Lesson Learned.O_LICirculating tumor cells, microRNA markers, or other biomarkers merit examination as part of correlative scientific analyses in prospective clinical trials. C_LI Background.Platinum chemotherapy resistance occurs in approximately 25% of patients with ovarian carcinoma; however, no biomarkers of ovarian carcinoma chemoresistance have been validated. We performed a prospective trial designed to identify tumor-based predictive biomarkers of platinum resistance. Methods.Tumor specimens were collected from 29 women with newly diagnosed histopathologically proven primary ovarian carcinoma. Of these, 23 women had specimens accessible for assessment and outcome data available regarding chemosensitive versus chemoresistance status via review of the medical record. Tumor slices were stained with antibodies against two microRNAs (miRNAs 29b and 199a) differentially expressed in chemoresistant ovarian cancer cell lines. Additionally, blood samples obtained at the time of diagnosis were analyzed for the presence of circulating tumor cells (CTCs). Results.The average age of the patients was 64 years, and 82.6% had high-grade epithelial carcinomas. The baseline median CA-125 was 464 (range 32-2,782). No statistically significant differences were observed in miR29b or 199a expression in platinum-resistant/refractory versus platinum-sensitive tumors. Furthermore, the presence of CTCs was not found to be statistically significantly predictive of eventual platinum resistance. Conclusion.Our analysis showed no differences in miR29b and 199a expression, and differences in baseline CTCs in women with newly diagnosed ovarian tumors were not statistically significant.

Lessons Learned.O_LIThis clinical trial, evaluating the efficacy and safety of a carboplatin plus paclitaxel regimen in a biweekly or weekly schedule instead of the more toxic 3-weekly administration, showed that the weekly regimen was better in efficacy than the biweekly regimen, with mild toxicities, for patients with non-small cell lung cancer (NSCLC). C_LIO_LIThe weekly carboplatin plus paclitaxel regimen could be considered as an alternative to the 3-weekly regimen in Japanese patients with NSCLC. C_LI Background.Combination therapy comprising carboplatin (C) and paclitaxel (P) is the most commonly used regimen for the treatment of advanced non-small cell lung cancer (NSCLC). Common toxicities associated with the regimen, such as neuropathy and myelosuppression, cause its discontinuation. In the present study, we conducted a clinical trial evaluating the efficacy of biweekly (B) and weekly (W) PC therapy to identify the appropriate chemotherapy schedule for Asian patients. Methods.Chemonaive patients with IIIB/IV NSCLC and a performance status of 0-1 were randomly assigned to a biweekly regimen (paclitaxel 135 mg/m2 with carboplatin area under the curve [AUC] 3 on days 1 and 15 of every 4 weeks) or to a weekly regimen (paclitaxel 90 mg/m2 on days 1, 8, and 15 with carboplatin AUC 6 on day 1 of every 4 weeks). Results.A total of 140 patients were enrolled in the study. The objective response rates (ORRs) were 28.1% (B) and 38.0% (W). The most common toxicity was neutropenia, with incidence rates of 62.0% (B) and 57.8% (W). Progression-free survivals (PFSs) were 4.3 months (B) and 5.1 months (W), and overall survival durations were 14.2 months (B) and 13.3 months (W). Conclusion.The ORR and PFS in the weekly regimen were better than those in the biweekly schedule, although a statistical difference was not observed. The toxicity profile was generally mild for both regimens. The weekly CP regimen was suitable to be considered as an alternative to the current 3-weekly regimen in NSCLC treatment.

Lessons Learned.O_LIThe NEO-CLASSIC study provided valuable insight for the clinical efficacy and tolerability profiles of perioperative chemotherapy with oxaliplatin and capecitabine, plus gastrectomy, in patients with localized resectable gastric cancer. C_LIO_LIThe study was designed to explore the potential survival benefits of an eight-cycle, perioperative oxaliplatin and capecitabine (XELOX) schedule in the above-mentioned setting and to explore the feasibility of prolonging the cycles of preoperative chemotherapy. The projected endpoint was not met. C_LI Background.This multicenter, open-label study (NEO-CLASSIC) evaluated the efficacy and safety of oxaliplatin and capecitabine (XELOX), plus D2 gastrectomy, in localized resectable gastric cancer. Methods.Patients aged 18-75 years with histologically-confirmed gastric adenocarcinoma (stage T2-4a/N+M0) were given eight cycles of XELOX (four preoperatively, four postoperatively). Each 3-week cycle comprised capecitabine 1,000 mg/m2 twice daily on days 1-14 and oxaliplatin 130 mg/m2 on day 1. Curative D2 gastrectomy was scheduled 2-4 weeks after the last preoperative cycle. The primary objective of the study was to determine the objective response rate (ORR) of XELOX in the preoperative setting. Sample size was calculated by assuming that a minimum of 47 cases would be required to increase the ORR by 15% (from 40% to 55%). With an estimated 10% dropout rate, 55 patients would have to be recruited. Results.Fifty-five patients were enrolled, and one was excluded because of screening failure. R0 resections were achieved in 45 of 54 intent-to-treat patients (83.3%), and four patients received R1 resections (Fig. 1). There were no complete responses, 27 (50.0%) partial responses, 22 cases (40.7%) of stable disease, and 4 (7.4%) of progressive disease. The objective response rate was 50.0%. Median follow-up was 52.97 months; 30 patients (55.6%) had disease progression (Table 1), and median progression-free survival was 20.10 (95% confidence interval: 4.31--35.89) months; median overall survival was 30.77 months (95% confidence interval was not yet available) (Fig. 2). Fifty-four patients completed 209 cycles of preoperative chemotherapy; 42 patients received 133 cycles of postoperative chemotherapy (Table 3). The rate of grade 3-4 adverse events was 8.5% (29/342 cycles); the most frequent events were neutropenia (9/342 cycles) and leukopenia (4/342 cycles). Conclusion.These findings suggest that combination therapy with capecitabine and oxaliplatin as perioperative chemotherapy, followed by D2 gastrectomy, is effective and safe in late-stage, locally advanced gastric cancer. Although enrollment exceeded the 47 patients required to identify an increase in the ORR by 15% (from 40% to 55%), results did not meet the primary endpoint.

Lessons Learned. O_LIThe combination of pexidartinib and binimetinib was safe and tolerable and demonstrated encouraging signs of efficacy in two patients with advanced gastrointestinal stromal tumor (GIST) refractory to tyrosine kinase inhibitors (TKIs). C_LIO_LIMolecular profiling of GISTs at diagnosis and upon progression may provide insight into the mechanisms of response or resistance to targeted therapies. C_LIO_LIAdditional trials are needed to further explore combined KIT and MEK inhibition in treatment-naive and TKI-refractory patients with advanced GIST. C_LI Background.Nearly all patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Dual inhibition of KIT and MAPK pathways has synergistic antitumor activity in preclinical GIST models. Methods.This was an investigator-initiated, phase I, dose escalation study of the MEK inhibitor binimetinib combined with pexidartinib, a potent inhibitor of CSF1R, KIT, and FLT3, in patients with advanced or metastatic GIST who progressed on imatinib. The primary endpoint was phase II dose determination; secondary endpoints included safety, tolerability, and efficacy. An expansion cohort to further evaluate safety and efficacy was planned. Results.Two patients were treated at dose level one (binimetinib 30 mg b.i.d. and pexidartinib 400 mg every morning and 200 mg every evening), after which the study was terminated by the manufacturer. No dose-limiting toxicities (DLTs) were reported, and treatment was well tolerated. The only grade [≥]3 treatment-emergent adverse event (TEAE) was asymptomatic elevated creatine phosphokinase (CPK). Both patients had a best response of stable disease (SD) by RECIST. Progression-free survival (PFS) and overall survival (OS) were 6.1 and 14.6 months, respectively, in one patient with five prior lines of therapy. The second patient with NF1-mutant GIST had a 27% decrease in tumor burden by RECIST and remains on study after 19 months of treatment. Conclusion.Pexidartinib combined with binimetinib was tolerable, and meaningful clinical activity was observed in two imatinib-refractory patients.

Lessons Learned. O_LIThe combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy. C_LIO_LIThe antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape. C_LI Background.Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC. Methods.This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naive patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed. Results.No patients in the dose-escalation phase (n = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade [≥]3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9-54.3), and progression-free survival was 5.6 months (95% CI, 3.5-not reached). Conclusion.The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.

Lessons Learned. O_LIThe negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC). C_LIO_LIThe negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge. C_LI Background.Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods.This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m2 intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events. Results.The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm). Conclusion.Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.