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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT00981240
First received: September 21, 2009
Last updated: March 26, 2012
Last verified: March 2012
  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 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 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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.

Resource links provided by NLM:


Further study details as provided by Sanofi:

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 ]
  • 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 ]

Enrollment: 30
Study Start Date: September 2009
Study Completion Date: February 2012
Primary Completion Date: January 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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


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

Locations
United States, Georgia
Sanofi-Aventis Investigational Site Number 840003
Atlanta, Georgia, United States, 30322
United States, New York
Sanofi-Aventis Investigational Site Number 840002
New York, New York, United States, 10021
United States, Texas
Sanofi-Aventis Investigational Site Number 840001
Houston, Texas, United States, 77030
Sponsors and Collaborators
Sanofi
Investigators
Principal Investigator: Farhad Ravandi-Kashani, MD M.D. Anderson Cancer Center, Houston, Texas
  More Information

No publications provided

Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00981240     History of Changes
Other Study ID Numbers: TED10416
Study First Received: September 21, 2009
Last Updated: March 26, 2012
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions

ClinicalTrials.gov processed this record on April 16, 2014