Society of Clinical Trials Conference Reassessing objectives and appropriate endpoints in early phase clinical trials Emily V. Dressler, PhD Associate Professor EmilyDressler@uky.edu Society of Clinical Trials Conference Liverpool, England May 9, 2017

Outline Brief overview of immunotherapies Outcomes for Early Phase Designs Toxicity & Target Goal Efficacy Considerations

IMMUNOTHERAPIES

Motivation Immunotherapy is one of the latest and greatest options entering clinical trials Everyone is wanting to add it to traditional standards including chemotherapy, radiation, targeted agents, and combinations of those This class of drugs doesn’t fit traditional clinical trial profiles, so what else do we need to take into consideration?

Introduction to Immunotherapy Utilizes immune system to fight cancer cells instead of targeting the cancer cell specifically Antibodies that block specific immune checkpoint compounds Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) Programmed cell death protein 1 (PD-1) Its ligand PD-L1 Immunostimulatory monoclonal antibodies (imAbs)

Approved compounds (April 2016) Yervoy Opdivo Keytruda First-line Metastatic NSCLC – Oct 2016 Tecentriq (atezolizumab) – FDA Approved – Bladder and NSCLC

Durvalumab approved May 1st for bladder after accelerated approval in February Over 30 other trials ongoing single or combination

How does this work? Immune activation and T-cell proliferation starts early after 1st administration Clinical measurable antitumor effects mediated by activated immune cells over weeks to months Potential delayed effect on patient survival several months after 1st administration compared with agents not requiring immune activation

Issues to Consider Why do they work in some cancers Do we need a ‘cocktail’ of treatments similar to AIDS regimens? We still do not fully understand the tumors’ micro-environments High price tag! Pembrolizumab can cost ~$150K/year

Toxicity Considerations

Primary Objective Traditional phase I trials aim to identify the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) Classically assumes toxicity and efficacy increase monotonically with dose levels With the onset of targeted agents, phase I have moved to focus more on a biomarker-driven approach

Are we doing a good job? With immunotherapies, often MTDs cannot be identified Postel-Vinay et al assessed 13 phase I immunotherapy trials 1 trial was able to identify per-protocol defined dose-limiting toxicities (DLTs) in the 1st cycle of treatment Most others identified the maximum administered dose as the RP2D

How is toxicity different? imAbs appear to not cause acute or cumulative toxicities Other than anaphylactic infusion reactions Immune-related adverse events (irAEs) are not usually observed during the 1st cycle but more around 8-10 weeks of starting treatment regardless of grade Most phase I trials do not incorporate late-onset DLTs

irAEs Unlocking of mechanisms of immune control on normal tissue can have many effects Dermatologic, gastrointestinal, hepatic, endocrine and other less common inflammatory events These profiles are different between PD-1/PD-L1 (70% experiencing an irAE) and CTLA-4 (90% with irAE) blockades But grade 3 or 4 toxicities are approximately 10-20%, similar to traditional cytotoxics But might not occur in the 1st cycle

irAEs Do not appear cumulative over time Unknown if rates of these events can be decreased by modifying dosage, or by using lower-than-approved doses in combination or in sequence Management of irAEs include temporary immunosuppression with corticosteroids, which often results in complete reversibility Failure to do so can lead to severe toxicity or death

Recommendations irAEs can rapidly evolve into potentially life-threatening conditions Grade 2 events might prompt treatment interruption until managed Recommendations: consider DLTs to include immune-related toxicity Take into account toxicity scoring as DLTs even past 1st cycle

New objective? Contrary to classical models, increase in dosage does not always result in increased toxicity or efficacy/activity Shifting away from MTD to identifying minimal immunologically active dose Dose that causes saturation phenomenon in specific PD and PK parameters Issues: what is the minimal degree of target modulation that is pharmacologically meaningful Could immunologic monitoring (CD4+ or CD8+ T-cells) be a good biomarker of immune response?

Design Options Allow for underlying tox/efficacy to not always be monotonic Use PK/PD as an outcome to monitor activity in addition to toxicity Toxicity should now include irAEs (which may present as less severe as the traditional DLT) and need to account for the late-onset presentation of those irAEs

Efficacy CONSIDERATIONS

Efficacy Early phase trials often aim to additionally show hint of efficacy or proof of biologic mechanism Traditional endpoint: RECIST criteria (CR, PR, SD, PD) – some patients respond in a classic fashion With immunologics some patients have decrease in lesion size after an initial increase Shown to be inflammatory cell infiltrates or necrosis Others actually have reduction in total tumor burden – initially found to be associated with edema and infiltrates of immune cells and transient increases in baseline tumor lesions Both would be progressive disease according to RECIST

Alternative criteria Immune-related response criteria (irRC) Example utilized in melanoma and ipilimumab Remains an exploratory endpoint but there is a push to use this more routinely

Conclusions Immunotherapies bring unique challenges that require closer interaction with biostatisticians and clinicians Need to understand the clinical implications to better design a trial for immunotherapies Endpoints, timing, and toxicity evaluation

Design Options Any design that includes both toxicity and efficacy outcomes Potential for efficacy outcomes might not be monotonically increasing Consideration of late-onset toxicity and efficacy outcomes Time to event extensions of current designs

A few options… (In no way exhaustive) Eff-Tox Design (Thall 2004) Tri-CRM (Zhang 2006, Mandrekar 2014) Partial Order CRM and CRM for non-monotonic assumptions (Wages et al 2015) Bayesian dose-finding design incorporating toxicity from multiple treatment cycles (Yin et al, Stat in Med, September 2016)

Thank You! Any Questions?