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

Sponsor

Sanofi (Industry)

Overall Status

Completed

CT.gov ID

NCT00981240

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia	Drug: SAR103168	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

30 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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.

Study Start Date :

Sep 1, 2009

Actual Primary Completion Date :

Jan 1, 2012

Actual Study Completion Date :

Feb 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose escalation 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 Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous infusion

Arm

Intervention/Treatment

Experimental: Dose escalation

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

Pharmaceutical form: Concentrate for solution for infusion Route of administration: Intravenous infusion

Outcome Measures

Primary Outcome Measures

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

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)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sanofi-Aventis Investigational Site Number 840003	Atlanta	Georgia	United States	30322
2	Sanofi-Aventis Investigational Site Number 840002	New York	New York	United States	10021
3	Sanofi-Aventis Investigational Site Number 840001	Houston	Texas	United States	77030