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The phase 3 RECORD-1 study demonstrated clinical benefit of everolimus over placebo (median progression-free survival: 4.9 mo compared with 1.9 mo, p0.001) in treatment-resistant patients with metastatic renal cell carcinoma (mRCC). However, the Response Evaluation Criteria in Solid Tumors (RECIST) objective response rate was low.To explore the potential role of tumor burden response to everolimus in predicting patient survival.RECORD-1 patients with at least two tumor assessments (baseline and weeks 2-14) were included (n=246).A multivariate Cox proportional hazard model was used to assess the impact of various prognostic factors on overall survival (OS). Components of RECIST progression were explored using univariate Cox regression.The baseline sum of longest tumor diameters (SLD) and progression at weeks 2-14 were prognostic factors of OS by multivariate analysis. Univariate analysis at weeks 2-14 demonstrated that growth of nontarget lesions and appearance of new lesions were predictive of OS (p0.001). This retrospective analysis used data from one arm of one trial; patients in the placebo arm were excluded because of confounding effects when they crossed over to everolimus.This analysis identified baseline SLD as a predictive factor of OS, and the appearance of a new lesion or progression of a nontarget lesion at first assessment after baseline also affects OS in patients with mRCC treated with everolimus.

Purpose: In this first-in-human study of AEE788, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), HER-2, and VEGFR-2, a comprehensive pharmacodynamic program was implemented in addition to the evaluation of safety, pharmacokinetics, and preliminary efficacy of AEE788 in cancer patients. Experimental design: Patients with advanced, solid tumors received escalating doses of oral AEE788 once daily. Primary endpoints were to determine dose-limiting toxicities (DLTs) and maximum-tolerated dose (MTD). A nonlinear model (Emax model) was used to describe the relationship between AEE788 exposure and target-pathway modulation in skin and tumor tissues. Results: Overall, 111 patients were treated (25 to 550 mg/day). DLTs included rash and diarrhea; MTD was 450 mg/day. Effects on biomarkers correlated to serum AEE788 concentrations. The concentration at 50% inhibition (IC50) for EGFR in skin (0.033 μmol/L) and tumor (0.0125 μmol/L) were similar to IC50in vitro suggesting skin may be surrogate tissue for estimating tumor EGFR inhibition. No inhibition of p-MAPK and Ki67 was observed in skin vessels at ≤MTD. Hence, AEE788 inhibited EGFR, but not VEGFR, at doses ≤MTD. A total of 16 of 96 evaluable patients showed a >10% shrinkage of tumor size; one partial response was observed. Conclusion: Our pharmacodynamic-based study showed effective inhibition of EGFR, but not of VEGFR at tolerable AEE788 doses. Emax modeling integrated with biomarker data effectively guided real-time decision making in the early development of AEE788. Despite clinical activity, target inhibition of only EGFR led to discontinuation of further AEE788 development. Clin Cancer Res; 18(22); 6364–72. ©2012 AACR.

Purpose To compare the safety and efficacy of carboplatin and paclitaxel administered with or without the multidrug resistance modulator valspodar (PSC 833) in untreated patients with advanced ovarian or primary peritoneal cancer. Patients and Methods Seven hundred sixty-two patients with stage IV or suboptimally debulked stage III ovarian or primary peritoneal cancer were randomly assigned to receive either valspodar 5 mg/kg every 6 hours for 12 doses, paclitaxel 80 mg/m2, and carboplatin area under the curve (AUC) 6 (PC-PSC; n = 381) or paclitaxel 175 mg/m2 and carboplatin AUC 6 (PC; n = 381). Time to disease progression (TTP) was the primary end point. Secondary end points were overall survival time (OS), response rate (RR), safety, and tolerability. Results With a median follow-up of 736 days (range, 1 to 2,280 days), the median TTP was 13.2 and 13.5 months in the PC-PSC and PC groups, respectively (P = .67); the median OS was 32 and 28.9 months, respectively (P = .94). The overall RR was higher in the PC group (41.5% v 33.6%; P = .02). Central and peripheral nervous system and GI toxicities were more common in the PC-PSC group. Ataxia occurred in 53.5% and 3.2% of PC-PSC–and PC-treated patients, respectively. Febrile neutropenia occurred more frequently in the PC-PSC group. More PC-PSC–treated patients discontinued therapy because of adverse events (AEs), experienced serious AEs, and required paclitaxel dose reductions. Conclusion The addition of valspodar to PC did not improve TTP or OS and was more toxic compared with PC in untreated patients with advanced ovarian or primary peritoneal cancer.