (MDS)
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• S64315 once a week
S64315 will be administered via i.v. infusion from 30 minutes and up to 3 hours once every week (21- day cycle), the starting dose is 50 mg. As data emerge during the study, the infusion duration and alternative dosing regimen may be changed.
• S64315 twice a week
S64315 will be administered via i.v. infusion from 30 minutes and up to 3 hours twice every week (28- day cycle), the starting dose is 50 mg. As data emerge during the study, the infusion duration and alternative dosing regimen may be changed.

Locations

Country	Name	City	State
Australia	Royal Melbourne Hospital, Department of Clinical Haematology and BMT Service	Melbourne
Australia	The Alfred Hospital Department of Haematology	Melbourne
France	Institut Paoli-Calmettes Departement d'Hématologie	Marseille
France	Hôpital Saint-Antoine Département d'Hematologie Clinique et de Thérapie cellulaire	Paris
France	Institut Universitaire du Cancer Toulouse Oncopole	Toulouse
Spain	Hospital Universitario Vall d' Hebron/VHIO Hematology Department	Barcelona
Spain	Hospital Universitario La Fe Hematology Department	Valencia
United States	The University of Texas MD Anderson Cancer Center, Department of Leukemia, Division of Cancer Medicine	Houston	Texas
United States	Patient Care Location: Smilow Cancer Hospital at Yale	New Haven	Connecticut

Sponsors (2)

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

Countries where clinical trial is conducted

United States,  Australia,  France,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of DLTs during the first cycle of treatment with single agent S64315		21-day cycle 1
Primary	Safety tolerance profile of S64315 assessed by:Incidence and severity of AEs		From first dose until 30 days after the last dose administration
Primary	Tolerability: Dose interruptions		From first dose until 30 days after the last dose administration
Primary	Tolerability: Dose reductions		From first dose until 30 days after the last dose administration
Primary	Tolerability: Dose intensity		From first dose until 30 days after the last dose administration
Secondary	Concentration at the end of infusion (C inf) in plasma		D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
Secondary	Cumulative amount of a compound excreted in the urine (Ae)		only D1 of cycle 1
Secondary	Preliminary efficacy assessment according to Cheson criteria (adapted for each disease)		From first dose until 30 days after the last dose administration
Secondary	Time corresponding to end of infusion (tinf/tend) in plasma		D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
Secondary	Area under the concentration-time curve from zero (time of drug administration) to tlast (AUC last) in plasma		D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
Secondary	Time corresponding to Clast (tlast) in plasma.		D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
Secondary	Last quantifiable observed concentration (Clast) in plasma		D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
Secondary	Area Under the Curve (AUC) in plasma		D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
Secondary	Terminal elimination half-life (t½,z) in plasma		D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
Secondary	total Clearance (CL)		D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
Secondary	Volume of distribution at steady-state (Vss) in plasma		D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
Secondary	Ae expressed as a percentage of the dose (fe) in urine		only D1 of cycle 1
Secondary	Renal clearance (CLR)		only D1 of cycle 1

External Links

•   Lay Summary
•   Results Summary