Dose Escalation, Safety and Pharmacokinetic Study of SAR103168 in Patients With Myelogenous Leukemia - Full Text View

Sponsor:	Sanofi-Aventis
Information provided by:	Sanofi-Aventis
ClinicalTrials.gov Identifier:	NCT00981240

Purpose

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 evaluate the inhibition of signal transducer and activators of transcription (STAT5) phosphorylation as a surrogate pharmacodynamic end point of 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	Intervention	Phase
Acute Myelogenous Leukemia	Drug: SAR103168	Phase I

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Single Group Assignment, Safety Study
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 Myelogenous Leukemia.

Resource links provided by NLM:

MedlinePlus related topics: Leukemia, Adult Acute Leukemia, Adult Chronic

U.S. FDA Resources

Further study details as provided by Sanofi-Aventis:

Primary Outcome Measures:

Incidence of DLTs during the initial 4-week period of treatment [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]
Pharmacokinetic parameters of SAR103168 [ Time Frame: First course: Days 1, 2, 5, 6, and 8; Second and subsequent courses: Day 5 only ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Global safety profile of SAR103168 based on treatment emergent adverse events (TEAEs), serious adverse events (SAEs), deaths, laboratory abnormalities [ Time Frame: Treatment period up to 1 year ] [ Designated as safety issue: Yes ]
Preliminary evidence of anti-leukemia activity [ Time Frame: Treatment period up to 1 year ] [ Designated as safety issue: No ]
Degree of inhibition of STAT5 phosphorylation at each dose level [ Time Frame: First course: Days 1, 2, 5, 8, and 12 to 14; Second and subsequent courses: Days 1, 8, and 12 to 14 ] [ Designated as safety issue: No ]
Pharmacokinetic parameters of midazolam in the absence and the presence of SAR103168. [ Time Frame: During second (Day-1 and Day 5) and forth course (Day 5) ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	40
Study Start Date:	September 2009
Estimated Study Completion Date:	March 2011
Estimated Primary Completion Date:	February 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Dose escalation: Experimental 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

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients with de novo or secondary acute myelogenous leukemia (AML) except acute promyelocytic leukemia meeting one of the following conditions:

Primary resistant or relapsed AML; in case of first relapse the complete remission duration should be less than 12 months. If relapse failed at least one prior salvage attempt, the complete remission duration may be more than 12 months.
Into the expanded cohort at the MTD, previously untreated AML in patients over age 60 with poor- risk cytogenetics who are not eligible for or do not accept induction chemotherapy may also be included.

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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00981240

Contacts

Contact: For site information, send an email with site number to

GV-contact-us@sanofi-aventis.com

Locations

United States, New York
Sanofi-aventis Investigational Site Number 840002	Recruiting
New York, New York, United States, 10021
United States, Texas
Sanofi-aventis Investigational Site Number 840001	Recruiting
Houston, Texas, United States, 77030

Sponsors and Collaborators

Sanofi-Aventis

Investigators

Principal Investigator:

Farhad Ravandi-Kashani, MD

M.D. Anderson Cancer Center, Houston, Texas

More Information

No publications provided

Responsible Party:	sanofi-aventis ( International Clinical Development, Study Director )
Study ID Numbers:	TED10416
Study First Received:	September 21, 2009
Last Updated:	February 8, 2010
ClinicalTrials.gov Identifier:	NCT00981240 History of Changes
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:

Leukemia
Neoplasms
Neoplasms by Histologic Type
Leukemia, Myeloid
Leukemia, Myeloid, Acute

ClinicalTrials.gov processed this record on February 08, 2010