Clinical trial NCT03672695: Phase I Dose Escalation Study of Intravenously Administered S64315 in Combination With Orally Administered Venetoclax in Patients With Acute Myeloid Leukaemia.
Official title: An International Phase Ib Multicentre Study to Characterize the Safety and Tolerability of Intravenously Administered S64315, a Selective Mcl-1 Inhibitor, in Combination With Orally Administered Venetoclax, a Selective Bcl-2 Inhibitor in Patients With Acute Myeloid Leukaemia (AML).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myeloid Leukaemia
Lead sponsor: Servier
Sponsor class: INDUSTRY
Collaborators: name: ADIR, a Servier Group company
First posted: 2018-09-14
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the safety profile, tolerability and the Recommended Phase 2 Dose of the combination S64315 with venetoclax in patients with Acute Myeloid Leukaemia.


Eligibility criteria: Inclusion Criteria:

1. Male or female aged ≥ 18 years;
2. Patients with cytologically confirmed and documented de novo, secondary or therapy-related AML as defined by World Health Organization (WHO) 2016 classification (Arber, 2016), 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 and without established alternative therapy or
   * ≥ 65 years not previously treated for AML and who are not candidates for intensive chemotherapy nor candidates for established alternative therapy
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
4. Able to comply with study procedures
5. Adequate renal function within 7 days before the inclusion of the patient defined as:

   • Serum creatinine ≤ 1.5 x ULN (upper normal limit) or calculated creatinine clearance (determined by MDRD) \> 50 mL/min/1.73m2
6. Adequate hepatic function within 7 days before the inclusion of the patient defined as:

   * AST and ALT ≤ 1.5 x ULN
   * Total serum bilirubin level ≤ 1.5 x ULN, except for patients with known Gilbert's syndrome, who are excluded if total bilirubin \> 3.0 x ULN or direct bilirubin \> 1.5 x ULN

Exclusion Criteria:

1. Participant already enrolled and treated in the study
2. Pregnancy, breastfeeding or possibility of becoming pregnant during the study
3. Participation in another interventional study requiring investigational treatment intake at the same time or within 2 weeks or at least 5 halflives (whichever is longer) prior to first dose of IMP (participation in non-interventional registries or epidemiological studies is allowed). In case of biologic agents with a long half life such as CART cells, immune checkpoint antibodies, bispecific antibodies a flat wash-out of 28 days will be acceptable
4. 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 (NCICTCAE, version 4.03).
5. Known carriers of HIV antibodies
6. Known history of significant liver disease
7. Uncontrolled hepatitis B or C infection
8. Known active acute or chronic pancreatitis
9. History of myocardial infarction (MI), unstable angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment
10. Any factors that could increase the risk of QTc prolongation or risk of arrhythmic events.

Primary outcomes:
measure: Incidence of Dose Limiting Toxicity (DLTs)
timeFrame: At the end of cycle 1 (each cycle is 21 or 28 days).
measure: Incidence and severity of AEs
timeFrame: Through study completion, an average of 6 months.
measure: Incidence and severity of SAEs
timeFrame: Through study completion, an average of 6 months.
measure: Number of participants with dose interruptions "will be measured and reported in the Outcome Measure results data table.
timeFrame: Through study completion, an average of 6 months.
measure: Number of participants with dose reductions "will be measured and reported in the Outcome Measure results data table.
timeFrame: Through study completion, an average of 6 months.
measure: Dose intensity
timeFrame: Through study completion, an average of 6 months.
Secondary outcomes:
measure: Anti-leukemic activity
timeFrame: Through study completion, an average of 6 months.
measure: Pharmacokinetic profile of S64315 administered in combination with Venetoclax in plasma: Area Under the Curve (AUC)
timeFrame: From Day 1 of cycle 1 to the end of cycle 2 (each cycle is 21 or 28 days).
measure: Pharmacokinetic profile of S64315 administered in combination with Venetoclax in plasma: Concentration at the end of infusion (Cinf)
timeFrame: From Day 1 of cycle 1 to the end of cycle 2 (each cycle is 21 or 28 days).
measure: Pharmacokinetic profile of S64315 administered in combination with Venetoclax in plasma: terminal half-life (t½z)
timeFrame: From Day 1 of cycle 1 to the end of cycle 2 (each cycle is 21 or 28 days).
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Smilow Cancer Hospital at Yale
state: Connecticut
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center, Houston, TX
state: Texas
city: Melbourne
country: Australia
facility: Peter MacCallum cancer centrer
city: Victoria Park
country: Australia
facility: The Alfred Hospital Department of Haematology
city: Marseille
country: France
facility: Institut Paoli-Calmettes
city: Paris
country: France
facility: Hopital Saint-Antoine
city: Toulouse
country: France
facility: Institut Universitaire du Cancer Toulouse - Oncopole
Study officials:
affiliation: The Alfred Hospital, Melbourne, Victoria
name: Andrew WEI
role: PRINCIPAL_INVESTIGATOR
References: