sar405838 and Liposarcoma

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.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Fatigue; Female; Gastrointestinal Neoplasms; Humans; Indoles; Liposarcoma; Lung Neoplasms; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Nausea; Neoplasms; Proto-Oncogene Proteins c-mdm2; Skin Neoplasms; Spiro Compounds; Thrombocytopenia; Vomiting; Young Adult

In tumours that harbour wild-type p53, p53 protein function is frequently disabled by the mouse double minute 2 protein (MDM2, or HDM2 in humans). Multiple HDM2 antagonists are currently in clinical development. Preclinical data indicate that TP53 mutations are a possible mechanism of acquired resistance to HDM2 inhibition; however, this resistance mechanism has not been reported in patients. Utilizing liquid biopsies, here we demonstrate that TP53 mutations appear in circulating cell-free DNA obtained from patients with de-differentiated liposarcoma being treated with an inhibitor of the HDM2-p53 interaction (SAR405838). TP53 mutation burden increases over time and correlates with change in tumour size, likely representing selection of TP53 mutant clones resistant to HDM2 inhibition. These results provide the first clinical demonstration of the emergence of TP53 mutations in response to an HDM2 antagonist and have significant implications for the clinical development of this class of molecules.

Topics: Adult; Antineoplastic Agents; Biopsy; Cell Differentiation; Circulating Tumor DNA; DNA Mutational Analysis; Drug Resistance, Neoplasm; Humans; Indoles; Liposarcoma; Mutation; Proto-Oncogene Proteins c-mdm2; Response Evaluation Criteria in Solid Tumors; Spiro Compounds; Time Factors; Tumor Suppressor Protein p53

Dedifferentiated liposarcoma (DDLPS) is an aggressive malignancy that can recur locally or disseminate even after multidisciplinary care. Genetically amplified and expressed MDM2, often referred to as a "hallmark" of DDLPS, mostly sustains a wild-type p53 genotype, substantiating the MDM2:p53 axis as a potential therapeutic target for DDLPS. Here, we report on the preclinical effects of SAR405838, a novel and highly selective MDM2 small-molecule inhibitor, in both in vitro and in vivo DDLPS models.. The therapeutic effectiveness of SAR405838 was compared with the known MDM2 antagonists Nutlin-3a and MI-219. The effects of MDM2 inhibition were assessed in both in vitro and in vivo. In vitro and in vivo microarray analyses were performed to assess differentially expressed genes induced by SAR405838, as well as the pathways that these modulated genes enriched.. SAR405838 effectively stabilized p53 and activated the p53 pathway, resulting in abrogated cellular proliferation, cell-cycle arrest, and apoptosis. Similar results were observed with Nutlin-3a and MI-219; however, significantly higher concentrations were required. In vitro effectiveness of SAR405838 activity was recapitulated in DDLPS xenograft models where significant decreases in tumorigenicity were observed. Microarray analyses revealed genes enriching the p53 signaling pathway as well as genomic stability and DNA damage following SAR405838 treatment.. SAR405838 is currently in early-phase clinical trials for a number of malignancies, including sarcoma, and our in vitro and in vivo results support its use as a potential therapeutic strategy for the treatment of DDLPS.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Indoles; Liposarcoma; Mice; Microarray Analysis; Neoplasm Recurrence, Local; Piperazines; Proto-Oncogene Proteins c-mdm2; Signal Transduction; Spiro Compounds; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays