Improving Our Understanding and Management of Symptomatic Toxicity

Improving Our Understanding and Management of Symptomatic Toxicity in Geriatric Oncology Trials and Cancer Care Delivery Research Sandra A. Mitchell, Ph. D, CRNP ___________ Research Scientist and Program Director Outcomes Research Branch, Applied Research Program mitchlls@mail. nih. gov May 13, 2015

Patient-Reported Outcomes version of Common Terminology Criteria for Adverse Events • Treatment-related toxicity (safety and tolerability) • Fundamental outcome when drawing conclusions about therapeutic effectiveness, including comparative effectiveness • Currently evaluated by clinicians using Common Terminology Criteria for Adverse Events (CTCAE)

Patient-Reported Outcomes version of Common Terminology Criteria for Adverse Events • 1 of 8 of the adverse events listed in CTCAE is a symptom outcome • Validity of reporting symptom outcomes is eroded when those reports filter through research staff and clinicians 1 -2 • Staff-based adverse event reporting occurs at clinic visits; adverse events that occur between visits may be missed • Real-time ascertainment of symptomatic adverse events using PROs could improve the precision and reproducibility of adverse event reporting • PRO reporting of symptomatic toxicities is valued by trialists 3 1 Xiao et al. (2013). Cancer Nurs. , 36(6): E 1 - E 16 2 Di. Maio et al. (2015). JCO, E Pub ahead of print. 3 Bruner et al. (2011). Translational Behavioral Medicine: Practice, Policy, Research, 1 (1), 110 -122.

PRO-CTCAE Measurement System 1. Symptom Library 2. System for Survey Administration • 78 symptomatic adverse events • Web-based system to customize surveys and drawn from CTCAE manage survey administration • PRO-CTCAE questions evaluate • Patient responds to surveys using web, symptom occurrence, tablet or interactive voice response (IVRS) frequency, severity, and telephone system interference • Conditional branching (skip patterns) • Write-ins with automatic mapping to standardized terminology • Alerts for missed surveys and severe symptoms For more information: http: //healthcaredelivery. cancer. gov/resource/outcomes. html

CTCAE vs. PRO-CTCAE Item Structures CTCAE Adverse Event Mucositis oral Grade 1 Asymptomatic or mild symptoms; intervention not indicated 2 3 Moderate Severe pain; not interfering with oral intake; modified diet indicated 4 5 Life-threatening consequences; urgent intervention indicated - PRO-CTCAE Please think back over the past 7 days: What was the severity of your MOUTH OR THROAT SORES at their WORST? None / Mild / Moderate / Severe / Very severe How much did MOUTH OR THROAT SORES interfere with your usual or daily activities? Not at all / A little bit / Somewhat / Quite a bit / Very much

PRO-CTCAE Symptom Library

• Psychometrically robust library of items • Electronic system fits data collection smoothly into trials workflow and offers favorable user-experience • Accommodate patients with limited English proficiency/digital literacy • Supply meaningful data to improve understanding of symptomatic AEs Electronic system for survey mgmt Usability testing Implement telephone reporting (IVRS) Spanish Validation Feasibility, Acceptability & Cost 2009 2015 Develop Items Evaluate utility for decisionmaking Cognitive Testing Validation Study

Reliability and 1 -3 Validity • Studies conducted in diverse samples all of whom were receiving cancer-directed therapy • Samples enriched for lower educational attainment, racial/ethnic diversity, and lower performance status • Item development: rigorous process mapping out of the CTCAE and building phrasing from legacy PRO measures • Cognitive interviewing to establish content validity • Psychometric validation • Almost all PRO-CTCAE items met one or more a priori criteria for validity • Majority of items distinguished subgroups based on PS, disease site, and/or treatment characteristics 1 Hay et al (2013). Cognitive interviewing of the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to support content validity. Quality of Life Research July 20 2013 [Epub ahead of print] 2 Dueck et al. Validity and reliability of the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Manuscript under review by JAMA Oncology 3 Basch, Reeve, Mitchell et al. Development of the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). JNCI, 106(9); 2014

PRO-CTCAE Implementation in 7 NCI Funded Trials RTOG 1012: Phase II Randomized Trial of Prophylactic Manuka Honey for the Reduction of Chemoradiation Therapy Induced Esophagitis-Related Pain During the Treatment of Lung Cancer NCCTG 1048: A Phase II/III trial of Neoadjuvant FOLFOX, with Selective Use of Combined Modality Chemoradiation versus Preoperative Combined Modality Chemoradiation for Locally Advanced Rectal Cancer Patients Undergoing Low Anterior Resection with Total Mesorectal Excision Alliance/ACCRU: Eribulin vs. Paclitaxel for First or Second Line Treatment of Locally Recurrent or Metastatic Breast Cancer Alliance/ACCRU: Single arm phase II trial of TDM-1 in older adult women with HER-2 positive early stage breast cancer

PRO-CTCAE Implementation in 7 NCI Funded Trials NCI Early Phase Trials Consortium: NCI 9568: A Randomized Phase II Placebo-controlled trial of Gemcitabine+MK-1775 vs. Gemcitabine alone for Women with Recurrent Platinum-resistant Ovarian, Fallopian Tube or Primary Peritoneal Cancer ECOG/ACRIN E 2112: A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Postmenopausal Patients with Hormone Receptor. Positive Advanced Breast Cancer ECOG/ACRIN EA 6134: A Randomized Phase III trial of Dabrafenib + Trametinib followed by Ipilimumab + Nivolumab at Progression vs. Ipilimumab + Nivolumab followed by Dabrafenib + Trametinib at Progression in Patients With Advanced BRAFV 600 Mutant Melanoma

NCI-Sponsored Implementation Studies: Objectives • Feasibility and acceptability with 400+ sites of performance • Data quality • Resource requirements and cost • Measurement characteristics/interpretability: • Responsiveness to change • Sensitivity to detect differences between treatment groups • Shared reporting of symptomatic toxicities • Comparative evaluation of algorithms for mapping PROCTCAE responses into CTCAE grades

NCI PRO-CTCAE Study Group Supported through NCI contracts HHSN 261200800043 C and HHSN 261201000063 C Ethan Basch Sandra Mitchell Catherine Coleman Stephanie Consoli Cori Couture Andrea Denicoff Amylou Dueck Jana Eisenstein Maria Fawzy Shanda Finnigan Steve Friedman Joshua Gagne Jose Galvez Vinay Gangoli Marcha Gatewood Araceli Garcia-Gonzalez Cindy Geoghegan Maria Gonzalez Mehul Gulati Gaurav Gupta Jennifer Hay Madeline Hernandez-Krause Jessica Hess Lori Hudson • PRO-CTCAE Team: Amy Abernethy Jeff Abrams Suneel Allareddy Benjamin Arnold Pamela Atherton Thomas Atkinson Natalie Barragan Paul Baumgartner Lauren Becker Antonia Bennett Nancy Breen Deborah Bruner Laurie Burke Kate Castro David Cella Alice Chen Ram Chilukuri Steven Clauser Charles Cleeland • • Paul Kluetz Reshma Koganti Edward Korn Virginia Kwitkowski Suzanne Lechner Lauren Lent Yuelin Li Carol Lowenstein Donna Malveaux Michael Mejia Tito Mendoza Lori Minasian Michael Montello Hannah O'Gorman Ann O'Mara Diane Paul John Payne Frank Penedo Barbara Perez Richard Piekarz Liora Pollick Katherine Ramsey Bryce Reeve Lauren Rogak Dave Rothfarb Sean Ryan Daniel Satele Martin Schoen Deborah Schrag Ann Setser Eve Shalley Mary Shaw Marwan Shouery Jeff Sloan Diane St. Germain Don Swan Ann Marie Trentascosti Ted Trimble Andy Trotti Andrea Vinard Vish Viswanath Amy Vitro Gordon Willis Jennifer Wind Organizational Affiliations: NCI Community Cancer Centers Program (NCCCP), NRG, Alliance, FDA We gratefully acknowledge our study participants and patient

Early Adopters • >120 early adopters from academia and industry are testing PRO-CTCAE in trials and observational studies • Collaboration agreements established with these investigators: • Stimulate efficient and coordinated testing of PRO-CTCAE in clinical trials • Develop and test language translations • Allow for sharing of data and collaborative analysis • Generate evidence about best approaches for particular study contexts and patient populations

Collaboration Agreements Established with Investigators in 10 Countries

Added Value of PRO-CTCAE Provide more comprehensive outcomes assessment of treatment effects, including the effects of interventions to improve toxicity Screen for trial eligibility and for stratification Characterize the sample at baseline for better attribution of treatment-related toxicities Identify meaningfully different subgroups within the sample, as a basis for determine if outcomes such as tumor response, treatment adherence, toxicity are differentially affected Explain treatment drop-out and missing data Drive tailoring of supportive care interventions Au et al. Expert Rev. Pharmacoeconomics Outcomes Res. 2010, 10 (2) 119 -128 Smith & Street , Health Economics, Jan 2012 Gotay et al, J of Clin. Oncology 2008, 26 (8), 1355 -1363 Carey & Gotay, International Journal of Gynecological Cancer 2011, 21 (4), 7842 -787 Wagner et al. J. of Clin. Oncology, 2007, 25 (32): 50585062)

URCC 13059 A Geriatric Assessment Intervention for Patients Aged 70 and Over Receiving Chemotherapy for Advanced Cancer: Reducing Chemotherapy Toxicity in Older Adults NCI R 01 (PI: Mohile) • Multi-site cluster randomized study through the University of Rochester NCORP Research Base evaluating whether a Geriatric Assessment intervention can reduce chemotherapy toxicity • n=700; assessments done at baseline, 4 weeks and 3 months after starting a new chemotherapy regimen

Study Objective • Determine if providing a baseline geriatric assessment and geriatric assessment-driven tailored recommendations to oncologists reduces grade 3 -5 chemotherapy toxicity in patients aged 70 and over with advanced solid tumor malignancy beginning their first line of treatment

PRO-CTCAE Exploratory Aims • Examine the association between patient-reported symptoms (as measured by PRO-CTCAE) and geriatric domains (as measured by geriatric assessment) • Compare PRO-CTCAE and physician-rated CTCAE in a sample of older patients receiving first line chemotherapy. • Explore the association between PRO-CTCAE and decisions about chemotherapy dose reduction or dose delay (that is relative dose intensity) • To examine the association between PRO-CTCAE and adverse outcomes (early discontinuation of chemotherapy, hospitalizations, and mortality)

Utility of PRO-CTCAE • Phase I: Exploratory • Gauge side effects relative to dose escalation; refine measurement approaches (items, timing) for later phase studies • Phase II: Describe Toxicity in Depth • Assess tolerablility of the recommended phase II dosing • Identify chronic symptomatic toxicities that may impair adherence • Explore approaches (schedule/dosing, supportive care) to reduce symptomatic adverse effects • Phase III: Assess Overall Benefit/Risk for Regimen • Evaluate efficacy and tolerability on a wider scale • Assess impact of dosing modifications to reduce chronic symptomatic toxicities on overall benefit/risk • Phase IV: Efficacy Effectiveness • Optimize tolerability • Tailor regimens for vulnerable sub-populations (comorbidities, frail, older adults)

Conclusions • Wide range of potential applications: • Capture symptomatic toxicity in early and late phase trials • Non-inferiority trials : reduction in toxicity provides evidence of treatment benefit/effectiveness • Comparative effectiveness studies • Phenotype participants in registries and biospecimen banks • Improve treatment tolerability and care delivery for frail and older patients