BACKGROUND: We report a proof-of-mechanism study of RG7112, a small-molecule 
MDM2 antagonist, in patients with chemotherapy-naive primary or relapsed 
well-differentiated or dedifferentiated MDM2-amplified liposarcoma who were 
eligible for resection.
METHODS: Patients with well-differentiated or dedifferentiated liposarcoma were 
enrolled at four centres in France. Patients received up to three 28-day 
neoadjuvant treatment cycles of RG7112 1440 mg/m(2) per day for 10 days. If a 
patient progressed at any point after the first cycle, the lesion was resected 
or, if unresectable, an end-of-study biopsy was done. The primary endpoint was 
to assess markers of RG7112-dependent MDM2 inhibition and P53 pathway activation 
(P53, P21, MDM2, Ki-67, macrophage inhibitory cytokine-1 [MIC-1], and 
apoptosis). All analyses were per protocol. This trial is registered with 
EudraCT, number 2009-015522-10.
RESULTS: Between June 3, and Dec 14, 2010, 20 patients were enrolled and 
completed pretreatment and day 8 biopsies. 18 of 20 patients had TP53 wild-type 
tumours and two carried missense TP53 mutations. 14 of 17 assessed patients had 
MDM2 gene amplification. Compared with baseline, P53 and P21 concentrations, 
assessed by immunohistochemistry, had increased by a median of 4·86 times (IQR 
4·38-7·97; p=0·0001) and 3·48 times (2·05-4·09; p=0·0001), respectively, at day 
8 (give or take 2 days). At the same timepoint, relative MDM2 mRNA expression 
had increased by a median of 3·03 times (1·23-4·93; p=0·003) that at baseline. 
The median change from baseline for Ki-67-positive tumour cells was -5·05% (IQR 
-12·55 to 0·05; p=0·01). Drug exposure correlated with blood concentrations of 
MIC-1 (p<0·0001) and haematological toxicity. One patient had a confirmed 
partial response and 14 had stable disease. All patients experienced at least 
one adverse event, mostly nausea (14 patients), vomiting (11 patients), asthenia 
(nine patients), diarrhoea (nine patients), and thrombocytopenia (eight 
patients). There were 12 serious adverse events in eight patients, the most 
common of which were neutropenia (six patients) and thrombocytopenia (three 
patients).
DISCUSSION: MDM2 inhibition activates the P53 pathway and decreases cell 
proliferation in MDM2-amplified liposarcoma. This study suggests that it is 
feasible to undertake neoadjuvant biopsy-driven biomarker studies in 
liposarcoma.
FUNDING: F Hoffmann-La Roche.