The Weighted Toxicity Score: Confirmation of a Simple Metric to Communicate Toxicity in Randomized Trials of Systemic Cancer Therapy.

INTRODUCTION: FDA's Project Optimus was developed in part to better identify appropriate dose and schedule of cancer therapeutics. The tabular method to summarize patients' maximum toxicity in a clinical trial does not allow for ready comparison to the treatment's benefit. In this manuscript, we apply a simple tool, the weighted toxicity score (WTS), to trials involving lung cancer immunotherapy and chemotherapy, as well as those cited in a recent publication as examples of trials that represent successful reduction of the appropriate dose of anti-cancer agents. METHODS: PubMed was queried for randomized controlled trials of therapy involving immune checkpoint inhibitors in lung cancer. Trial data from studies highlighting initial success with dose adjustments after FDA approval also were assembled and analyzed according to the WTS procedure described previously, compared to clinical outcomes data. RESULTS: The WTS provided, with the clinical outcome(s), a data pair that leads to easy interpretation of the expected benefit versus relative toxicity of studies involving immunotherapy or chemoimmunotherapy in lung cancers. The WTS was consistent with the conclusions of the primary studies, helping to quantitate the toxicity difference between treatments in a previously unavailable way. CONCLUSION: The WTS provides a tool to show the cost in toxicity of therapy in a randomized clinical trial, with applicability to studies involving chemotherapy, immunotherapy, or kinase-directed therapy. Inclusion of a running tally of WTS during conduct of a trial could serve as one means to adjust dosing or to provide feedback during data safety monitoring of a clinical trial.

Bayesian dose escalation with overdose and underdose control utilizing all toxicities in Phase I/II clinical trials.

Escalation with overdose control (EWOC) is a commonly used Bayesian adaptive design, which controls overdosing risk while estimating maximum tolerated dose (MTD) in cancer Phase I clinical trials. In 2010, Chen and his colleagues proposed a novel toxicity scoring system to fully utilize patients' toxicity information by using a normalized equivalent toxicity score (NETS) in the range 0 to 1 instead of a binary indicator of dose limiting toxicity (DLT). Later in 2015, by adding underdosing control into EWOC, escalation with overdose and underdose control (EWOUC) design was proposed to guarantee patients the minimum therapeutic effect of drug in Phase I/II clinical trials. In this paper, the EWOUC-NETS design is developed by integrating the advantages of EWOUC and NETS in a Bayesian context. Moreover, both toxicity response and efficacy are treated as continuous variables to maximize trial efficiency. The dose escalation decision is based on the posterior distribution of both toxicity and efficacy outcomes, which are recursively updated with accumulated data. We compare the operation characteristics of EWOUC-NETS and existing methods through simulation studies under five scenarios. The study results show that EWOUC-NETS design treating toxicity and efficacy outcomes as continuous variables can increase accuracy in identifying the optimized utility dose (OUD) and provide better therapeutic effects.

Evaluation of Scores to Reflect Toxicity Impact on Quality of Life of Patients With Platinum-Resistant Ovarian Cancer: AURELIA Substudy.

BACKGROUND: Current standards for toxicity reporting do not fully capture the impact of adverse events (AEs) on patients' quality of life (QoL). This study aimed to evaluate the association between toxicity and QoL by using toxicity scores that take into account CTCAE grade grouping and AE duration and cumulation. METHODS: Analyses were performed on the AURELIA trial dataset, including 361 patients with platinum-resistant ovarian cancer treated with chemotherapy alone or with bevacizumab. Global and physical functioning QoL were issued from the EORTC QoL Questionnaire-Core 30 (QLQ-C30), collected at baseline and 8/9 and 16/18 weeks after treatment initiation. Four toxicity scores were computed: the total number of AEs, multiplied by their grade and not, and the cumulative duration of AEs, weighted by their grade and not. Each score included all AEs or only grade 3/4 nonlaboratory or treatment-related AEs. The relationship between toxicity scores and QoL was assessed through linear mixed regression. RESULTS: We found that 171 (47.5%) and 43 (11.9%) patients experienced at least one grade 3 or 4 AE, respectively, whereas 113 (31.4%) experienced grade 2 AEs only. Physical QoL was negatively associated with all toxicity scores when computed with all grades of AEs (all P<.01), with a weaker association when treatment-related AEs were considered. Global QoL was negatively associated with toxicity scores computed with nonlaboratory all-grade AEs only (ß, -3.42 to -3.13; all P<.01). Degrees of association were lower when considering the AE duration. CONCLUSIONS: In this analysis of patients with platinum-resistant ovarian cancer, toxicity scores based on the cumulative number of AEs, modulated or not by grade, were more effective at predicting QoL changes than those based on AE duration. Toxicity impact on QoL was better reflected when grade 2 AEs were taken into account together with grade 3/4 AEs, whatever their treatment imputability, and when laboratory AEs were excluded.

Impact of the Cancer and Aging Research Group score and treatment intensity on survival and toxicity outcomes in older adults with advanced noncolorectal gastrointestinal cancers.

BACKGROUND: Little is known regarding the predictive value of the Cancer and Aging Research Group (CARG) score, a validated chemotherapy toxicity prediction tool for older adults with cancer, for survival outcomes. METHODS: This was a prospective observational study of patients ≥65 years old receiving first-line chemotherapy for advanced noncolorectal gastrointestinal cancer for which combination chemotherapy is the standard of care. Overall survival (OS), time to treatment failure (TTF), which was defined as the time from the start of first-line chemotherapy to the discontinuation of first-line chemotherapy for any reason, and toxicity were compared in 4 groups of patients: 1) non-high-risk (nHR) CARG score (<10) and standard-intensity therapy (ST), 2) nHR score and reduced-intensity therapy (RT), 3) high-risk (HR) CARG score (≥10) and ST, and 4) HR score and RT. RESULTS: Fifty patients (median age, 71 years) were enrolled. The median OS in months was 19.7 in nHR/ST (n = 19) group, 12.7 in nHR/RT (n = 9) group, 4.5 in HR/ST (n = 12) group, and 3.9 in HR/RT (n = 10) group (log-rank test, P = .005). The median TTF in months was 9.1 in nHR/ST group, 2.5 in nHR/RT group, 2.3 in HR/ST group, and 3.0 in HR/RT group (log-rank test, P = .04). The CARG-score category was prognostic of OS (HR, 3.04; 95% confidence interval [CI], 1.59-5.83, P = .001) and TTF (HR, 2.60; 95% CI, 1.31-5.20, P = .007). The incidence of grade 3-5 toxicity was 68% in nHR/ST group, 33% in nHR/RT group, 92% in HR/ST group, and 70% in HR/RT group (Fisher exact test, P = .048). CONCLUSIONS: Risk-adapted chemotherapy based on the CARG-score may improve treatment outcomes.

A modified multiparametric assay using HepaRG cells for predicting the degree of drug-induced liver injury risk.

The approach for predicting the degree of drug-induced liver injury (DILI) risk was investigated quantitatively in a modified multiparametric assay using HepaRG cells. Thirty-eight drugs were classified by DILI risk into five categories based on drug labels approved by the Food and Drug Administration (FDA) as follows: withdrawn (WDN), boxed warning (BW), warnings and precautions (WP), adverse reactions (AR), and no match (NM). Also, WP was classified into two categories: high and low concern. Differentiated HepaRG cells were treated with drugs for 24 h. The maximum concentration was set at 100-fold the therapeutic maximum plasma concentration (Cmax ). After treatment with drugs, the cell viability, glutathione content, caspase 3/7 activity, lactate dehydrogenase leakage and albumin secretion were measured. As modified cut-off values of each parameter, the TC50 (toxic concentration that decreased the response by 50%) and EC200 (effective concentration giving a response equal to 200% of controls) were calculated. In addition, the toxicity score (total sum score of the cytotoxic level of each parameter) was calculated. This modified multiparametric assay showed an 87% sensitivity and 87% specificity for predicting the DILI risk. The toxicity score showed a good predictive performance for WDN, BW and WP (high concern) categories [cut-off: score ≥ 1; area under a receiver operating characteristic curve (ROC-AUC): 0.88], and for WDN and BW categories (cut-off: score ≥ 3; ROC-AUC: 0.88). This study newly indicated that the degree of DILI risk might be predictable quantitatively by assessing the toxicity score in the modified multiparametric assay using HepaRG cells. Copyright © 2016 John Wiley & Sons, Ltd.

Dose finding with continuous outcome in phase I oncology trials.

The goal of a phase I clinical trial in oncology is to find a dose with acceptable dose-limiting toxicity rate. Often, when a cytostatic drug is investigated or when the maximum tolerated dose is defined using a toxicity score, the main endpoint in a phase I trial is continuous. We propose a new method to use in a dose-finding trial with continuous endpoints. The new method selects the right dose on par with other methods and provides more flexibility in assigning patients to doses in the course of the trial when the rate of accrual is fast relative to the follow-up time.

Challenges and Innovations in Phase I Dose-Finding Designs for Molecularly Targeted Agents and Cancer Immunotherapies.

Phase I oncology trials are designed to identify a safe dose with an acceptable toxicity profile. In traditional phase I dose-finding design, the dose is typically determined based on the probability of severe toxicity observed during the first treatment cycle. The recent development of molecularly targeted agents and cancer immunotherapies call for new innovations in phase I designs, because of prolonged treatment cycles often involved. Various phase I designs using toxicity and efficacy endpoints from multiple treatment cycles have been developed for these new treatment agents. Here, we will review the novel endpoints and designs for the phase I oncology clinical trials.

Escalation with overdose control using all toxicities and time to event toxicity data in cancer Phase I clinical trials.

The primary purposes of Phase I cancer clinical trials are to determine the maximum tolerated dose (MTD) and the treatment schedule of a new drug. Phase I trials usually involve a small number of patients so that fully utilizing all toxicity information including time to event toxicity data is key to improving the trial efficiency and the accuracy of MTD estimation. Chen et al. proposed a novel normalized equivalent toxicity score (NETS) system to fully utilize multiple toxicities per patient instead of a binary indicator of dose limiting toxicity (DLT). Cheung and Chappell developed the time to toxicity event (TITE) approach to incorporate time to toxicity event data. Escalation with overdose control (EWOC) is an adaptive Bayesian Phase I design which can allow rapid dose escalation while controlling the probability of overdosing patients. In this manuscript, we use EWOC as a framework and integrate it with the NETS system and the TITE approach to develop an advanced Phase I design entitled EWOC-NETS-TITE. We have conducted simulation studies to compare its operating characteristics using selected derived versions of EWOC because EWOC itself has already been extensively compared with common Phase I designs [3]. Simulation results demonstrate that EWOC-NETS-TITE can substantially improve the trial efficiency and accuracy of MTD determination as well as allow patients to be entered in a staggered fashion to significantly shorten trial duration. Moreover, user-friendly software for EWOC-NETS-TITE is under development.

Interactive Software "Isotonic Design using Normalized Equivalent Toxicity Score (ID-NETS©TM)" for Cancer Phase I Clinical Trials.

Isotonic Design using Normalized Equivalent Toxicity Score (ID-NETS) is a novel Phase I design that integrates the novel toxicity scoring system originally proposed by Chen et al. [1] and the original Isotonic Design proposed by Leung et al. [2]. ID-NETS has substantially improved the accuracy of maximum tolerated dose (MTD) estimation and trial efficiency in the Phase I clinical trial setting by fully utilizing all toxicities experienced by each patient and treating toxicity response as a quasi-continuous variable instead of a binary indicator of dose limiting toxicity (DLT). To facilitate the incorporation of the ID-NETS method into the design and conduct of Phase I clinical trials, we have designed and developed a user-friendly software, ID-NETS(©TM), which has two functions: 1) Calculating the recommended dose for the subsequent patient cohort using available completed data; and 2) Performing simulations to obtain the operating characteristics of a trial designed with ID-NETS. Currently, ID-NETS(©TM)v1.0 is available for free download at http://winshipbbisr.emory.edu/IDNETS.html.