Phase I Study of S64315 Administred Intravenously in Patients With Acute Myeloid Leukaemia or Myelodysplastic Syndrome

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Acute Myeloid Leukaemia (AML), Myelodysplastic Syndrome (MDS)

Intervention / Treatment
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* Drug: S64315 once a week
* Drug: S64315 twice a week


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, 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.

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: S64315 (also referred as MIK665) administered once a week<br> | Drug: S64315 once a week<br>* S64315 will be administered via i.v. infusion from 30 minutes and up to 3 hours once every week (21- day cycle), the starting dose is 50 mg. As data emerge during the study, the infusion duration and alternative dosing regimen may be changed.<br>* Other names: MIK665;|
| Experimental: S64315 (also referred as MIK665) administered twice a week<br> | Drug: S64315 twice a week<br>* S64315 will be administered via i.v. infusion from 30 minutes and up to 3 hours twice every week (28- day cycle), the starting dose is 50 mg. As data emerge during the study, the infusion duration and alternative dosing regimen may be changed.<br>* Other names: MIK665;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of DLTs during the first cycle of treatment with single agent S64315 |  | 21-day cycle 1 | 
| Safety tolerance profile of S64315 assessed by:Incidence and severity of AEs |  | From first dose until 30 days after the last dose administration | 
| Tolerability: Dose interruptions |  | From first dose until 30 days after the last dose administration | 
| Tolerability: Dose reductions |  | From first dose until 30 days after the last dose administration | 
| Tolerability: Dose intensity |  | From first dose until 30 days after the last dose administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration at the end of infusion (C inf) in plasma |  | D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6. | 
| Cumulative amount of a compound excreted in the urine (Ae) |  | only D1 of cycle 1 | 
| Preliminary efficacy assessment according to Cheson criteria (adapted for each disease) |  | From first dose until 30 days after the last dose administration | 
| Time corresponding to end of infusion (tinf/tend) in plasma |  | D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6. | 
| Area under the concentration-time curve from zero (time of drug administration) to tlast (AUC last) in plasma |  | D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6. | 
| Time corresponding to Clast (tlast) in plasma. |  | D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6. | 
| Last quantifiable observed concentration (Clast) in plasma |  | D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6. | 
| Area Under the Curve (AUC) in plasma |  | D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6. | 
| Terminal elimination half-life (t½,z) in plasma |  | D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6. | 
| total Clearance (CL) |  | D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6. | 
| Volume of distribution at steady-state (Vss) in plasma |  | D1 and D2 of cycle 1 and 2, D15 and D16 of cycle 1 and D1 from cycle 3 to cycle 6. | 
| Ae expressed as a percentage of the dose (fe) in urine |  | only D1 of cycle 1 | 
| Renal clearance (CLR) |  | only D1 of cycle 1 |