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Purpose: Many of the therapeutic agents that are being used currently were developed using the 3+3 decision rule for dose finding. Over the past 30 years, several dose-finding designs have been proposed and evaluated, including the “continual reassessment method” (CRM) and the “Bayesian optimal interval design” (BOIN). This research investigates the role of the choice of an early-phase design on the likelihood that drugs entering the drug development pipeline will have 2 successful phase III trials. Experimental Design: Using simulation, each agent in a population of hypothetical agents was tracked through the drug development process, from initial dose finding to 2 confirmatory phase III trials. Varying the designs of the phase I, II, and III trials allows for an assessment of the effect of the choice of designs on the proportion of agents with successful phase III trials. Results: The results indicate that using the CRM or BOIN, rather than the 3+3, substantially enhances the proportion of effective agents that have successful phase III trials, with the CRM having a greater effect than BOIN. A larger phase II trial magnifies the effect of the phase I design. Conclusions: The results underscore the importance of the choice of the early-phase designs. Use of the 3+3 results in fewer agents with successful phase III trials compared with the CRM or BOIN. The difference is more pronounced among highly effective agents. In addition, the results show the importance of a sufficiently powered phase II trial.

In recent years, investigators have recognized the rigidity of single-agent, safety-only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and/or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed/refractory mantle cell lymphoma. Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations. Clin Cancer Res; 23(23); 7158–64. ©2017 AACR.

Though the necessity for ovarian cancer detection at earlier stages has long been acknowledged, biomarker-based discoveries have yielded underwhelming outcomes. The failures of CA-125 and other approaches have raised concern over the sensitivity and robustness of serum biomarkers. However, the discovery that most ovarian cancers originate in the fallopian tube may offer a unique opportunity; since the natural washdown of fallopian tube cells and debris travels through the uterus and into the cervix and vagina, we hypothesized that biomarkers may be concentrated in these proximal fluids. Though we previously demonstrated that tumor DNA is present in the vaginal tract of ovarian cancer patients, the deep sequencing required and low sensitivity (60%) render it insufficient for clinical use. Therefore, we examined other potential biomarkers with high stability that are detectable with methods that are cost effective and noninvasive, such as endocervical sampling. We performed mass spectroscopy on 41 endocervical cytobrush (ECC) samples and found the greatest discriminating pathway between ovarian cancer and benign patients was exosomal composition and trafficking (p=1.3 × 10−21). MicroRNAs (miRNAs) are common exosomal cargo, boast high extracellular stability in bodily fluids, and govern a multitude of cellular processes that can influence ovarian cancer initiation and progression. We therefore used NanoString to perform comprehensive miRNA profiling in matched ECC and plasma samples from high-grade serous ovarian cancer and normal patients. We discovered 13 significant differentially expressed ECC miRNAs and 7 plasma miRNAs individually capable of distinguishing cancer from normal. Not only did ECC samples yield a higher number of significant hits than plasma samples, but these hits also showed better sensitivity and specificity as assessed through their concordance index (c-index) scores generated by area under receiver operator curve analysis (c-index averages of 0.9141 in ECC vs. 0.8796 in plasma). 3 miRNAs overlapped between ECC and plasma, and in each case higher c-index scores were present in ECC samples than in plasma. ECC samples also showed more dramatic differences in expression between cancer and benign (1.4 log2 fold change in ECC vs. 0.8 log2 fold change in plasma), suggesting ECC may yield more consistent and detectable differences in miRNA expression than its plasma counterpart. The miRNAs discovered in our ECC samples showed individual sensitivities and specificities that lie within 95% confidence intervals, indicating potential for a viable positive predictive value for a clinical screening test. Crucial next steps are to validate these data in a larger cohort and determine if a similar distinguishing signature is present in the earliest events in fallopian tube transformation. Together, these data support further investigation of proximal tissue sampling for detection of ovarian cancer. Citation Format: Alexandra R. Harris, Danielle C. Llaneza, Mark R. Conaway, Thomas P. Conrads, Katherine Croft, John R. Cornelison, Charles N. Landen. Endocervical microRNA profiling for detection of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B31.

Dr. Ratain's letter allows us to reiterate the primary message of the publication: to meet the challenges of contemporary dose-finding, the 3+3 algorithm should be abandoned. This commonly used algorithm performed poorly even in the simple, single-agent, monotonic dose toxicity scenario presented in

Purpose: Minimally invasive methods of predicting the risk of muscle-invasive urothelial bladder carcinoma may expedite appropriate therapy and reduce morbidity and cost. Experimental Design: Here, capillary electrophoresis coupled mass spectrometry was used to identify urinary polypeptide bladder cancer biomarkers in 127 patients. These markers were used to construct a panel discriminating muscle-invasive from noninvasive disease, which was refined in 297 additional samples from healthy volunteers, patients with malignant and nonmalignant genitourinary conditions. Sequencing of panel polypeptides was then done. Finally, the ability of the panel to predict muscle-invasive disease was evaluated prospectively in 130 bladder carcinoma patients. Four sequenced polypeptides formed a panel predictive of muscle-invasive disease. Results: Prospective evaluation of this panel revealed a sensitivity of 81% [95% confidence interval (CI), 69-90] and specificity of 57% (95% CI, 45-69) for muscle-invasive disease. Multivariate analysis revealed the panel (P < 0.0001) and tumor grade (P = 0.0001), but not urine cytology, predict muscle invasion. A model including grade and panel polypeptide levels improved sensitivity [92% (95% CI, 82-97)] and specificity [68% (95% CI, 55-79)] for muscle-invasive disease. A model score of >0.88 provided a negative predictive value of 77% and positive predictive value of 90% for muscle invasion. Conclusions: Use of urinary peptides seems promising in estimating the probability a patient harbors muscle-invasive urothelial bladder cancer. These peptides may also shed novel insights into the biology of bladder tumor progression not obtainable by other methods. Clinical trials seem warranted to evaluate the effect of this approach on practice.

Purpose: Androgen ablation therapy leads to mild regression or stabilization of prostate cancer, followed by progression to the fatal androgen-independent state. Whereas androgen ablation diminishes tumor angiogenesis by suppressing vascular endothelial growth factor (VEGF) production, androgen-independent disease is marked by androgen-independent VEGF expression. We examined combined androgen ablation and inhibition of VEGF signaling in an androgen-sensitive human prostate cancer xenograft model (LNCaP) that is known to develop androgen-independent growth after androgen ablation. Experimental Design: N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine (ZD6474) is an orally active inhibitor of VEGF receptor tyrosine kinase activity, with additional activity against epidermal growth factor receptor tyrosine kinase. ZD6474 (50 mg/kg/d, per os) was administered to groups of castrated and noncastrated athymic mice bearing established (4–616 mm3) LNCaP xenografts. To evaluate the extent of tumor regrowth after ZD6474, treatment was stopped after 40 days of continuous dosing, and subsequent tumor growth was monitored. Prostate-specific antigen expression was assessed to determine the effect of ZD6474 on androgen-regulated genes. Results: In comparison with orchiectomy, ZD6474 treatment produced greater tumor growth inhibition (P < 0.001), inducing complete cytostasis for the duration of dosing. An analysis of serum prostate-specific antigen concentration and tumor weight indicated that ZD6474 did not have a direct effect on androgen-related gene expression. Combination therapy (castration plus ZD6474) produced a comparable therapeutic effect to treatment with ZD6474 alone (in noncastrated mice), for the duration of ZD6474 administration. However, when ZD6474 treatment was discontinued, the rate of tumor regrowth was significantly less in the combination group. Tumors from mice receiving combined treatment were also found to be more necrotic than tumors from mice receiving either androgen ablation or ZD6474 alone. Conclusions: These data indicate that inhibition of VEGF signaling produces a highly significant inhibition of tumor growth in a human androgen-dependent prostate tumor model, which far exceeds that produced by androgen ablation alone. However, when ZD6474 treatment is removed, concurrent androgen ablation produces a greater inhibition of tumor regrowth than is observed in mice without androgen ablation. Increased necrosis observed in tumors from orchiectomized mice receiving ZD6474 also suggests benefit from combining anti-androgen and anti-VEGF signaling approaches.

Purpose: RhoGDI2 was recently shown to be a metastasis suppressor gene in models of bladder cancer. We sought to further understand its importance in human cancer by determining the level of its expression and the distribution of its encoded protein in normal human tissues and cell lines and to evaluate whether its protein expression is a determinant of human bladder cancer progression. Experimental Design: RhoGDI2 mRNA and protein expression was evaluated in cell lines and human tissues using Affymetrix and tissue microarrays, respectively. Tissue microarrays represented most human normal adult tissues and material from 51 patients that had undergone radical cystectomy for bladder cancer. In these 51 patients, the χ2 test was used to test for associations between RhoGDI2 and stage, grade of urothelial carcinoma, histological type, and disease-specific survival status. Cox proportional hazards regression analyses were used to estimate the effect of RhoGDI2 expression level on time to development of metastatic disease and disease-specific survival time, adjusting for grade, stage, and histological type. Results: In normal tissues, there was strong RhoGDI2 protein expression in WBCs, endothelial cells, and transitional epithelium. RhoGDI2 mRNA expression was inversely related to the invasive and metastatic phenotype in human bladder cancer cell lines. In patients with bladder cancer, univariate analysis indicated that reduced tumor RhoGDI2 protein expression was associated with a lower actuarial 5-year disease-free and disease-specific survival (P = 0.01). In addition, patients with tumors that had low or absent RhoGDI2 had a shorter time to disease-specific death (P ≤ 0.01). When tumor grade, stage, histological type, and RhoGDI2 staining level were examined using multivariate analysis, RhoGDI2 expression was found to be an independent predictive factor for disease-specific death (P = 0.03). Conclusions: These results suggest that RhoGDI2 is an independent predictor of prognosis for patients with bladder cancer and provide clinical evidence in support of its involvement in cancer metastasis.

The inability to successfully treat women with ovarian cancer is due in large part to the advanced stage of disease at diagnosis, the development of platinum resistance, and the lack of sensitive methods to monitor tumor progression and response to treatment. Vascular cell adhesion molecule-1 (VCAM-1) is expressed on the mesothelium of ovarian cancer patients. We investigated VCAM-1 expression as a marker of peritoneal metastasis and tumor response to platinum-based chemotherapy. Immunohistochemical staining of peritoneal or omental biopsies obtained from women diagnosed with Stage I, Stage II or Stage III/IV ovarian cancer demonstrated that VCAM-1 expression correlated with tumor stage. All specimens from Stage I patients were negative, while 29% of Stage II patients and the 73% of Stage III/IV patients were positive. While the majority of women with advanced stage disease expressed VCAM-1, the incidence of expression was reduced among women who received neoadjuvant chemotherapy, suggesting a role for chemotherapy in regulating VCAM-1 expression. The effects of carboplatin on mesothelial VCAM-1 expression were determined in a mouse model of ovarian cancer peritoneal metastasis using radiolabeled VCAM-1-specific peptide imaging probes and single photon emission computed tomography (SPECT). This approach showed that 1) VCAM-1 is a viable imaging target in ovarian cancer metastasis, 2) maximal expression was detected with microscopic tumor burden, and 3) VCAM-1 expression reflected the effect of platinum-based treatment on tumor burden. Specifically, carboplatin treatment of mice with platinum-sensitive tumors showed reduced VCAM-1 expression, which correlated with reduced tumor burden; mice with platinum-resistant tumors retained elevated VCAM-1 expression and tumor burden following treatment. These observations support testing the utility of VCAM-1 imaging probes to monitor treatment response in ovarian cancer patients, thus providing the potential to improve management of women with this disease. Citation Format: Jill K. Slack-Davis, Jennifer M. Scalici, Stephanie Thomas, Christine Harrer, Timothy A. Raines, Joanna Curran, Kristen A. Atkins, Mark R. Conaway, Linda Duska, Kimberly A. Kelly. Imaging the tumor micro-environment to monitor ovarian cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A62.