Phase I Safety and Feasibility Pilot of Hepatic Artery Infusion Chemotherapy in a Rural Catchment Area Using The Codman Vascular Catheter with The Medtronic SynchroMed II Pump for Intrahepatic Cancers.

BACKGROUND: Discontinuation of the Codman 3000 pump in 2018 left no Food and Drug Administration (FDA)-approved hepatic artery infusion (HAI) device for unresectable colorectal liver metastases (uCLM) and intrahepatic cholangiocarcinoma (uIHC). Historically, HAI has been performed at academic medical centers in large metropolitan areas, which are often inaccessible to rural patients. Consequently, feasibility of dissemination of HAI to rural populations is unknown. PATIENTS AND METHODS: Under an FDA investigational device exemption, we opened the only HAI program in Kentucky and enrolled patients with uCLM and uIHC in a phase I clinical trial. The trial examined the safety of the hybrid Codman catheter/Medtronic SynchroMed II pump (hCMP) combination, defined as successful completion of one cycle of HAI chemotherapy. Rural feasibility was assessed by number of missed pump fills appointments. RESULTS: A total of 21 patients (n = 17 uCLM, n = 4 uIHC) underwent hCMP implantation before accrual was stopped early owing to FDA approval of the Intera 3000 pump. 20/21 (95%) patients met the primary safety endpoint. Serious adverse events (AEs) included a grade 5 coronavirus disease 2019 (COVID-19) infection (n = 1) and a grade 3 catheter erosion into the bowel (n = 1). Biliary sclerosis developed in two patients (9.5%). Median distance to infusion center was 47.6 miles (2-138 miles), and 62% were from Appalachia, yet there were no missed pump fill appointments. The 2-year overall survival was 82.4% (uCLM) and 50% (uIHC). CONCLUSIONS: The hCMP device had an acceptable safety profile. Despite the complexity of starting a new HAI program, early results showed feasibility for HAI delivery in a rural catchment area and comparable outcomes to larger urban-based HAI centers.

Estimating the distribution of ratio of paired event times in phase II oncology trials.

With the rapid development of new anti-cancer agents which are cytostatic, new endpoints are needed to better measure treatment efficacy in phase II trials. For this purpose, Von Hoff (1998) proposed the growth modulation index (GMI), that is, the ratio between times to progression or progression-free survival times in two successive treatment lines. An essential task in studies using GMI as an endpoint is to estimate the distribution of GMI. Traditional methods for survival data have been used for estimating the GMI distribution because censoring is common for GMI data. However, we point out that the independent censoring assumption required by traditional survival methods is always violated for GMI, which may lead to severely biased results. In this paper, we construct both nonparametric and parametric estimators for the distribution of GMI, accounting for the dependent censoring of GMI. Extensive simulation studies show that our nonparametric estimators perform well in practical situations and outperform existing estimators, and our parametric estimators perform better than our nonparametric estimators and existing estimators when the parametric model is correctly specified. A phase II clinical trial using GMI as the primary endpoint is provided for illustration.

Macrophage Repolarization as a Therapeutic Strategy for Osteosarcoma.

Macrophages are versatile immune cells and can adapt to both external stimuli and their surrounding environment. Macrophages are categorized into two major categories; M1 macrophages release pro-inflammatory cytokines and produce protective responses that lead to antimicrobial or antitumor activity. M2 or tumor-associated macrophages (TAM) release anti-inflammatory cytokines that support tumor growth, invasion capacity, and metastatic potential. Since macrophages can be re-polarized from an M2 to an M1 phenotype with a variety of strategies, this has emerged as an innovative anti-cancer approach. Osteosarcoma (OS) is a kind of bone cancer and consists of a complex niche, and immunotherapy is not very effective. Therefore, immediate attention to new strategies is required. We incorporated the recent studies that have used M2-M1 repolarization strategies in the aspect of treating OS cancer.

SYNE1 Mutation Is Associated with Increased Tumor Mutation Burden and Immune Cell Infiltration in Ovarian Cancer.

SYNE1, a nuclear envelope protein critical for cellular structure and signaling, is downregulated in numerous malignancies. SYNE1 alterations are found in 10% of gynecologic malignancies and 5% of epithelial ovarian cancers. Previous studies demonstrated an association between SYNE1 mutation, increased tumor mutation burden (TMB), and immunotherapy response. This study evaluates the SYNE1 mutation frequency, association with TMB, and downstream effects of SYNE1 mutation in ovarian cancer. Genetic information, including whole-exome sequencing, RNA analysis, and somatic tumor testing, was obtained for consenting ovarian cancer patients at an academic medical center. Mutation frequencies were compared between the institutional cohort and The Cancer Genome Atlas (TCGA). Bioinformatics analyses were performed. In our cohort of 50 patients, 16 had a SYNE1 mutation, and 15 had recurrent disease. Median TMB for SYNE1 mutated patients was 25 compared to 7 for SYNE1 wild-type patients (p < 0.0001). Compared to the TCGA cohort, our cohort had higher SYNE1 mutation rates (32% vs. 6%, p < 0.001). Gene expression related to immune cell trafficking, inflammatory response, and immune response (z > 2.0) was significantly increased in SYNE1 mutated patients. SYNE1 mutation is associated with increased TMB and immune cell infiltration in ovarian cancer and may serve as an additional biomarker for immunotherapy response.

Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers.

The prevalence of obesity, defined as the body mass index (BMI) ≥ 30 kg/m2, has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) tract both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p < 0.05 and |logFC| > 0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in six patients (two obese and four normal weight) via CD8+/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Overall, obesity is associated with differential transcriptional and metabolic programs in various disease sites. Further, these alterations, such as kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy.

Local data commons: the sleeping beauty in the community of data commons.

BACKGROUND: Public Data Commons (PDC) have been highlighted in the scientific literature for their capacity to collect and harmonize big data. On the other hand, local data commons (LDC), located within an institution or organization, have been underrepresented in the scientific literature, even though they are a critical part of research infrastructure. Being closest to the sources of data, LDCs provide the ability to collect and maintain the most up-to-date, high-quality data within an organization, closest to the sources of the data. As a data provider, LDCs have many challenges in both collecting and standardizing data, moreover, as a consumer of PDC, they face problems of data harmonization stemming from the monolithic harmonization pipeline designs commonly adapted by many PDCs. Unfortunately, existing guidelines and resources for building and maintaining data commons exclusively focus on PDC and provide very little information on LDC. RESULTS: This article focuses on four important observations. First, there are three different types of LDC service models that are defined based on their roles and requirements. These can be used as guidelines for building new LDC or enhancing the services of existing LDC. Second, the seven core services of LDC are discussed, including cohort identification and facilitation of genomic sequencing, the management of molecular reports and associated infrastructure, quality control, data harmonization, data integration, data sharing, and data access control. Third, instead of commonly developed monolithic systems, we propose a new data sharing method for data harmonization that combines both divide-and-conquer and bottom-up approaches. Finally, an end-to-end LDC implementation is introduced with real-world examples. CONCLUSIONS: Although LDCs are an optimal place to identify and address data quality issues, they have traditionally been relegated to the role of passive data provider for much larger PDC. Indeed, many LDCs limit their functions to only conducting routine data storage and transmission tasks due to a lack of information on how to design, develop, and improve their services using limited resources. We hope that this work will be the first small step in raising awareness among the LDCs of their expanded utility and to publicize to a wider audience the importance of LDC.

MEScan: a powerful statistical framework for genome-scale mutual exclusivity analysis of cancer mutations.

MOTIVATION: Cancer somatic driver mutations associated with genes within a pathway often show a mutually exclusive pattern across a cohort of patients. This mutually exclusive mutational signal has been frequently used to distinguish driver from passenger mutations and to investigate relationships among driver mutations. Current methods for de novo discovery of mutually exclusive mutational patterns are limited because the heterogeneity in background mutation rate can confound mutational patterns, and the presence of highly mutated genes can lead to spurious patterns. In addition, most methods only focus on a limited number of pre-selected genes and are unable to perform genome-wide analysis due to computational inefficiency. RESULTS: We introduce a statistical framework, MEScan, for accurate and efficient mutual exclusivity analysis at the genomic scale. Our framework contains a fast and powerful statistical test for mutual exclusivity with adjustment of the background mutation rate and impact of highly mutated genes, and a multi-step procedure for genome-wide screening with the control of false discovery rate. We demonstrate that MEScan more accurately identifies mutually exclusive gene sets than existing methods and is at least two orders of magnitude faster than most methods. By applying MEScan to data from four different cancer types and pan-cancer, we have identified several biologically meaningful mutually exclusive gene sets. AVAILABILITY AND IMPLEMENTATION: MEScan is available as an R package at https://github.com/MarkeyBBSRF/MEScan. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Correlation Between Trough Level of Abiraterone and Prostate-Specific Antigen (PSA) Response in Metastatic Hormone-Sensitive Prostate Cancer.

BACKGROUND Prostate cancer growth is primarily driven by testosterone and 5a-dihydrotestosterone. Abiraterone is an irreversible inhibitor of CYP17, and CYP17 inhibition is a required step in testosterone biosynthesis. Previous studies have shown that abiraterone trough levels are predictive of prostate-specific antigen (PSA) response in metastatic castrate-resistant prostate cancer (mCRPC). It has not been demonstrated if this association exists for patients with metastatic hormone-sensitive prostate cancer (mHSPC). In this study, we aimed to explore the correlation and association between abiraterone trough levels and PSA levels in patients with mHSPC. MATERIAL AND METHODS This was a single-center, prospective, observational study of patients with mHSPC being treated with abiraterone acetate (AA) 1000 mg once daily. Abiraterone trough levels (22-26 h after drug administration) were drawn at 1, 3, and 7 months after treatment initiation. RESULTS Thirteen patients with mHSPC were enrolled, and complete pharmacokinetic data were available for 8 patients. The mean trough levels at 1 month, 3 months, and 7 months were 34.49 ng/mL (3.36-240.46), 13.82 ng/mL (2.91-29.96), and 15.7 ng/mL (3.58-26.86), respectively. The correlation between the 1-month abiraterone trough level and 1-month PSA level was 0.29 (P=0.38), between 3-month abiraterone trough and 3-month PSA was -0.61 (P=0.08), and between 7-month abiraterone trough and 7-month PSA was -0.31 (P=0.54). CONCLUSIONS This study demonstrated a trend toward a negative correlation between 3-month abiraterone trough levels and PSA levels, but the correlation was not statistically significant. A study with a larger prospective sample size is needed to validate these findings.

Assessment of adherence and relative dose intensity with oral chemotherapy in oncology clinical trials at an academic medical center.

Background/Aims Oral chemotherapy is increasingly utilized leaving the patient responsible for self-administering an often complex regimen where adverse effects are common. Non-adherence and reduced relative dose intensity are both associated with poorer outcomes in the community setting but are rarely reported in clinical trials. The purpose of this study is to quantify adherence and relative dose intensity in oncology clinical trials and to determine patient and study related factors that influence adherence and relative dose intensity. Methods Patients were identified from non-industry-funded clinical trials conducted between 1 January 2009 and 31 March 2013 at the University of Wisconsin Carbone Cancer Center. Data were extracted from primary research records. Descriptive statistics and linear regression modeling was performed using SAS 9.4. Results A total of 17 clinical trials and 266 subjects were included. Mean adherence was greater than 97% for the first eight cycles. Mean relative dose intensity was less than 90% for the first cycle and declined over time. Male gender, a performance status of 1 or 2, metastatic disease, and traveling more than 90 miles to reach the cancer center were associated with higher relative dose intensity. Conclusions Patients with cancer enrolled in clinical trials are highly adherent but unlikely to achieve protocol specified relative dose intensity. Given that determining the phase II dose is the primary endpoint of phase I trials, incorporating relative dose intensity into this determination should be considered.

A phase 1/2 trial of ublituximab, a novel anti-CD20 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma or chronic lymphocytic leukaemia previously exposed to rituximab.

This phase 1/2 study evaluated the safety, pharmacokinetic behavior and anti-tumour activity of ublituximab, a unique type I, chimeric, glycoengineered anti-CD20 monoclonal antibody, in rituximab-relapsed or -refractory patients with B-cell non-Hodgkin lymphoma (B-NHL) or chronic lymphocytic leukaemia (CLL). Induction therapy (doses of 450-1200 mg) consisted of 4 weekly infusions in cycle 1 for NHL and 3 weekly infusions in cycles 1 and 2 for CLL. Patients received ublituximab maintenance monthly during cycles 3-5, then once every 3 months for up to 2 years. Enrolled patients with B-NHL (n = 27) and CLL (n = 8) had a median of 3 prior therapies. No dose-limiting toxicities or unexpected adverse events (AEs) occurred. The most common AEs were infusion-related reactions (40%; grade 3/4, 0%); fatigue (37%; grade 3/4, 3%); pyrexia (29%; grade 3/4, 0%); and diarrhoea (26%; grade 3/4, 0%). Common haematological AEs were neutropenia (14%; grade 3/4, 14%) and anaemia (11%; grade 3/4, 6%). The overall response rate for evaluable patients (n = 31) was 45% (13% complete responses, 32% partial responses). Median duration of response and progression-free survival were 9·2 months and 7·7 months, respectively. Ublituximab was well-tolerated and efficacious in a heterogeneous and highly rituximab-pre-treated patient population.

A phase I study of tivantinib in combination with temsirolimus in patients with advanced solid tumors.

Background A wide variety of human cancers exhibit dysregulated c-Met activity that has implications in oncogenesis. Phosphorylation of c-Met results in activation of the PI3K/AKT/mTOR pathway. Combined blockade of c-Met and mTOR pathways has shown efficacy in preclinical studies. Tivantinib is a c-Met inhibitor and temsirolimus is a selective mTOR inhibitor. We aimed to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods This open-label phase I study used a 3 + 3 dose escalation design. Patients (pts) were treated with escalating doses of tivantinib (120-360 mg tablets orally twice daily) and temsirolimus (20 mg IV weekly) followed by dose expansion at the MTD. Separate cohorts were planned for extensive (normal) and poor tivantinib metabolizers based on CYP2C19 genotypes. Cycles were 28 days besides cycle 1 that was 35 days to allow for PK analysis. Results Twenty-nine pts. [median age 58 (range 28-77)] were enrolled (21 in dose escalation and 8 in dose expansion). All were extensive CYP2C19 metabolizers. The most common types of cancer were colorectal, ovarian and non-small cell lung. Sixteen out of 21 and 6 out of 8 pts. were evaluable for DLT evaluation per protocol in the dose escalation and dose expansion phases, respectively. Pts remained on study for a median of 71 days (range 18-296). The MTD and RP2D was tivantinib 240 mg twice daily and temsirolimus 20 mg weekly. DLTs included grade (gr) 4 neutropenia (2 pts.; 1 with gr 3 febrile neutropenia), gr 3 abdominal pain (1 pt) and gr 2 mucositis resulting in inadequate drug delivery. The most common treatment related AEs grade ≥ 2 included: anemia (gr 2 in 9 pts., gr 3 in 3 pts), fatigue (gr 2 in 10 pts), anorexia (gr 2 in 9 pts), hypoalbuminemia (gr 2 in 6 pts., gr 3 in 2 pts), hypophosphatemia (gr 2 in 2 pts., gr 3 in 5 pts) and nausea (gr 2 in 6 pts., gr 3 in 1 pt). One pt. with ovarian cancer had a confirmed partial response and remained on study for 10 months, a second patient with ovarian cancer had stable disease and remained on study for 6 months and a third pt. with squamous cell carcinoma of the tongue had stable disease and remained on study for 7 months. Pharmacokinetic analysis showed that there is no interaction in the plasma concentrations between tivantinib and temsirolimus. Conclusions The combination of tivantinib with temsirolimus appears to be well tolerated with evidence of clinical activity.

A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors.

BACKGROUND: The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination. PROCEDURE: We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25-75 mg/m2 /day) and temsirolimus (25-75 mg/m2 IV weekly) were investigated. RESULTS: Twenty-three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high-grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose-limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single-agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high-grade glioma; no partial or complete responses were achieved. CONCLUSIONS: The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.

A phase I study of selumetinib (AZD6244/ARRY-142866), a MEK1/2 inhibitor, in combination with cetuximab in refractory solid tumors and KRAS mutant colorectal cancer.

BACKGROUND: KRAS mutations are clinically important predictors of resistance to EGFR-directed therapies in colorectal cancer (CRC). Oncogenic activation of the RAS/RAF/MEK/ERK signaling cascade mediates proliferation independent of growth factor signaling. We hypothesized that targeting MEK with selumetinib could overcome resistance to cetuximab in KRAS mutant CRC. METHODS: A phase I study (NCT01287130) was undertaken to determine the tolerability, and pharmacokinetic profiles of the combination of selumetinib and cetuximab, with an expanded cohort in KRAS-mutant CRC. RESULTS: 15 patients were treated in the dose escalation cohort and 18 patients were treated in the expansion cohort. Two dose-limiting toxicities were observed. One grade 3 acneiform rash and one grade 4 hypomagnesemia occurred. The most common grade 1 and 2 adverse events included rash, nausea/vomiting, diarrhea, and fatigue. The maximum tolerated dose was established at selumetinib 75 mg p.o. BID and cetuximab 250 mg/m(2) weekly following a 400 mg/m(2) load. Best clinical response in the dose escalation group included 1 unconfirmed partial response in a patient with CRC and stable disease (SD) in 5 patients (1 squamous cell carcinoma of the tonsil, 1 non-small cell lung cancer, and 3 CRC), and in the KRAS-mutant CRC dose expansion cohort, of the 14 patients who were evaluable for response, 5 patients had SD and 9 patients had progressive disease. CONCLUSIONS: The combination of selumetinib and cetuximab is safe and well tolerated. Minimal anti-tumor activity was observed in KRAS-mutant refractory metastatic CRC. Further investigations might be warranted in other cancer subtypes.

Three-arm, randomized, phase 2 study of carboplatin and paclitaxel in combination with cetuximab, cixutumumab, or both for advanced non-small cell lung cancer (NSCLC) patients who will not receive bevacizumab-based therapy: An Eastern Cooperative Oncology Group (ECOG) study (E4508).

BACKGROUND: Preclinical evidence supports the clinical investigation of inhibitors to the insulin-like growth factor receptor (IGFR) and the epidermal growth factor receptor (EGFR) either alone or in combination as treatment for patients with non-small cell lung cancer (NSCLC). METHODS: Patients with chemotherapy-naïve, advanced NSCLC who had an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomized to receive carboplatin intravenously at an area under the plasma drug concentration-time curve of 6.0 plus paclitaxel 200 mg/m(2) intravenously on day 1 every 3 weeks combined with either intravenous cetuximab weekly (arm A), intravenous cixutumumab every 2 weeks (arm B), or both (arm C). Patients who had nonprogessing disease after 12 weeks of therapy were permitted to continue on maintenance antibody therapy until they developed progressive disease. The primary endpoint was progression-free survival (PFS). The study design required 180 eligible patients and had 88% power to detect a 60% increase in median PFS for either comparison (arm A vs arm C or arm B vs arm C) using the log-rank test. RESULTS: From September 2009 to December 2010, 140 patients were accrued. The study was closed to accrual early because of an excessive number of grade 5 events reported on arms A and C. Thirteen patients died during treatment (6 patients on arm A, 2 patients on arm B, and 5 patients on arm C), including 9 within approximately 1 month of starting therapy. The estimated median PFS for arms A, B, and C were similar at 3.4 months, 4.2 months, and 4 months, respectively. CONCLUSIONS: On the basis of the apparent lack of efficacy and excessive premature deaths, the current results do not support the continued investigation of carboplatin, paclitaxel, and cixutumumab either alone or in combination with cetuximab for patients with advanced NSCLC.

Soy food frequency questionnaire does not correlate with baseline isoflavone levels in patients with bladder cancer.

BACKGROUND: The isoflavone genistein, a natural soy product with receptor tyrosine kinase-inhibiting activity, as well as phytoestrogenic and other potential anticarcinogenic effects, is being studied as an anticancer agent. Since isoflavones are commonly consumed in food products containing soy proteins, a method to control for baseline isoflavone consumption is needed. METHODS: HPLC was used to evaluate baseline plasma and urine concentrations of isoflavone in fifty-four participants with bladder cancer enrolled on a phase II chemoprevention study of G-2535. The soy food frequency questionnaire was used to assess participant's baseline soy intake. The association between baseline isoflavone concentrations and intakes for genistein and daidzein was assessed by the Spearman's rank correlation coefficient. RESULTS: The majority of participants had no detectable genistein or daidzein in plasma at baseline. The median and range of values were 0 (0-1480) nmol/L for genistein, and 0 (0-1260) nmol/L for daidzein. In urine, the median and range of values were 91.0 (0-9030) nmol/L for genistein and 623 (0-100,000) nmol/L for daidzein. The median and range of weekly estimated genistein intake was 0 (0-236) mg/wk; the median and range of weekly estimated daidzein intake was 0 (0-114) mg/wk. There was no relationship to soy intake as measured by the food frequency questionnaire and baseline isoflavone levels in plasma or urine and the Spearman's rank correlation coefficients were not significant. CONCLUSION: The soy food frequency questionnaire did not correlate with plasma or urine concentrations of either isoflavone. IMPACT: Alternative methods for controlling for soy consumption, including measuring plasma and urine concentrations, in isoflavone chemoprevention trials should be considered.

A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors.

BACKGROUND: Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib. METHODS: Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11. RESULTS: 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST. CONCLUSIONS: The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.

A phase I study of AT-101 with cisplatin and etoposide in patients with advanced solid tumors with an expanded cohort in extensive-stage small cell lung cancer.

BACKGROUND: A phase I, dose-escalation study of AT-101 with cisplatin and etoposide was conducted to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and pharmacokinetics in patients with advanced solid tumors, with an expanded cohort in patients with extensive-stage small cell lung cancer (ES-SCLC) to assess preliminary activity. METHODS: In the dose escalation portion, increasing doses of AT-101 were administered orally BID on days 1-3 along with cisplatin on day 1 and etoposide on days 1-3 of a 21 day cycle. At the RP2D, an additional 7 patients with untreated ES-SCLC were enrolled. RESULTS: Twenty patients were enrolled in the dose-escalation cohort, and 7 patients with ES-SCLC were enrolled in the expanded cohort. The MTD/RP2D was established at AT-101 40 mg BID days 1-3 with cisplatin 60 mg/m2 and etoposide 120 mg/m2 on day 1 of a 21 day cycle with pegfilgrastim support. Two DLTs of neutropenic fever were seen at dose level 1. After the addition of pegfilgrastim, no additional DLTs were observed. Grade 3/4 treatment-related toxicities included: diarrhea, increased AST, neutropenia, hypophosphatemia, hyponatremia, myocardial infarction and pulmonary embolism. No apparent PK interactions were observed between the agents. Preliminary activity was observed with PRs in patients with ES-SCLC, high-grade neuroendocrine tumor, esophageal cancer and NSCLC. CONCLUSIONS: AT-101 with cisplatin and etoposide is well tolerated with growth factor support. Anti-tumor activity was observed in a variety of cancers including ES-SCLC, supporting further investigation with BH-3 mimetics in combination with standard chemotherapy for ES-SCLC.

Vorinostat and bortezomib as third-line therapy in patients with advanced non-small cell lung cancer: a Wisconsin Oncology Network Phase II study.

INTRODUCTION: The primary objective of this phase II trial was to evaluate the efficacy and tolerability of vorinostat and bortezomib as third-line therapy in advanced non-small cell lung cancer (NSCLC) patients. METHODS: Eligibility criteria included recurrent/metastatic NSCLC, having received 2 prior systemic regimens, and performance status 0-2. Patients took vorinostat 400 mg PO daily days 1-14 and bortezomib 1.3 mg/m2 IV day 1, 4, 8 and 11 in a 21-day cycle. Primary endpoint was 3-month progression free survival (3m-PFS), with a goal of at least 40 % of patients being free of progression at that time point. This study followed a two-stage minimax design. RESULTS: Eighteen patients were enrolled in the first stage. All patients had two prior lines of treatment. Patients received a median of two treatment cycles (range: 1-6) on study. There were no anti-tumor responses; stable disease was observed in 5 patients (27.8 %). Median PFS was 1.5 months, 3m-PFS rate 11.1 %, and median overall survival 4.7 months. The most common grade 3/4 toxicities were thrombocytopenia and fatigue. Two patients who had baseline taxane-related grade 1 peripheral neuropathy developed grade 3 neuropathy. The study was closed at its first interim analysis for lack of efficacy. CONCLUSIONS: Bortezomib and vorinostat displayed minimal anti-tumor activity as third-line therapy in NSCLC. We do not recommend this regimen for further investigation in unselected patients.

Non-melanoma skin cancer event rates in a formalized clinical trial setting: considerations for clinical trial design.

BACKGROUND: Here we report clinical risk factors and event rates for the development of new non-melanoma skin cancer (NMSC) in a randomized, double-blind, placebo-controlled trial of the irreversible ornithine decarboxylase (ODC) inhibitor, difluromethylornithine (DFMO), over a 3-5-year follow-up. METHODS: 147 placebo patients (white; mean age 60.2 years; 60% male) were evaluated for event rates and association of initial skin biomarkers and baseline patient characteristics with the development of squamous cell (SCC) and basal cell (BCC) carcinomas. RESULTS: Post-study evaluation (median follow-up 4.4 years) indicates the measures of prior NMSCs ( P  ≤ 0.001), prior BCCs ( P  ≤ 0.001), prior SCCs ( P  = 0.011), prior tumor rate ( P  = 0.002), hemoglobin ( P  = 0.022), and gender ( P  = 0.045) as significant predictors for new NMSC development. Similarly, all measures of prior BCCs and NMSCs ( P  < 0.001), prior tumor rate ( P  = 0.014), and SCCs in the prior 2 years ( P  = 0.047) were statistically significant predictors for new BCC development. Total prior NMSCs and those in the prior 5 years ( P  < 0.001), total prior SCCs and those in the prior 5 years ( P  < 0.001), total prior BCCs and those in the prior 5 years ( P  ≤ 0.001), prior tumor rate ( P  = 0.011) as well as age ( P  = 0.008), hemoglobin ( P  = 0.002), and gender ( P  = 0.003) were statistically significant predictors of new SCC development. TPA-induced ODC activity at baseline showed no statistically significant association with the development of new NMSC ( P  = 0.35), new BCCs ( P  = 0.62), or new SCCs ( P  = 0.25). CONCLUSION: In the studied population, the history of and rate at which prior NMSCs occur are predictive and should be controlled for in future NMSC prevention trials.