Phase I Dose Escalation Study of Intravenously Administered S64315 in Combination With Orally Administered Venetoclax in Patients With Acute Myeloid Leukaemia.

Acute Myeloid Leukaemia Clinical Trial

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).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03672695
• Other study ID #: CL1-64315-002
• Secondary ID: 2018-001809-88
• Status: Completed
• Phase: Phase 1
• Start date: November 28, 2018
• Est. completion date: May 30, 2023

Study information

• Verified date: February 2024
• Source: Servier
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. completion date: May 30, 2023
• Est. primary completion date: November 12, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukaemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Combination Product:
• S 64315 (also referred as MIK665) and venetoclax
The treatment combination period can only begin after the planned dose of venetoclax is reached. Depending on the administration dosing schedule, the combination treatment at the planned doses may be preceded by a 2-week Lead-In Dose period of S64315 (fixed dose) during which the patient continues to receive venetoclax daily. Once the planned dose of both drugs is reached the schedule will be a 21-day cycle with a weekly regimen for S64315 and a daily regimen for venetoclax. S64315 should be administered 2 to 4 hours after venetoclax intake, via IV infusion. The dose escalation will start at 50 mg once a week and doses up to 250 mg once a week might be explored. Venetoclax will be administered orally once a day. The dose escalation will start at 100 mg daily and doses up to 600 mg daily might be explored. Venetoclax must be taken with a meal (ideally during breakfast) in order to avoid reduced efficacy.

Locations

Country	Name	City	State
Australia	Peter MacCallum cancer centrer	Melbourne
Australia	The Alfred Hospital Department of Haematology	Victoria Park
France	Institut Paoli-Calmettes	Marseille
France	Hopital Saint-Antoine	Paris
France	Institut Universitaire du Cancer Toulouse - Oncopole	Toulouse
United States	The University of Texas MD Anderson Cancer Center, Houston, TX	Houston	Texas
United States	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, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Dose Limiting Toxicity (DLTs)		At the end of cycle 1 (each cycle is 21 or 28 days).
Primary	Incidence and severity of AEs		Through study completion, an average of 6 months.
Primary	Incidence and severity of SAEs		Through study completion, an average of 6 months.
Primary	Number of participants with dose interruptions "will be measured and reported in the Outcome Measure results data table.		Through study completion, an average of 6 months.
Primary	Number of participants with dose reductions "will be measured and reported in the Outcome Measure results data table.		Through study completion, an average of 6 months.
Primary	Dose intensity		Through study completion, an average of 6 months.
Secondary	Anti-leukemic activity	Using blood, bone marrow aspirate and medullary biopsy if available according to ELN 2017 criteria	Through study completion, an average of 6 months.
Secondary	Pharmacokinetic profile of S64315 administered in combination with Venetoclax in plasma: Area Under the Curve (AUC)		From Day 1 of cycle 1 to the end of cycle 2 (each cycle is 21 or 28 days).
Secondary	Pharmacokinetic profile of S64315 administered in combination with Venetoclax in plasma: Concentration at the end of infusion (Cinf)		From Day 1 of cycle 1 to the end of cycle 2 (each cycle is 21 or 28 days).
Secondary	Pharmacokinetic profile of S64315 administered in combination with Venetoclax in plasma: terminal half-life (t½z)		From Day 1 of cycle 1 to the end of cycle 2 (each cycle is 21 or 28 days).

External Links

•   Find Results on Servier Clinical Trial Data website
•   Link to Lay Summary and Results Summary