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

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

5. IMMUNOTHERAPIES

6. 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?

7. 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)

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

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

11. 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

12. 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

13. Toxicity Considerations

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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?

21. 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

22. Efficacy CONSIDERATIONS

23. 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

24. 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

28. 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

29. 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

30. 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)

31. Thank You!
Any Questions?