Phase I/II Trial of S64315 Plus Azacitidine in Acute Myeloid Leukaemia

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety, tolerability and clinical activity of the combination S64315 with azacitidine in patients with acute myeloid leukaemia.

Official Title
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Phase I/II, International, Multicentre, Open-label, Non-randomised, Non-comparative, Study Evaluating the Safety, Tolerability and Clinical Activity of Intravenously Administered S64315, a Selective Mcl-1 Inhibitor, in Combination With Azacitidine in Patients With Acute Myeloid Leukaemia (AML)

Conditions
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Acute Myeloid Leukaemia

Intervention / Treatment
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* Drug: S 64315 (also referred as MIK665) and azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged ≥ 18 years Patients with cytologically confirmed and documented de novo, secondary or therapy-related AML as defined by World Health Organization 2016 classification (Arber, 2016) excluding acute promyelocytic leukaemia (APL, French American-British M3 classification) with: relapsed or refractory disease and without established alternative therapy, or secondary to MyeloDysplastic Syndrome and without established alternative therapy or, newly diagnosed AML, not previously treated for AML and who are not candidate for intensive chemotherapy due to age or comorbidities. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Adequate haematological, renal and hepatic functions based on the last assessment performed within 7 days prior to the first Investigational Medicinal Product administration. Exclusion Criteria: Previous myeloproliferative syndrome (MPS). Patients previously treated with any Mcl-1 inhibitor. Patients who have not recovered from toxicity of previous anticancer therapy, including Grade ≥ 2 toxicity (except alopecia of any grade) according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI CTCAE) version 5.0, prior to the first IMP administration. Severe or uncontrolled active acute or chronic infection. Uncontrolled hepatitis B or C infection. Known carriers of HIV antibodies, history of significant liver disease, active acute or chronic pancreatitis, active central nervous system disease. Troponin > ULN (Upper Limit of reference range) or Troponin T > ULN if Troponin I cannot be assessed. Clinically significant cardiac dysfunction (including New York Heart Association class ≥II heart failure, Left Ventricular Ejection Fraction (LVEF) < 50% as assessed by echocardiography (ECHO) or Multi-Gated Acquisition (MUGA) scan). QT prolongation defined as QTc (QT interval corrected for heart rate) interval (corrected with Fridericia's formula) > 450 ms for males and > 470 ms for females, obtained from triplicate 12-lead ECG. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age. Uncontrolled arterial hypertension (systolic blood pressure (SBP) > 150 mmHg or diastolic blood pressure (DBP) > 95 mmHg).

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: S64315 (also referred as MIK665) with azacitidine<br> | Drug: S 64315 (also referred as MIK665) and azacitidine<br>* The combination treatment at the planned doses may be preceded by a 2-week Lead-In Dose period of S64315 (fixed dose) administered via intravenous (IV) infusion over at least 2 hours. During the combination treatment period S64315 will be administered according to a dose escalation scheme starting at 50 mg up to 250 mg might be explored. The schedule will be a 21-day cycle with a weekly regimen for S64315 and a daily regimen of azacitidine administered at 75 mg/m² via subcutaneous (SC) injection for 7 days from D1 to D7 of each cycle followed by a rest period of 21 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity (DLT) (Phase I - dose escalation) | Incidence of DLTs starting from the Lead-In Dose period to the end of the first cycle of treatment of S64315 in combination with azacitidine. | Day -13 to Cycle 1 Day 28 (each cycle is 28 days) | 
| Incidence and severity of Adverse Events (AEs) (Phase I - dose escalation) | Incidence and severity of AEs and SAEs according to NCI CTCAE v5.0 | an average of 6 months | 
| Incidence and severity of Serious Adverse Event (SAEs) (Phase I - dose escalation) | Incidence and severity of SAEs according to NCI CTCAE v5.0 | Day -13 up to 30 calendar days after the patient's last study visit | 
| Number of participants with dose interruptions (Phase I - dose escalation) |  | Through study completion, an average of 6 months | 
| Number of participants with dose reductions (Phase I - dose escalation) |  | Through study completion, an average of 6 months | 
| Dose intensity (Phase I - dose escalation) |  | Through study completion, an average of 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation) | Overall survival (OS) | Through study completion, an average of 6 months | 
| Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation) | Duration of response (DOR) | Through study completion, an average of 6 months | 
| Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation) | Best overall response (BOR) | Through study completion, an average of 6 months | 
| Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation) | Progression-free survival (PFS) | Through study completion, an average of 6 months | 
| Assess anti-leukemic activity of S64315 in combinaison with azacitidine (Phase I - dose escalation) | Disease-free survival (DFS) | Through study completion, an average of 6 months | 
| Pharmacokinetic profile of S64315 administered in combination with Azacitidine in plasma: Area Under the Curve (AUC) (Phase I - dose escalation) |  | At Day -13, Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 3, Cycle 1 Day 5, Cycle 1 Day 7 and Cycle 1 Day 9 (each cycle is 28 days) | 
| Pharmacokinetic profile of S64315 administered in combination with Azacitidine in plasma: maximum Concentration (Cmax) (Phase I - dose escalation) |  | At Day -13, Cycle 1 Day 1, Cycle 1 Day 2, Cycle 1 Day 3, Cycle 1 Day 5, Cycle 1 Day 7 and Cycle 1 Day 9 (each cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukaemia, Oncology, Mcl-1 inhibitor, Azacitidine, Combination, Phase I/II, International, Safety, Maximum tolerated dose