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Table S1. Plasma pharmacokinetic sampling times Table S2. Identified Alterations, Listed by Patient Table S3. Adverse events reported in {greater than or equal to}10% of patients (safety cohort) Table S4. Grade 3 to 5 adverse events reported in >1 patient (safety cohort) Table S5. Evaluation of Best Overall Response in Patients with Initial Measurable Disease and Evaluable by CA-125 Figure S1. Geometric mean (standard deviation) plasma concentrations of binimetinib (top) and its metabolite AR00426032 (bottom) on cycle 1 days 7, 8, and 15: semi-logarithmic scale (pharmacokinetic set [30 mg BID binimetinib continuous]) Figure S2. Geometric mean (standard deviation) plasma concentrations of binimetinib (top) and its metabolite AR00426032 (bottom) on cycle 1 days 7, 8, and 15: semi-logarithmic scale (pharmacokinetic set [45 mg BID binimetinib continuous]) Figure S3. Geometric mean (standard deviation) plasma concentrations of binimetinib (top) and its metabolite AR00426032 (bottom) on cycle 1 days 1, 8, and 15: semi-logarithmic scale (pharmacokinetic set [45 mg BID binimetinib intermittent]) Figure S4. Representative CT Resolution of Implant in a Complete Responder

Supplemental Figure Legends

Supplemental Figure 1 Species-specific activation of TLR8 by motolimod. Supplemental Figure 2 Full human immune cell reconstitution in NSG-HIS mice. Supplemental Figure 3 Response to PLD + motolimod is not schedule-sensitive in the NSG-HIS mouse. Supplemental Figure 4 Assessment of macrophage-induced apoptosis using motolimod in combination with PLD. Supplemental Figure 5 Isolation of tumor-infiltrating T cells with specific tumor recognition and lysis ex vivo. Supplemental Figure 6 Pharmacokinetic (PK) evaluations. Supplemental Figure 7 Biological efficacy of motolimod in combination with paclitaxel.

Table S1. Subject demographics and baseline characteristics Table S2. Tumor response as assessed by RECIST 1.1 and biochemical response

Purpose: Epithelial ovarian cancer (EOC) is a molecularly diverse disease. MEK inhibition targets tumors harboring MAPK pathway alterations and enhances paclitaxel-induced apoptosis in EOC. This phase Ib study evaluated the MEK inhibitor binimetinib combined with paclitaxel in patients with platinum-resistant EOC.Patients and Methods: Patients received intravenous weekly paclitaxel with oral binimetinib in three different administration schedules. Outcomes were assessed by RECIST and CGIC CA-125 response criteria. Tumor samples were analyzed using next-generation sequencing.Results: Thirty-four patients received ≥1 binimetinib dose. A 30-mg twice-a-day continuous or 45-mg twice-a-day intermittent binimetinib dose was deemed the recommended phase II dose (RP2D) in combination with 80 mg/m2 i.v. weekly paclitaxel. Rate of grade 3/4 adverse events was 65%. The best overall response rate was 18%—one complete (CR) and four partial responses (PR)—among 28 patients with RECIST-measurable disease. Eleven patients achieved stable disease (SD), yielding a clinical benefit rate (CR+PR+SD) of 57%. Response rates, per both RECIST and CA-125 criteria, were highest in the 45-mg twice-a-day continuous cohort and lowest in the 45-mg twice-a-day intermittent cohort. All four evaluable patients with MAPK pathway–altered tumors experienced clinical benefit.Conclusions: The combination of binimetinib and intravenous weekly paclitaxel was tolerable in this patient population. The RP2D of binimetinib in combination with paclitaxel was 30 mg twice a day as a continuous or 45 mg twice a day as an intermittent dose. Although response rates were modest, a higher clinical benefit rate was seen in patients harboring alterations affecting the MAPK pathway. Clin Cancer Res; 24(22); 5525–33. ©2018 AACR.

Supplemental Methods

ObjectiveWe sought to describe clinicopathologic and treatment factors associated with oncologic outcomes in patients with early-stage ovarian clear cell carcinoma undergoing complete staging and in a sub-set of these patients undergoing fertility-conserving surgery.MethodsWe retrospectively identified patients with ovarian clear cell carcinoma initially treated at our institution from January 1, 1996 to March 31, 2020. Survival was estimated using Kaplan–Meier curves and compared by log-rank test. Survival-associated variables were identified by Cox proportional hazards regression.ResultsOf 182 patients, mismatch repair and p53 protein expression were assessed by immunohistochemistry on 82 and 66 samples, respectively. There were no significant differences in progression-free survival or overall survival between mismatch repair-deficient (n=6, including 4 patients with Lynch syndrome; 7.3%) and mismatch repair-proficient patients, whereas aberrant p53 expression (n=3; 4.5%) was associated with worse progression-free (pConclusionsIn patients with completely staged ovarian clear cell carcinoma, those with stage IA/IC1 disease have an excellent prognosis, regardless of chemotherapy. Aberrant p53 expression may portend worse outcomes. Additional investigation is warranted on the safety of fertility conservation in patients with stage IA/IC1 disease.

The current single-arm, open-label trial was designed to evaluate the activity of apitolisib (GDC-0980), a dual phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor, in patients with advanced endometrial cancer (EC).Patients with recurrent or persistent EC who were treated with 1 to 2 prior lines of chemotherapy but no prior PI3K/mTOR inhibitor received oral apitolisib at a dose of 40 mg daily during 28-day cycles until disease progression or intolerable toxicity occurred. Patients with type I/II diabetes who required insulin were excluded. The primary endpoints were progression-free survival (PFS) at 6 months and objective response rate.A total of 56 women were enrolled, including 13 (23%) with well-controlled diabetes. Reasons for discontinuation were disease progression (24 patients; 43%), adverse events (13 patients; 23%), and withdrawal by subject (12 patients; 21%). Grade 3/4 apitolisib-related adverse events were hyperglycemia (46%), rash (30%), colitis (5%), and pneumonitis (4%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The PFS rate at 6 months was 20% (Kaplan-Meier estimate; 95% confidence interval [95% CI], 7%-33%). The objective response rate was 6% (confirmed). The median PFS was 3.5 months (95% CI, 2.7-3.7 months) and the median overall survival was 15.7 months (95% CI, 9.2-17.0 months). Nineteen patients discontinued the study before the first tumor assessment. Dose reductions were required for 4 diabetic (31%) and 18 nondiabetic (42%) patients. Comprehensive molecular profiling of 46 evaluable archival tumor samples demonstrated that 57% of patients had at least 1 alteration in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), phosphatase and tensin homolog (PTEN), or AKT1. All 3 patients with a confirmed response had at least 1 alteration in a PI3K pathway gene.The antitumor activity noted with the use of a dose of 40 mg of apitolisib daily was limited by tolerability, especially in diabetic patients. Patients with PI3K pathway mutations may have derived enhanced benefit from apitolisib. Cancer 2016;122:3519-28. © 2016 American Cancer Society.