A phase I study of SAR405838, a novel human double minute 2 (HDM2) antagonist,in patients with solid tumours
Affiliation:
1. Erasmus MC Cancer Institute, Rotterdam, The Netherlands;2. The Netherlands Cancer Institute, Amsterdam, The Netherlands;3. Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, USA;4. UMC Utrecht Cancer Center, Utrecht, The Netherlands;5. Gustave Roussy, Villejuif, France;6. Dana-Farber Cancer Institute, Boston, USA;7. Sanofi Oncology, Cambridge, USA;8. Sanofi R&D, Oncology, Vitry-sur-Seine, France;9. Sanofi R&D, DSAR, Montpellier, France;1. Princess Margaret Cancer Center, University Health Network, Toronto, Canada;2. Department of Medical Biophysics, University of Toronto, Toronto, Canada;3. Department of Radiation Oncology, University of Toronto, Toronto, Canada;1. Department of Pulmonary, Critical Care and Sleep Medicine, Malcom Randall VA Medical Center, University of Florida, Gainesville, FL;2. Department of Anatomic and Clinical Pathology, Malcom Randall VA Medical Center, University of Florida, Gainesville, FL;3. Department of Medicine, West Virginia University Charleston Division, Charleston, WV;1. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas;2. Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas;3. Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas;4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee;5. Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China;6. Key Laboratory of Food Safety Research Center, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China;7. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota;1. Harvard Medical School, Boston, MA 02115, USA;2. Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA;3. Department of Surgery, Massachusetts General Hospital, Boston, MA, USA;4. Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA;5. Basic and Translational Research Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA;1. RTI Health Solutions, Research Triangle Park, NC;;2. Genentech Inc., South San Francisco, CA;;3. The Leukemia & Lymphoma Society, Rye Brook, NY; and;4. Lymphoma Research Foundation, New York, NY
Abstract:
PurposeIn tumours with wild-type TP53, the tumour-suppressive function of p53 is frequently inhibited by HDM2. This phase I, dose-escalating study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and pharmacodynamics of SAR405838, an HDM2 inhibitor, in patients with advanced solid tumours (NCT01636479).MethodsIn dose escalation, patients with any locally advanced/metastatic solid tumour with TP53 mutation prevalence below 40%, or documented as TP53 wild-type, were eligible. In the MTD expansion cohort, only patients with de-differentiated liposarcoma were included. Primary end-points were MTD and efficacy in the MTD expansion cohort. Secondary end-points included safety, pharmacokinetics and pharmacodynamics biomarkers.ResultsSeventy-four patients were treated with SAR405838 (50–800 mg once daily [QD], 800–1800 mg weekly and 1800 mg twice weekly). Two patients treated with SAR405838 400 mg QD had thrombocytopaenia as a dose-limiting toxicity (DLT). The MTD for the QD schedule of SAR405838 was 300 mg QD. No DLTs were observed with the weekly schedule; one patient had a DLT of nausea with the 1800 mg twice-weekly dose. Treatment with SAR405838 was associated with increased plasma MIC-1, reflecting p53 pathway activation. In the de-differentiated liposarcoma MTD cohort, 89% of the patients had HDM2 amplification at baseline and no TP53 mutations were observed; best response was stable disease in 56% and progression-free rate at 3 months was 32%.ConclusionSAR405838 had an acceptable safety profile with limited activity in patients with advanced solid tumours. The MTD of SAR405838 was 300 mg QD; MTD was not reached with the weekly schedule.
