Abstract
10007b Background: WD/DD LPS are a prominent subset (15%) of sarcomas, where cytotoxic treatments have limited activity. MDM2 gene amplifications (and MDM2 overexpression) are potential molecular drivers. We report a neoadjuvant study of RG7112, a small molecule MDM2 antagonist, in chemotherapy-naive primary or relapsed LPS patients (pts) eligible for tumor resection. Methods: Pts with WD/DD LPS were treated orally at 1440 mg/m2 (Ph 1 MTD) QD for 10 days on a 28 day cycle. 3 cycles were planned, followed by complete resection. PK was collected d1 and d8 in cycle 1 (C1), with tumor biopsies collected at baseline and d8. Tumor p53 mutation (AmpliChip), MDM2 amplification (SISH) and expression (PCR), apoptosis (TUNEL) and proliferation (Ki67) were compared pre-treatment and at d8, along with serum MIC-1 (macrophage inhibitory cytokine-1), a p53 transcriptional target. Results: Between June-Dec 2010, 20 pts (12 M/8 F, med. 62y) completed pre-treatment and d8 biopsy. 12 pts had WD and 8 DD LPS. 9 were untreated, 1 metastatic. To date, 13 of 14 evaluable pts had MDM2 amplification, 2/19 had p53 mutations. 13 pts completed > 1 course (med 3); 6 received only C1. High grade adverse events included vomiting (G3-4, n=2), neutropenia (Gr 3-4 n= 3), and thrombocytopenia (Gr 3-4 n=5). Platelet nadir was highly correlated to exposure (R=0.85 and 0.86 for Cmaxss and AUCss, respectively). Increase in serum MIC-1 was also highly associated with exposure (R=0.77). Preliminary tumor analyses are available on 18/20 pts. 9/14 pts had increased TUNEL activity, 9/13 decreased Ki67 by IHC. 2 pts progressed. 7 pts have been resected with 3 patients still on treatment. Conclusions: This neoadjuvant biomarker study of RG7112, a novel MDM2 antagonist in WD/DD LPS, required sequential biopsies, was feasible, and achieved rapid completion of accrual. Preliminary data are consistent with induction of apoptosis and/or decrease in proliferation after treatment with RG7112. Treatment and assessments are ongoing. Biomarker analyses (including evidence of p53 activation by RG7112), PK clinical response data will be presented and updated with biomarker data from tumors obtained at debulking surgery.
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