A phase I study of SAR405838, a novel human double minute 2 (HDM2) antagonist, in patients with solid tumours.
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).



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.



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%.



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.
Erasmus MC Cancer Institute, Rotterdam, The Netherlands. Electronic address: m.dejonge@erasmusmc.nl.
Maja
M
de Jonge
The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: v.d.weger@nki.nl.
Vincent A
VA
de Weger
Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, USA. Electronic address: dicksonm@mskcc.org.
Mark A
MA
Dickson
UMC Utrecht Cancer Center, Utrecht, The Netherlands. Electronic address: M.Langenberg@umcutrecht.nl.
Marlies
M
Langenberg
Gustave Roussy, Villejuif, France. Electronic address: Axel.LECESNE@gustaveroussy.fr.
Axel
A
Le Cesne
Dana-Farber Cancer Institute, Boston, USA. Electronic address: Andrew_Wagner@dfci.harvard.edu.
Andrew J
AJ
Wagner
Sanofi Oncology, Cambridge, USA.
Karl
K
Hsu
Sanofi Oncology, Cambridge, USA. Electronic address: Wei.Zheng2@sanofi.com.
Wei
W
Zheng
Sanofi R&D, Oncology, Vitry-sur-Seine, France. Electronic address: Sandrine.Mace@sanofi.com.
Sandrine
S
Macé
Sanofi R&D, DSAR, Montpellier, France. Electronic address: Gilles.Tuffal@sanofi.com.
Gilles
G
Tuffal
Sanofi Oncology, Cambridge, USA. Electronic address: Koruth.Thomas@sanofi.com.
Koruth
K
Thomas
The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: j.schellens@nki.nl.
Jan H M
JH
Schellens
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000855:Anorexia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008080:Liposarcoma / Q000188:drug therapy / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000473:pathology; D013141:Spiro Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013921:Thrombocytopenia / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced; D055815:Young Adult
D000970:Antineoplastic Agents; D007211:Indoles; D013141:Spiro Compounds; C000593797:SAR405838; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
De-differentiated liposarcoma; HDM2; MDM2; Pharmacodynamics; Pharmacokinetics; SAR405838; Solid tumours; p53