Designs of Early Phase Cancer Trials with Drug Combinations

We discuss several innovative phase I and phase I--II designs for early phase cancer clinical trial with drug combinations focusing on continuous dose levels of both agents. For phase I trials with drug combinations, the main objective is to estimate the maximum tolerated dose (MTD) curve in the two-dimensional Cartesian plane. A parametric model is used to describe the relationship between the doses of the two agents and the probability of dose-limiting toxicity (DLT). Trial design proceeds using cohorts of two patients receiving doses according to univariate escalation with overdose control (EWOC) or continual reassessment method (CRM). At the end of the trial, the MTD is estimated as a function of Bayes estimates of the model parameters. Furthermore, we present the model where a fraction of DLTs can be attributed to one or both agents, and show how the parametric designs can be adapted to account for an unknown fraction of attributable DLTs. We also consider the inclusion of a binary baseline covariate to describe sub-groups with different frailty levels. In phase I--II trials, it may not be possible to evaluate efficacy in a short window of time. In this case, two-stage designs are frequently employed. First, a set of maximum tolerated dose combinations is selected. Next, the selected set is then tested for efficacy, sometimes in a different patient population than that used in the first stage. We discuss binary and time-to-event endpoints to identify dose combinations along the MTD curve with maximum probability of efficacy in the second stage

Development of a Web-Based Interactive Tool for Visualizing Breast Cancer Clinical Trial Tolerability Data

PurposeLongitudinal patient tolerability data collected as part of randomized controlled trials are often summarized in a way that loses information and does not capture the treatment experience. To address this, we developed an interactive web application to empower clinicians and researchers to explore and visualize patient tolerability data.MethodsWe used adverse event (AE) data (Common Terminology Criteria for Adverse Events) and patient-reported outcomes (PROs) from the NSABP-B35 phase III clinical trial, which compared anastrozole with tamoxifen for breast cancer-free survival, to demonstrate the tools. An interactive web application was developed using R and the Shiny web application framework that generates Sankey diagrams to visualize AEs and PROs using four tools: AE Explorer, PRO Explorer, Cohort Explorer, and Custom Explorer.ResultsTo illustrate how users can use the interactive tool, examples for each of the four applications are presented using data from the NSABP-B35 phase III trial and the NSABP-B30 trial for the Custom Explorer. In the AE and PRO explorers, users can select AEs or PROs to visualize within specified time periods and compare across treatments. In the cohort explorer, users can select a subset of patients with a specific symptom, severity, and treatment received to visualize the trajectory over time within a specified time interval. With the custom explorer, users can upload and visualize structured longitudinal toxicity and tolerability data.ConclusionWe have created an interactive web application and tool for clinicians and researchers to explore and visualize clinical trial tolerability data. This adaptable tool can be extended for other clinical trial data visualization and incorporated into future patient-clinician interactions regarding treatment decisions

Overall side effect assessment of oxaliplatin toxicity in rectal cancer patients in NRG oncology/NSABP R04

PurposeRegulatory guidance suggests capturing patient-reported overall side effect impact in cancer trials. We examined whether the Functional Assessment of Cancer Therapy (FACT) GP5 item ("I am bothered by side effects of treatment") post-neoadjuvant chemotherapy/radiotherapy differed between oxaliplatin vs. non- oxaliplatin arms in the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial of stage II-III rectal cancer patients.MethodsThe R-04 neoadjuvant trial compared local-regional tumor control between patients randomized to receive 5-fluorouracil or capecitabine with radiation, with or without oxaliplatin (4 treatment arms). Participants completed surveys at baseline and immediately after chemoradiotherapy. GP5 has a 5-point response scale: "Not at all" (0), "A little bit" (1), "Somewhat" (2), "Quite a bit" (3), and "Very much" (4). Logistic regression compared the odds of reporting moderate-high side effect impact (GP5 2-4) between patients receiving oxaliplatin or not after chemoradiotherapy, controlling for relevant patient characteristics. We examined associations between GP5 and other patient-reported outcomes reflecting side effects.ResultsAnalyses were performed among 1132 study participants. Participants receiving oxaliplatin were 1.58 times (95% CI: 1.22-2.05) more likely to report moderate-high side effect bother at post-chemotherapy/radiation. In both arms, worse overall side effect impact was associated with patient-reported diarrhea, nausea, vomiting, and peripheral sensory neuropathy (p < 0.01 for all).ConclusionThis secondary analysis of R-04 found that GP5 distinguished between patients receiving oxaliplatin or not as part of their post-neoadjuvant chemoradiotherapy, adding patient-centric evidence on the reduced tolerability of oxaliplatin and demonstrating that GP5 is sensitive to known toxicity differences between treatments.ClinicaltrialsGOV: NCT00058474

Clinician and Patient Perspectives on a Patient-Facing Online Breast Cancer Symptom Visualization Tool

PurposeEndocrine treatments for patients with hormone-sensitive breast cancer are associated with significant side effects that can negatively affect health-related quality of life and result in treatment discontinuation. The objective of this qualitative study was to obtain feedback from stakeholder clinicians and patients about an online interactive tool that was designed to provide information and visualizations of breast cancer symptoms.MethodsThe online Breast Cancer Symptom Explorer tool was developed to allow patients to visualize trajectories for common symptoms associated with tamoxifen and anastrozole using symptom data from the NSABP B35 breast cancer clinical trial. To refine the tool, virtual focus groups were conducted among oncology clinicians and women with a history of breast cancer who had received treatment with an aromatase inhibitor or tamoxifen, seeking feedback on the tool and its potential usefulness. Discussions took place using a secure web-conferencing platform following a semi-structured interview guide. Focus groups were audio-recorded, transcribed, and analyzed using reflexive thematic analysis.ResultsNine focus groups were conducted (n = 21 participants: eight clinicians and 13 patients). Key benefits and barriers to tool use emerged from the discussions. Both patients and oncologists valued the ability to engage with the tool and visualize symptoms over time. They indicated that ideal settings for its use would be at home before treatment initiation. Combinations of graphical representations with text were perceived to be most effective in communicating symptoms. Key barriers identified included concerns about accessibility to the tool and digital literacy, with recommendations to simplify the text and provide health literacy support to enhance its clinical utility in the future.ConclusionClinician and patient involvement was critical for refinement of the breast cancer symptom explorer and provided insights into its future use and evaluation of the tool in clinical decision making