Center-Specific Modeling Predicts Cancer Trial Accrual More Accurately Than Investigators and Random Effects Modeling at 16 Cancer Centers.

PURPOSE: Clinical trials often exceed their anticipated enrollment periods, and study sites often do not meet accrual goals. We previously reported the development and validation of a single-site accrual prediction model. Here, we describe the expansion of this methodology at 16 cancer centers (CCs) and compare an overall model versus site-specific models. METHODS: This retrospective cohort study used data from treatment and supportive care intervention studies permanently closed to accrual between 2009 and 2015 at 16 United States-based CCs. Center and ClinicalTrials.gov data were used to generate both site-specific and random effects mixed models (random effect: institution). Accrual predictions were generated from each model and compared with the accrual prediction of the disease team (DT). RESULTS: Sixteen institutions submitted 5,787 eligible trials (range, 93 to 697 trials per institution). Local accrual ranged from 363 to 6,716 participants; 1,053 studies (18%) accrued no participants. Actual average accrual was 8.5 participants (median, four participants). Site-specific models predicted accrual at 99% of actual and correctly predicted whether a study would accrue four or more participants 73% of the time versus DT prediction of 58%. Correlation at the category level was 30%; model sensitivity and specificity were 83% and 62%, respectively. The overall model predicted accrual 93% of actual and correctly predicted accrual of four or more participants 66% of the time, with a correlation at the category level of 28%. CONCLUSION: Both regression models predicted clinical trial accrual at least as or more accurately than DT at all but one center. Site-specific models generally performed slightly better than the random effects model. This study confirms the previous finding that this method is an accurate and objective metric that can be easily implemented to improve clinical research resource allocation across multiple centers.

Development and Validation of a Clinical Trial Accrual Predictive Regression Model at a Single NCI-Designated Comprehensive Cancer Center.

BACKGROUND: Clinical study sites often do not achieve anticipated accrual to clinical trials, wasting critical patient, material, and human resources. The expensive and extensive process to bring a drug to approval highlights the need to streamline clinical pipeline processes. We sought to create a predictive accrual model to be used when considering clinical trial activation at the level of the individual site. MATERIALS AND METHODS: This retrospective cohort study used 7 years of registry data from treatment and supportive care interventional studies at a single academic cancer center to build a negative binomial regression model with local and protocol variables known prestudy. Actual, team-predicted, and model-predicted accrual and sensitivity/specificity were calculated. RESULTS: To build the model, 207 trials were used. Investigational drug application, disease team, number of national sites, local Institutional Review Board use, total national accrual time, accrual completed, and national enrollment goal were independently and significantly associated with accrual. Predicted accrual was 94% of actual, maintaining predictive value at multiple cutoff values. Validation included 61 trials. The model correctly predicted whether a study would accrue at least 4 subjects 75% of the time. Correlation at the category level was 44.3%, and model sensitivity and specificity are 70% and 78%, respectively. CONCLUSIONS: We identified and validated national and local key factors associated with accrual at our site. This methodology has not been previously validated broadly with the intent of trial feasibility. Model validation shows it to be an accurate and quick metric in anticipating accrual success that can be used for resource allocation.

Quality-adjusted time without symptoms or toxicity (Q-TWiST): patient-reported outcome or mathematical model? A systematic review in cancer.

OBJECTIVE: Successful cancer treatment is defined as an increase in overall survival and/or progression-free survival. Despite their importance, these metrics omit patient quality of life. Quality-adjusted time without symptoms or toxicity (Q-TWiST) was developed to adjust survival gained, accounting for quality of life. The purpose of this systematic review was to assess the methods reported in cancer literature to determine Q-TWiST values and how these are currently translated to the clinic. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used to conduct a systematic review of studies indexed on MEDLINE and Web of Science through April 2013. Cancer studies that measured Q-TWiST either as a primary outcome or retrospectively and determined utility coefficients from a patient population were identified, and their methods reviewed to determine how the utility coefficient was calculated. Additionally, other relevant factors such as definitions of health states and significant findings were collected and summarized. RESULTS: Out of 284 studies, 11 were identified that calculated patient-defined utility coefficients. Several methods to determine utility coefficients were reported, and multiple definitions of health state toxicity were applied. Of these studies, seven reported significant differences (p < 0.05) in quality-adjusted survival. No studies, however, directly discussed the clinical relevance of their findings. CONCLUSIONS: Currently, Q-TWiST is utilized as a mathematical theory rather than a clinical tool. Standardization of terminology plus reliability and validity testing of determining both utility coefficients and time frame definitions must be performed before Q-TWiST can become clinically useful to physicians and patients alike for making treatment decisions.

Clinical and economic burden of Richter syndrome in inpatient cases of chronic lymphocytic leukemia within the United States, 2001-2010.

Richter syndrome (RS) is an aggressive transformation of chronic lymphocytic leukemia (CLL) characterized by poor prognoses. The purpose of this study was to assess clinical and economic characteristics of RS within inpatient hospital settings in the United States from 2001 to 2010. This retrospective cohort study employed data from the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project. Overall, 46 613 cases of RS were observed across 695 080 inpatient cases of CLL, representing a national bill of $2.74 billion and involving a 9.3% inpatient mortality rate. Multivariate analyses found decreased national inpatient mortality from 2001 to 2010 of - 61.1% (p < 0.001), shorter length of stay of - 15.5% (p < 0.001) and higher charges of +20.9% (p = 0.003). Numerous characteristics were also associated with increased likelihoods of death, lengths of stay and charges. Clinically, the findings allow for an increased understanding of population-based RS case-mixes, outcome prediction and clinical risk assessments. The continued burden of illness of either RS or CLL ultimately remains contingent upon the comparative- and cost-effectiveness of both existing interventions and those in development.

Identification of thioredoxin-interacting protein 1 as a hypoxia-inducible factor 1alpha-induced gene in pancreatic cancer.

OBJECTIVE: To investigate the expression of thioredoxin-interacting protein (TXNIP) during hypoxia and its dependency on hypoxia-inducible factor 1alpha (HIF-1alpha) in pancreatic cancer cell lines. METHODS: MiaPaCa-2 pancreatic cancer cells were transiently transfected with siRNA to HIF-1alpha and TXNIP protein measured after growth in normoxia or hypoxia. In addition, HIF-1alpha dependency was assessed by transiently transfecting MiaPaCa-2 pancreatic cancer cells with HIF-1alpha with a mutated oxygen degradation domain resulting in stable HIF-1alpha expression in normoxic conditions. Panc-1 pancreatic cancer cells with low endogenous TXNIP expression were stably transfected with TXNIP, and cell survival and response to platinum cancer agents were tested. Quantitative immunohistochemistry was utilized to measure the expression of TXNIP and thioredoxin 1 in human pancreatic cancer tissues. RESULTS: Thioredoxin-interacting protein was induced during hypoxia in pancreatic cancer cells in a HIF-1alpha-dependent manner. Overexpression of TXNIP in the Panc-1 cells resulted in a higher basal apoptosis and increased sensitivity to cisplatin and oxaliplatin. A negative correlation was observed between TXNIP and thioredoxin 1 expression in human pancreatic cancer tissues. CONCLUSIONS: Thioredoxin-interacting protein, a putative tumor suppressor gene, is induced in response to hypoxia in a HIF-1alpha-dependent manner in pancreatic cancer cells, resulting in increased apoptosis and increased sensitivity to platinum anticancer therapy. Increased TXNIP may be a mechanism to counterbalance the prosurvival effects of HIF-1alpha.

The antitumor agent imexon activates antioxidant gene expression: evidence for an oxidative stress response.

PURPOSE: The aim of this study was to identify biomarkers that may be predictive for the clinical activity of the redox-active antitumor agent imexon. EXPERIMENTAL DESIGN: cDNA microarray and quantitative real-time PCR were used to identify global changes in gene expression in peripheral blood mononuclear cells (PBMC) collected from patients treated with imexon during a phase I trial. Electrophoretic mobility shift assays and Western blot analysis were done using the RPMI8226 myeloma cell line grown in vitro and PBMCs treated ex vivo to investigate the molecular mechanism responsible for these gene changes. RESULTS: Both cDNA microarray and quantitative real-time PCR showed the up-regulation of many antioxidant genes, including thioredoxin reductase-1, glutaredoxin-2, and peroxiredoxin-3 in PBMCs collected from patients treated with imexon. Studies in PBMCs treated ex vivo and RPMI8226 myeloma cells showed that imexon increased binding to the activator protein-1 consensus sequence measured by electrophoretic mobility shift assay. Supershift analysis showed that the majority of the activator protein-1 DNA binding activity was c-Jun, with minor contribution of Jun-D. Nuclear translocation of the nuclear factor (erythroid-derived 1)-like 2 transcription factor and its binding to the antioxidant response element was also increased after imexon treatment, which correlated with an increase in the message levels for nuclear factor (erythroid-derived 1)-like 2/antioxidant response element-regulated antioxidant genes. CONCLUSIONS: Together, these results show that a predominant biological effect of imexon is a change in redox state that can be detected in surrogate normal tissues as increased redox-sensitive transcription factor binding and increased antioxidant gene expression.

The antitumor thioredoxin-1 inhibitor PX-12 (1-methylpropyl 2-imidazolyl disulfide) decreases thioredoxin-1 and VEGF levels in cancer patient plasma.

Thioredoxin-1 (Trx-1) is a small redox protein that is overexpressed in many human tumors, where it is associated with aggressive tumor growth and decreased patient survival. Trx-1 is secreted by tumor cells and is present at increased levels in the plasma of cancer patients. PX-12 is an irreversible inhibitor of Trx-1 currently in clinical development as an antitumor agent. We have used SELDI-TOF mass spectroscopy to measure plasma Trx-1 from patients treated with PX-12 during a phase I study. Mean plasma Trx-1 levels at pretreatment were significantly elevated in the cancer patients at 182.0 ng/mL compared with 27.1 ng/mL in plasma from healthy volunteers. PX-12 treatment significantly lowered plasma Trx-1 in cancer patients having the highest plasma Trx-1 pretreatment levels. High-plasma vascular endothelial growth factor (VEGF) levels have been correlated to decreased patient survival. PX-12 treatment also significantly lowered plasma VEGF levels in cancer patients with high pretreatment VEGF levels. SELDI-TOF mass spectrometry identified seven additional plasma proteins whose levels decreased after PX-12 administration, one of which was identified as a truncated form of transthyretin. The results of this study suggest that the lowering of elevated levels of plasma Trx-1 in cancer patients may provide a surrogate for the inhibition of tumor Trx-1 by PX-12. Furthermore, PX-12 decreases plasma VEGF levels that may contribute to the antitumor activity of PX-12.

The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts.

Epidermal growth factor receptor (EGFR) inhibitors such as gefitinib show antitumor activity in a subset of non-small cell lung cancer (NSCLC) patients having mutated EGFR. Recent work shows that phosphatidylinositol-3-kinase (PI3-K) is coupled to the EGFR only in NSCLC cell lines expressing ErbB-3 and that EGFR inhibitors do not inhibit PI3-K signaling in these cells. The central role PI3-K plays in cell survival suggests that a PI3-K inhibitor offers a strategy to increase the antitumor activity of EGFR inhibitors in resistant NSCL tumors that do not express ErbB-3. We show that PX-866, a PI3-K inhibitor with selectivity for p110alpha, potentiates the antitumor activity of gefitinib against even large A-549 NSCL xenografts giving complete tumor growth control in the early stages of treatment. A-549 xenograft phospho-Akt was inhibited by PX-866 but not by gefitinib. A major toxicity of PX-866 administration was hyperglycemia with decreased glucose tolerance, which was reversed upon cessation of treatment. The decreased glucose tolerance caused by PX-866 was insensitive to the AMP-activated protein kinase inhibitor metformin but reversed by insulin and by the peroxisome proliferator-activated receptor-gamma activator pioglitazone. Prolonged PX-866 administration also caused increased neutrophil counts. Thus, PX-866, by inhibiting PI3-K signaling, may have clinical use in increasing the response to EGFR inhibitors such as gefitinib in patients with NSCLC and possibly in other cancers who do not respond to EGFR inhibition.

The thioredoxin-1 inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) decreases vascular permeability in tumor xenografts monitored by dynamic contrast enhanced magnetic resonance imaging.

PURPOSE: The purpose of this study was to use dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to measure changes in tumor xenograft permeability produced by the antitumor thioredoxin-1 (Trx-1) inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) and to assess the relationship to Trx-1 and vascular endothelial growth factor (VEGF) levels. EXPERIMENTAL DESIGN: DCE-MRI was used to monitor the dynamics of gadolinium-diethylenetriaminepentaacetic acid coupled bovine serum albumin as a macromolecular contrast reagent to measure hemodynamic changes in HT-29 human colon xenografts in immunodeficient mice treated with PX-12. Blood vessel permeability was estimated from the slope of the enhancement curves, and tumor vascular volume fraction from the ordinate. Tumor Trx-1 and VEGF was also measured. RESULTS: PX-12 caused a rapid 63% decrease in the average tumor blood vessel permeability within 2 hours of administration. The decrease lasted 24 hours and had returned to pretreatment values by 48 hours. The changes in vascular permeability were not accompanied by alterations in average tumor vascular volume fraction. There was a decrease in tumor and tumor-derived VEGF in plasma at 24 hours after treatment with PX-12, but not at earlier time points. However, tumor redox active Trx-1 showed a rapid decline within 2 hours following PX-12 administration that was maintained for 24 hours. CONCLUSION: The rapid decrease in tumor vascular permeability caused by PX-12 administration coincided with a decrease in tumor redox active Trx-1 and preceded a decrease in VEGF. DCE-MRI responses to PX-12 in patients of Trx-1 inhibition at early time points and decreased VEGF at later times, may be useful to follow tumor response and even therapeutic benefit.