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.

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

开始日期2009-09-01

申办/合作机构

Sanofi

100 项与 SAR-103168 相关的临床结果

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100 项与 SAR-103168 相关的转化医学

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100 项与 SAR-103168 相关的专利（医药）

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项与 SAR-103168 相关的文献（医药）

2015-02-01·Leukemia & Lymphoma4区 · 医学

Phase I trial of SAR103168, a novel multi-kinase inhibitor, in patients with refractory/relapsed acute leukemia or high-risk myelodysplastic syndrome

4区 · 医学

Article

作者: H. Jean Khoury ; Eric J. Feldman ; Harry Miao ; Martha Arellano ; Ellen K. Ritchie ; Wilena Session ; Wei Zheng ; Stefan Faderl ; Elias Jabbour ; Farhad Ravandi ; Gail J. Roboz ; J. Gilmour Morrison

There is no effective treatment for relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We conducted a phase I dose escalation trial of SAR103168, a novel multi-targeted kinase inhibitor with activity against the Src kinase family, the BCR-Abl kinase and several angiogenic receptor kinases. Twenty-nine patients 18-83 years old were treated with SAR103168. Pharmacokinetics was characterized by plasma peak concentration (Cmax) at the end of the infusion, followed by a biphasic decline in the elimination profile. Adverse events were as expected for the patient population and there were no individual toxicities specific to SAR103168. Due to the unpredictable nature of drug exposure, the sponsor decided to discontinue the study prior to reaching the maximum tolerated dose.

2013-07-01·Leukemia & Lymphoma4区 · 医学

SAR103168: a tyrosine kinase inhibitor with therapeutic potential in myeloid leukemias

4区 · 医学

Article

作者: Bourrié, Bernard ; Demur, Cécile ; Larroze-Chicot, Philippe ; Bouaboula, Monsif ; Morrison, J. Gil ; Casellas, Pierre ; Yu, Kin ; Jegham, Samir ; Perreaut, Pierre ; Cosnier-Pucheu, Sylvie ; Zilberstein, Asher ; Guiot, Cécile ; Hilairet, Sandrine ; Penarier, Geraldine ; Brassard, Diana L. ; Laurent, Guy ; Levit, Mikhail

SAR103168, a tyrosine kinase inhibitor of the pyrido [2,3-d] pyridimidine subclass, inhibited the kinase activities of the entire Src kinase family, Abl kinase, angiogenic receptor kinases (vascular endothelial growth factor receptor [VEGFR] 1 and 2), Tie2, platelet derived growth factor (PDGF), fibroblast growth factor receptor (FGFR) 1 and 3, and epidermal growth factor receptor (EGFR). SAR103168 was a potent Src inhibitor, with 50% inhibitory concentration (IC50) = 0.65 ± 0.02 nM (at 100 μM ATP), targeting the auto-phosphorylation of the kinase domain (Src(260-535)) and activity of the phosphorylated kinase. Phosphorylation of Src, Lyn and Src downstream signaling pathways (PYK2, P-130CAS, FAK, JNK and MAPK) were inhibited in a dose-dependent manner. SAR103168 inhibited the phosphorylation of STAT5 in KG1 cells and fresh cells from patients with acute myeloid leukemia (AML). SAR103168 inhibited proliferation and induced apoptosis in acute and chronic myeloid leukemic cells at nanomolar IC50. SAR103168 induced anti-proliferation of leukemic progenitors (CFU-L) from 29 patients with AML, and > 85% of AML patient samples were sensitive to SAR103168. These antagonist activities of SAR103168 were independent of FLT3 expression. SAR103168 treatment was effective in 50% of high-risk patient samples carrying chromosome 7 abnormalities or complex rearrangement. SAR103168 administration (intravenous or oral) impaired tumor growth and induced tumor regression in animals bearing human AML leukemic cells, correlating with potent inhibition of Src downstream signaling pathways in AML tumors. SAR103168 showed potent anti-tumor activity in SCID (severe combined immunodeficiency) mice bearing AML (KG1, EOL-1, Kasumi-1, CTV1) and chronic myeloid leukemia (CML) (K562) tumors. The combination of cytarabine and SAR103168 showed synergistic activity in AML and CML tumor models. These results highlight the therapeutic potential of SAR103168 in myeloid leukemias and support the rationale for clinical investigations.

100 项与 SAR-103168 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
急性白血病	临床1期	美国	Sanofi	2009-09-01
急性髓性白血病	临床1期	美国	Sanofi	2009-09-01
骨髓增生异常综合征	临床1期	美国	Sanofi	2009-09-01