Maja de Jonge1, Vincent A de Weger2, Mark A Dickson3, Marlies Langenberg4, Axel Le Cesne5, Andrew J Wagner6, Karl Hsu7, Wei Zheng8, Sandrine Macé9, Gilles Tuffal10, Koruth Thomas11, Jan H M Schellens12. 1. Erasmus MC Cancer Institute, Rotterdam, The Netherlands. Electronic address: m.dejonge@erasmusmc.nl. 2. The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: v.d.weger@nki.nl. 3. Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, USA. Electronic address: dicksonm@mskcc.org. 4. UMC Utrecht Cancer Center, Utrecht, The Netherlands. Electronic address: M.Langenberg@umcutrecht.nl. 5. Gustave Roussy, Villejuif, France. Electronic address: Axel.LECESNE@gustaveroussy.fr. 6. Dana-Farber Cancer Institute, Boston, USA. Electronic address: Andrew_Wagner@dfci.harvard.edu. 7. Sanofi Oncology, Cambridge, USA. 8. Sanofi Oncology, Cambridge, USA. Electronic address: Wei.Zheng2@sanofi.com. 9. Sanofi R&D, Oncology, Vitry-sur-Seine, France. Electronic address: Sandrine.Mace@sanofi.com. 10. Sanofi R&D, DSAR, Montpellier, France. Electronic address: Gilles.Tuffal@sanofi.com. 11. Sanofi Oncology, Cambridge, USA. Electronic address: Koruth.Thomas@sanofi.com. 12. The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: j.schellens@nki.nl.
Abstract
PURPOSE: In 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). METHODS: In 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. RESULTS: Seventy-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%. CONCLUSION: SAR405838 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.
PURPOSE: In 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). METHODS: In 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. RESULTS: Seventy-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%. CONCLUSION:SAR405838 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.
Authors: J Cornillie; A Wozniak; H Li; Y K Gebreyohannes; J Wellens; D Hompes; M Debiec-Rychter; R Sciot; P Schöffski Journal: Clin Transl Oncol Date: 2019-06-14 Impact factor: 3.405