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

Study Overview
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Brief Summary
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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.

Official Title
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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).

Conditions
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Acute Myeloid Leukaemia

Intervention / Treatment
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* Combination Product: S 64315 (also referred as MIK665) and venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged ≥ 18 years; 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 Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Able to comply with study procedures 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 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: Participant already enrolled and treated in the study Pregnancy, breastfeeding or possibility of becoming pregnant during the study 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 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). Known carriers of HIV antibodies Known history of significant liver disease Uncontrolled hepatitis B or C infection Known active acute or chronic pancreatitis History of myocardial infarction (MI), unstable angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment Any factors that could increase the risk of QTc prolongation or risk of arrhythmic events.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: S64315 and venetoclax administered in combination<br> | Combination Product: S 64315 (also referred as MIK665) and venetoclax<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicity (DLTs) |  | At the end of cycle 1 (each cycle is 21 or 28 days). | 
| Incidence and severity of AEs |  | Through study completion, an average of 6 months. | 
| Incidence and severity of SAEs |  | Through study completion, an average of 6 months. | 
| 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. | 
| 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. | 
| Dose intensity |  | Through study completion, an average of 6 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| 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). | 
| 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). | 
| 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). |