sar405838 and Lung-Neoplasms

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

There are currently no effective targeted therapies for KRAS mutant cancers. Therapeutic strategies that combine MEK inhibitors with agents that target apoptotic pathways may be a promising therapeutic approach. We investigated combining MEK and MDM2 inhibitors as a potential treatment strategy for KRAS mutant non-small cell lung cancers (NSCLC) and colorectal carcinomas that harbor wild-type TP53. The combination of pimasertib (MEK inhibitor) and SAR405838 (MDM2 inhibitor) was synergistic and induced the expression of PUMA and BIM, led to apoptosis and growth inhibition in vitro, and tumor regression in vivo. Acquired resistance to the combination commonly resulted from the acquisition of TP53 mutations, conferring complete resistance to MDM2 inhibition. In contrast, resistant clones exhibited marked variability in sensitivity to MEK inhibition, which significantly impacted sensitivity to subsequent treatment with alternative MEK inhibitor-based combination therapies. These results highlight both the potential promise and limitations of combining MEK and MDM2 inhibitors for treatment of KRAS mutant NSCLC and colorectal cancers.

Topics: A549 Cells; Animals; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Colorectal Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; Gene Knockdown Techniques; HCT116 Cells; Humans; Indoles; Lung Neoplasms; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mice; Mice, Nude; Mutation; Niacinamide; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Proto-Oncogene Proteins p21(ras); RNA Interference; RNA, Small Interfering; Spiro Compounds; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays