Clinical trial NCT02979366: Phase I Study of S64315 Administred Intravenously in Patients With Acute Myeloid Leukaemia or Myelodysplastic Syndrome
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myeloid Leukaemia (AML)
Myelodysplastic Syndrome (MDS)
Lead sponsor: Servier
Sponsor class: INDUSTRY
Collaborators: name: ADIR, a Servier Group company
First posted: 2016-12-01
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of DLTs during the first cycle of treatment with single agent S64315
timeFrame: 21-day cycle 1
measure: Safety tolerance profile of S64315 assessed by:Incidence and severity of AEs
timeFrame: From first dose until 30 days after the last dose administration
measure: Tolerability: Dose interruptions
timeFrame: From first dose until 30 days after the last dose administration
measure: Tolerability: Dose reductions
timeFrame: From first dose until 30 days after the last dose administration
measure: Tolerability: Dose intensity
timeFrame: From first dose until 30 days after the last dose administration
Secondary outcomes:
measure: Concentration at the end of infusion (C inf) in plasma
timeFrame: D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
measure: Cumulative amount of a compound excreted in the urine (Ae)
timeFrame: only D1 of cycle 1
measure: Preliminary efficacy assessment according to Cheson criteria (adapted for each disease)
timeFrame: From first dose until 30 days after the last dose administration
measure: Time corresponding to end of infusion (tinf/tend) in plasma
timeFrame: D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
measure: Area under the concentration-time curve from zero (time of drug administration) to tlast (AUC last) in plasma
timeFrame: D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
measure: Time corresponding to Clast (tlast) in plasma.
timeFrame: D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
measure: Last quantifiable observed concentration (Clast) in plasma
timeFrame: D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
measure: Area Under the Curve (AUC) in plasma
timeFrame: D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
measure: Terminal elimination half-life (t½,z) in plasma
timeFrame: D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
measure: total Clearance (CL)
timeFrame: D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
measure: Volume of distribution at steady-state (Vss) in plasma
timeFrame: D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6.
measure: Ae expressed as a percentage of the dose (fe) in urine
timeFrame: only D1 of cycle 1
measure: Renal clearance (CLR)
timeFrame: only D1 of cycle 1
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Patient Care Location: Smilow Cancer Hospital at Yale
state: Connecticut
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center, Department of Leukemia, Division of Cancer Medicine
state: Texas
city: Melbourne
country: Australia
facility: The Alfred Hospital Department of Haematology
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital, Department of Clinical Haematology and BMT Service
city: Marseille
country: France
facility: Institut Paoli-Calmettes Departement d'Hématologie
city: Paris
country: France
facility: Hôpital Saint-Antoine Département d'Hematologie Clinique et de Thérapie cellulaire
city: Toulouse
country: France
facility: Institut Universitaire du Cancer Toulouse Oncopole
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d' Hebron/VHIO Hematology Department
city: Valencia
country: Spain
facility: Hospital Universitario La Fe Hematology Department
Study officials:
affiliation: The Alfred Hospital, Melbourne, Victoria
name: Andrew WEI
role: PRINCIPAL_INVESTIGATOR
References: