Dose Escalation, Safety and Pharmacokinetic Study of SAR103168 in Patients Refractory/ Relapsed Acute Leukemias or High-risk Myelodysplastic Syndromes

Study Overview
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Brief Summary
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Primary objectives: To determine the maximum tolerated dose (MTD) of SAR103168 and to characterize the dose limiting toxicities (DLTs) in the proposed dose regimen To evaluate the pharmacokinetic (PK) profile of SAR103168 Secondary objectives: To characterize the global safety profile of SAR103168 To evaluate preliminary anti-leukemia activity To investigate the potential induction effect on CYP3A4 and persistence of this effect by using oral midazolam as a probe substrate in patients enrolled into the expanded cohort at the MTD To determine the metabolic pathways of SAR103168 and identify the chemical structures of metabolites To determine the potential impact of SAR103168 on the QTc interval in patients enrolled at the MTD

Detailed Description
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Patients will receive the study drug until unacceptable toxicity, clinically significant disease progression, withdrawal of consent or investigator's decision, and for a maximum of 1 year.

Official Title
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A Dose Escalation Safety and Pharmacokinetic Study of SAR103168 Administered as a Single Agent by Intravenous Infusion, Once Daily for 5 Consecutive Days to Patients With Refractory/ Relapsed Acute Leukemias or High-risk Myelodysplastic Syndromes.

Conditions
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Acute Myelogenous Leukemia

Intervention / Treatment
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* Drug: SAR103168


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with refractory/relapsed acute leukemias or high-risk myelodysplastic syndromes with no curative option available including any of the following: Patients with de novo or secondary acute myelogenous leukemia (AML) (except acute promyelocytic leukemia), meeting one of the following conditions: Refractory or relapsed AML; In case of first relapse the CR duration should be less than 12 months. If the relapse failed at least one prior salvage attempt, the CR duration may be more than 12 months. Into the expanded cohort at the MTD, previously untreated AML patients over age 60 with poor- risk cytogenetics who are not eligible for or do not accept induction chemotherapy may also be included. Patients with refractory/relapsed acute lymphoblastic leukemia (ALL) Patients with high-risk myelodysplastic syndrome (MDS) as defined by the International Prognostic Scoring System Patients with chronic myeloid leukemia in blast phase (CML-BP) Exclusion Criteria: performance status > 2 Active uncontrolled central nervous system leukemia Cytotoxic therapy within 2 weeks prior to the first dose of SAR103168. For the non cytotoxic agents/investigational drugs this washout period should be at least 2 weeks or at least 5 half-lives whichever is longer. Hydroxyurea must be stopped at least 24 hours prior to the first dose of SAR103168 Lack of recovery from toxicities from prior therapies to grade < 1 White blood cells > 30 x 10^9/L prior to the first dose of SAR103168 Prior allogeneic stem cell transplantation or donor lymphocytes infusion within 3 months preceding the first dose of SAR103168 Any of the following within 6 months prior to the first dose of SAR103168: Myocardial infarction, congestive heart failure, documented angina pectoris, arrhythmia requiring medication (in particular atrial fibrillation or flutter), severe conduction disorder (second or third atrio-ventricular block, pacemaker), coronary/peripheral artery bypass graft surgery Arterial or venous thromboembolism, deep venous thrombosis Left ventricular ejection fraction < 50% by echocardiography or multiple gated acquisition scan Cardiac ischemia on 12-lead ECG Baseline QTc-interval > 500 msec Hypertension uncontrolled with appropriate therapy Active infection (viral, bacterial or fungal) uncontrolled with appropriate therapy Major surgery within 6 weeks prior to the first dose of SAR103168 Poor organ function defined by one of the following: Total bilirubin > 1.5 x upper limit of normal (ULN) unless related to leukemia (i.e. hemolysis) or Gilbert's syndrome Aspartate aminotransferase (AST), alanine aminotransferase (ALT) > 2.5 x ULN Serum creatinine > 1.5 x ULN or calculated creatinine clearance < 50 mL/min Patients under treatment with potent inhibitors of CYP3A4 unless these treatments may be stopped at least 3 days prior to the first dose of SAR103168 Patients under treatment with CYP3A4 or CYP2C9 inducers, unless these treatments may be stopped at least 3 days prior to the first dose of SAR103168 Pregnant or breast-feeding women or refusal to use adequate contraceptive method, when applicable.

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: Dose escalation<br>Cohorts of 3 to 6 patients will be included at each dose level. The starting dose is 1.2mg/m2/day. The dose will be increased in new cohorts of patients according to toxicities observed during the first 4-week treatment period. The escalation process will continue until the MTD is determined. Additional 15 patients will be included at the MTD. | Drug: SAR103168<br>* Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of DLTs during the initial 4-week period of treatment |  | 4 weeks | 
| Pharmacokinetic parameters of SAR103168 |  | First course: Days 1, 2, 5, 6, and 8; Second and subsequent courses: Day 5 only | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global safety profile of SAR103168 based on treatment emergent adverse events (TEAEs), serious adverse events (SAEs), deaths, laboratory abnormalities |  | Treatment period up to 1 year | 
| Preliminary evidence of anti-leukemia activity |  | Treatment period up to 1 year | 
| Pharmacokinetic parameters of midazolam in the absence and the presence of SAR103168. |  | During second (Day-1 and Day 5) and forth course (Day 5) |