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

2. 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

3. 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 Patient-Reported Outcomes version of Common Terminology Criteria for Adverse Events 1 Xiao et al. (2013). Cancer Nurs.,36(6):E1- E16 2 DiMaio et al. (2015). JCO, E Pub ahead of print. 3 Bruner et al. (2011). Translational Behavioral Medicine: Practice, Policy, Research, 1 (1), 110-122.

4. PRO-CTCAE Measurement System 1. Symptom Library2. System for Survey Administration 78 symptomatic adverse events drawn from CTCAE PRO-CTCAE questions evaluate symptom occurrence, frequency, severity, and interference Web-based system to customize surveys and manage survey administration Patient responds to surveys using web, tablet or interactive voice response (IVRS) telephone system 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

5. CTCAE vs. PRO-CTCAE Item Structures CTCAE Adverse Event Grade 12345 Mucositis oral Asymptomatic or mild symptoms; intervention not indicated Moderate pain; not interfering with oral intake; modified diet indicated Severe pain; interfering with oral intake 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

6. PRO-CTCAE Symptom Library

7. Feasibility, Acceptability & Cost Develop Items Cognitive Testing Usability testing Electronic system for survey mgmt Validation Study Evaluate utility for decision- making Spanish Validation Implement telephone reporting (IVRS) 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 2009 2015

8. Reliability and Validity 1-3 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

9. 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

10. PRO-CTCAE Implementation in 7 NCI Funded Trials NCI Early Phase Trials Consortium: NCI9568: 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 E2112: A Randomized Phase III Trial of Endocrine Therapy plus Entinostat/Placebo in Postmenopausal Patients with Hormone Receptor- Positive Advanced Breast Cancer ECOG/ACRIN EA6134: 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 BRAFV600 Mutant Melanoma

11. 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 PRO-CTCAE responses into CTCAE grades

12. NCI PRO-CTCAE Study Group NCI PRO-CTCAE Study Group Supported through NCI contracts HHSN261200800043C and HHSN261201000063C PRO-CTCAE Team: Organizational Affiliations: NCI Community Cancer Centers Program (NCCCP), NRG, Alliance, FDA We gratefully acknowledge our study participants and patient representatives!

13. 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

14. Collaboration Agreements Established with Investigators in 10 Countries

15. 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 Added Value of PRO-CTCAE 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)

16. URCC13059 A Geriatric Assessment Intervention for Patients Aged 70 and Over Receiving Chemotherapy for Advanced Cancer: Reducing Chemotherapy Toxicity in Older Adults NCI R01 (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

17. 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

18. 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)

19. 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)

20. 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