Ashley Bruns

Abstract Purpose: The Wee1 kinase inhibitor adavosertib abrogates cell-cycle arrest, leading to cell death. Prior testing of twice-daily adavosertib in patients with advanced solid tumors determined the recommended phase II dose (RPh2D). Here, we report results for once-daily adavosertib. Patients and Methods: A 3 + 3 dose-escalation design was used, with adavosertib given once daily on days 1 to 5 and 8 to 12 in 21-day cycles. Molecular biomarkers of Wee1 activity, including tyrosine 15–phosphorylated Cdk1/2 (pY15-Cdk), were assessed in paired tumor biopsies. Whole-exome sequencing and RNA sequencing of remaining tumor tissue identified potential predictive biomarkers. Results: Among the 42 patients enrolled, the most common toxicities were gastrointestinal and hematologic; dose-limiting toxicities were grade 4 hematologic toxicity and grade 3 fatigue. The once-daily RPh2D was 300 mg. Six patients (14%) had confirmed partial responses: four ovarian, two endometrial. Adavosertib plasma exposures were similar to those from twice-daily dosing. On cycle 1 day 8 (pre-dose), tumor pY15-Cdk levels were higher than baseline in four of eight patients, suggesting target rebound during the day 5 to 8 dosing break. One patient who progressed rapidly had a tumor WEE1 mutation and potentially compensatory PKMYT1 overexpression. Baseline CCNE1 overexpression occurred in both of two responding patients, only one of whom had CCNE1 amplification, and in zero of three nonresponding patients. Conclusions: We determined the once-daily adavosertib RPh2D and observed activity in patients with ovarian or endometrial carcinoma, including two with baseline CCNE1 mRNA overexpression. Future studies will determine whether CCNE1 overexpression is a predictive biomarker for adavosertib.

Abstract Purpose: MuscadinePlus (MPX), a commercial preparation of pulverized muscadine grape skin, was evaluated as a therapeutic option for men with biochemically recurrent (BCR) prostate cancer wishing to defer androgen deprivation therapy. Experimental Design: This was a 12-month, multicenter, placebo-controlled, two-dose, double-blinded trial of MPX in 125 men with BCR prostate cancer, powered to detect a PSA doubling time (PSADT) difference of 6 months (low dose) and 12 months (high dose) relative to placebo. Participants were stratified (baseline PSADT, Gleason score) and randomly assigned 1:2:2 to receive placebo, 500 mg MPX (low), or 4,000 mg MPX (high) daily. Correlates included superoxide dismutase-2 (SOD2) genotype, lipid peroxidation, and polyphenol pharmacokinetics. Results: The evaluable population included 112 patients, all treated for at least 6 months and 62% treated for 12 months. No significant difference was found in PSADT change between control and treatment arms (P = 0.81): control 0.9 months (n = 20; range, 6.7–83.1), low dose 1.5 months (n = 52; range, 10.3–87.2), high dose 0.9 months (n = 40; range, 27.3–88.1). One high-dose patient experienced objective response. No drug-related CTCAE grade 3–4 adverse events were seen. In a preplanned exploratory analysis, PSADT pre-to-post increase was significant in the 27 (26%) genotyped patients with SOD2 Alanine/Alanine genotype (rs4880 T>C polymorphism) on MPX (pooled treatment arms; 6.4 months, P = 0.02), but not in control (1.8 months, P = 0.25). Conclusions: Compared with placebo, MPX did not significantly prolong PSADT in BCR patients over two different doses. Exploratory analysis revealed a patient population with potential benefit that would require further study. Clin Cancer Res; 24(2); 306–15. ©2017 AACR.

PurposeSoft-tissue sarcomas (STS) are a rare, heterogeneous group of mesenchymal tumors. For decades the mainstay of treatment for advanced, unresectable STS has been palliative chemotherapy. High levels of activated MET receptor have been reported in various sarcoma cell lines, together with elevated vascular endothelial growth factor (VEGF) levels in patients with STS, suggesting that dual targeting of the VEGF and MET pathways with the multi-receptor tyrosine kinase inhibitor cabozantinib would result in clinical benefit in this population.Patients and methodsWe performed an open-label, multi-institution, single-arm phase II trial of single-agent cabozantinib in adult patients with advanced STS and progressive disease after at least 1 standard line of systemic therapy. Patients received 60 mg oral cabozantinib once daily in 28-day cycles, and dual primary endpoints of overall response rate and 6-month progression-free survival (PFS) were assessed. Changes in several circulating biomarkers were assessed as secondary endpoints.ResultsSix (11.1%; 95% CI, 4.2%-22.6%) of the 54 evaluable patients enrolled experienced objective responses (all partial responses). Six-month PFS was 49.3% (95% CI, 36.2%-67.3%), with a median time on study of 4 cycles (range, 1-99). The most common grade 3/4 adverse events were hypertension (7.4%) and neutropenia (16.7%). Patients' levels of circulating hepatocyte growth factor (HGF), soluble MET, and VEGF-A generally increased after a cycle of therapy, while soluble VEGFR2 levels decreased, regardless of clinical outcome.ConclusionsCabozantinib single-agent antitumor activity was observed in patients with selected STS histologic subtypes (alveolar soft-part sarcoma, undifferentiated pleomorphic sarcoma, extraskeletal myxoid chondrosarcoma, and leiomyosarcoma) highlighting the biomolecular diversity of STS.