Methodological challenges of studying CIPN during chemotherapy March 23, 2017 Jennifer Gewandter, PhD, MPH

Presentation objectives Outline the design challenges and issues to consider when designing a CIPN study during chemotherapy Summarize how published RCTs have addressed these design challenges Propose topics for design discussion

Challenges Trial objectives Eligibility Measurement Endpoints Limited epidemiology and natural history Analyses

Challenges Trial objectives Eligibility Measurement Endpoints Limited epidemiology and natural history Analyses

Challenge: Trial objectives Identify study objective: Primary prevention – initiate preventive treatment before chemotherapy Secondary prevention – initiate preventive treatment after start of chemotherapy but before CIPN symptoms Tertiary prevention – initiate preventive treatment after detecting neuropathy signs or symptoms in order to prevent worsening Symptomatic treatment – treatment of established CIPN symptoms

Published RCTs - Objectives Systematic Review 38 RCTs of pharmacologic treatments published prior to November 2015 Prevention Trials (36) 23 (61%) primary prevention (treatment initiated before or on the same day as chemotherapy) 10 (26%) exact timing of treatment initiation was not clear, but there was no indication that CIPN symptoms appeared prior to treatment 1 (2.5%) “As close as possible to the beginning of chemotherapy” 1 (2.5%) “Ideally before the first cycle, but required to be before the second cycle” 1 (2.5%) “Within 4 days of the first dose of chemotherapy” 2 (5%) symptomatic treatment trials

Challenges Trial objectives Eligibility Measurement Endpoints Limited epidemiology and natural history Analyses

Challenges: Eligibility Balance feasibility and generalizability with internal validity All trials Patient characteristics Multiple cancer types Multiple chemotherapy types / agents / regimens Early stage vs. metastatic Diabetic / Alcoholic / HIV+ patients Prior exposure to neurotoxic treatments Concomitant treatments for neuropathy

Published RCTs – Cancer characteristics Percentage of Trials (of 38) Included cancer stages 15 (40%) early and advanced 8 (21%) advanced only

Published RCTs - Chemotherapy characteristics Percentage of Trials (of 38) 15 (40%) specifically stated that they included only 1 regimen

Published RCTs - Common exclusion criteria Percentage of Trials (of 38)

Challenges: Eligibility Balance feasibility and generalizability with internal validity All trials Symptomatic treatment trials Patient characteristics Multiple cancer types Multiple chemotherapy types / agents / regimens Early stage vs. metastatic Diabetic / Alcoholic / HIV+ patients Prior exposure to neurotoxic treatments Concomitant treatments for neuropathy Definition of CIPN Assessment tool vs. clinician diagnosis? Who can administer assessment tool? When to assess CIPN in relation to: Chemotherapy treatments Enrollment in the study Minimum severity required? Which symptom(s), sign(s)?

Published RCTs - Treatment trials: Inclusion criteria CIPN-related inclusion criteria for the 2 symptomatic treatment trials Symptomatic treatment trial 1 “Patients reporting a distressing acute neurotoxicity after administration of their oxaliplatin-based chemotherapy” Symptomatic treatment trial 2 ≥ 3 out of 10 pain, numbness, or tingling

Challenges Trial objectives Eligibility Measurement Endpoints Limited epidemiology and natural history Analyses

Challenges: Measurement All trials Variability in between-patient symptom / sign presentation Pain Tingling Cramping Weakness Numbness Burning Cold-induced symptoms Impaired balance Primary outcome measure Clinically meaningful Sensitive to change Symptoms, signs, both? Does the treatment target specific symptoms?

Published RCTs - Primary outcome measures (22 identified) Clinician or patient reported symptom and/or function interference measure NCI-CTCAE (n=4; 18%) EORTC-CIPN20 (n=2; 9%) Other (n=6; 26%) Clinician reported symptom and sign composite TNS (n= 3; 14%) Other (n=2; 10%) Sign measure Vibration test (n=3; 14%) Composite of electrophysiology outcomes (n=1; 5%) Receipt of 6 cycles of chemotherapy without significant peripheral neuropathy or impairments in electrophysiology (n=1; 5%)

Challenges: Measurement Severity of CIPN is dependent on Type of chemotherapy Cumulative dosage of chemotherapy Timing of the dosing regimen Time since last dose of chemotherapy Dose delays and discontinuations Scheduling of assessments # of different chemotherapy regimens included

Published RCTs – Timing of assessments Prevention trials (9 reported timing) Assessments made prior to chemotherapy doses (n=7; 78%) Assessments made on specified days after chemotherapy doses (n=2; 12%) Symptomatic treatment trial (1 reported timing) Assessments made on specified days after chemotherapy doses

Challenges Trial objectives Eligibility Measurement Endpoints Limited epidemiology and natural history Analyses

Challenges: Primary endpoints - Prevention Considerations Neuropathy occurrence: By end of chemo (Y/N) Time to Cumulative dosage to Variability in timing of chemotherapy dosing (if multiple regimens allowed) Neuropathy severity: At specified cycle number At specified time point after chemo initiation At specified time point after chemo completion Summary of multiple time points during chemo Dichotomous endpoint; potentially has lower power Chemotherapy discontinuation: Due to other causes Due to neuropathy Chemotherapy received: Full course (Y/N) Percentage of full course

Published RCTs: Primary endpoints – Prevention (18 identified) Percentage of Primary Endpoints (of 18) Severity

Challenges: Primary endpoints – Symptomatic treatment Considerations Severity At one or multiple specified time points Before or after a chemotherapy dose Variability in timing of chemotherapy dosing (if multiple regimens allowed) Chemotherapy discontinuation: Due to neuropathy Due to other causes Percentage improvement in symptoms: From experimental treatment initiation Relative to previous chemotherapy dose (with no experimental treatment) Dichotomous endpoint; potentially has lower power After single or multiple chemotherapy doses

Challenges Trial objectives Eligibility Measurement Endpoints Limited epidemiology and natural history Analyses

Challenges: Limited epidemiology and natural history Prevention Trials Limited literature on: Neuropathy incidence rates by cancer and chemotherapy type Studies use inconsistent CIPN measurement tools Rates of chemotherapy discontinuation due to neuropathy All Trials Limited literature on effects of CIPN symptoms on function and quality of life

Challenges Trial objectives Eligibility Measurement Endpoints Limited epidemiology and natural history Analyses

Challenges: Primary analysis Prevention Trials and some symptomatic treatment trials All trials Accommodating missing data from participants who discontinue the trial The neuropathy-causing agent (i.e., chemotherapy) is: Sometimes altered after randomization Can be affected by the treatment How to handle participants who discontinue or delay chemotherapy in the analyses

Published trials – handling of premature discontinuation of chemotherapy Prevention trials: Excluded unless they reached a minimum cycle number or cumulative dosage of chemotherapy (n=6) Excluded if didn’t complete the planned chemotherapy up until the time point of assessment (n=2) Summary statistic prorated for #of chemotherapy cycles completed (n = 1) Symptomatic treatment trial: Discontinued chemotherapy before achieving responder status = non-responders

Challenges Trial objectives Eligibility Measurement Endpoints Limited epidemiology and natural history Analyses

Considerations for designing eligibility criteria Goal - establish recommendations for eligibility criteria related to the following: Localized or metastatic cancers or both One or multiple cancer types One or multiple chemotherapy types / agents / regimens Diabetic / Alcoholic / HIV+ patients Prior exposure to neurotoxic treatments Concomitant treatments for neuropathy Others? Recommendations may be different for different study objectives.

Considerations for Endpoints Goal – Create a list of recommended endpoints Discuss the advantages and disadvantages of different endpoints Create a roadmap of future research to support our recommendations

Considerations for analyses Goal – create recommendations regarding how to handle participants who prematurely discontinue chemotherapy Discuss the following possibilities: Include all participants as randomized regardless of chemotherapy received Remove participants who don’t receive a minimum cumulative dosage of chemotherapy Adjust for the amount of chemotherapy received Which of these are reasonable as primary analyses or only as sensitivity analyses?

Acknowledgements Robert Dworkin, PhD Roy Freeman, MD Shannon Smith, PhD Lynn Gauthier, PhD Rachel Kitt, BS Guido Cavaletti, MD Mike McDermott, PhD Nimish Mohile, MD Supriya Mohile, MD Gordon Smith, MD Mohamed Tejani, MD Dennis Turk, PhD

Characterization of outcome measures reported in each publication Considering all reported outcome measures Symptom measures only Symptom and sign measures Symptom measures and electrophysiology outcomes Sign measures only Symptom measures and objective function measures (e.g., pegboard test) Symptom and sign measures and electrophysiology outcomes   15 (40%) 6 (16%) 5 (13%) 2 (5%)

Timing of experimental treatments and assessments   N (%) Frequency of treatment (of the 34 (89%) articles that reported it) Daily or multiple times daily On the same day as each chemotherapy dose Daily for a specified number of days following each chemotherapy dose Other 16 (47%) 11 (32%) 2 (6%) 5 (15%) Timing of assessment (of the 36 (95%) articles that reported it) At particular cycle numbers (but not every cycle) Every cycle At specified weeks post chemotherapy initiation After participant receives a pre-specified cumulative dosage of chemotherapy Biweekly for some measures only at study endpoint for other measures 15 (42%) 12 (33%) 6 (17%)  1 (3%)

Published trials - disposition reporting Percentage of articles (of 38)

Safety considerations Challenge: Administering an experimental treatment in conjunction with chemotherapy – possible affects on chemotherapy efficacy. CIPN efficacy studies likely won’t be powered to detect differences in chemotherapy efficacy. Can we provide any recommendations for standards for monitoring this safety concern? When should experimental treatments only be used in advanced cancer patients? Considering available preclinical and clinical data and theoretical mechanisms

Published RCTs: Primary endpoints – Acute treatment 100% relief of acute neuropathy symptoms (days 2-5 post chemotherapy doses) on the NPSI Included multiple chemotherapy cycles and not clear if 100% relief was required at multiple cycles or last cycle If a participant discontinued chemotherapy before reaching 100% response, they were counted as not achieving relief.

Published RCTs: Primary endpoints - Prevention Primary endpoints (of the 19 (51%) prevention articles that identify a primary endpoint) Occurrence of a grade 2 neuropathy using the NCI-CTCAE Occurrence of neuropathy measured using another measure Vibration threshold at completion of chemotherapy Severity of neuropathy measured by the EORTC-CIPN20 or electrophysiology composite score after specific number of chemotherapy cycles AUC of neuropathy severity during chemotherapy measured by the EORTC-CIPN20 (sensory subscale) Severity of neuropathy measured using the FACT/NTX at a specific time point after initiation of chemotherapy Severity and occurrence of neuropathy 1 month after completion of chemotherapy, measured by the TNS (both identified as primary) Severity of author-developed symptom/sign composite score 3 months after completion of chemotherapy Response, defined as receipt of 6 cycles of chemotherapy without significant peripheral neuropathy or impairments in electrophysiology Neuropathy free interval, defined by the time receiving chemotherapy before the occurrence of bilateral paresthesia rated as 3 or higher on a 0 – 10 NRS   4 (20%) 3 (15%) 2 (10%) 2 10(%) 1 (5%)