Early drug development and emerging new treatments Unmasking Side Effects from First-in-Man Antineoplastic Medicine

Transcription

1 Early drug development and emerging new treatments Unmasking Side Effects from First-in-Man Antineoplastic Medicine Ulrik Lassen, Professor, MD, PH.D. Phase 1 Unit, Department of Oncology, Rigshospitalet

2 Faculty Disclosure x No, nothing to disclose Yes, please specify: Company Name Honoraria/ Expenses Consulting/ Advisory Board Funded Research Royalties/ Patent Stock Options Ownership / Equity Position Employee Other (please specify)

3 Phases in Drug Development The proces lasts Pre-clinical testing: proof of concept Phase 1: dose-finding Phase 2: activity and safety Phase 3: randomised controlled trials 6-12 years, and the cost extends 1.5 bio. $ for each approved agent

4 Endpoints Phase 1: Toxicity - CTCAE version 4 Phase 2: Response or response duration and safety - RECIST Phase 3: Survical, PFS, safety and QoL

5 Background for FIH First human study Preclinical proof of principle must be available Chemical, pharmaceutical and animal PD and tox studies must be available Endpoints are to define safety and PK/PD profiles Identify organs at risk sqcc skincancer???

6 AE Properties Evaluation of the causality of adverse events Grade all AE and note causality with: Study drug (treatment) Disease (cancer) Concomitant medication Other causes (car accident etc.)

7 Classical Design Dose-escalation Starting dose based on animal-pk 3-6 patients/dose level MTD, DLT Now OBD! Recommended Phase 2 Dose Toxicity as surrogate marker -CTCAE

8 A safe starting dose should be driven by pharmacology and toxicology

9 Which Patients? Healthy volunteers? (non- cytostatics) - high-risk groups in studies of chemoprevention, - Phase 0 microdosing Cancer patients without other standard treatment options Live expectancy > 12 weeks Different tumor types PS 0, 1 (2)

10 The Paradox 4 Palliative Care PS 0 Standard of Care Phase 1 Disease Progression

11 Pattern of Referral Time PD local hospital PS 0-1 PS 2-4 Follow up Phase 1 Palliative Care Phase 1 Unit PS 0-1 PS 2-4 Inclusion Waiting list PD PR/SD PD

12 What is driving the patients? Activity (hope) Secondary psycological benefit Safety (new biological agents in stead of cytotoxic treatment) Denial Refuse to give up - an alternative to hospice

13 So what is the risk? Phase I Oncology Studies: Evidence That in the Era of Targeted Therapies, Patients on Lower Doses Do Not Fare Worse Jain R et al. Clin Cancer Res. 2010

14 Bevacizumab FIM No response in 20 patients Stable disease in 12 patients (including 5 renal cancers) No DLT Gordon MS et al. Journal of Clinical Oncology, Vol 19, Issue 3 (February), 2001:

15 Success rates from first-in-human studies to drug registration in different therapeutic areas. Adjei A A et al. Clin Cancer Res 2009;15: by American Association for Cancer Research

16 Yap T et al. 2010

17 New track for early clinical trials Yap T et al. 2010

18 The academic medical center precision medicine tumor board model. Jürgensmeier J M et al. Clin Cancer Res 2014;20: by American Association for Cancer Research

19 Basket trial 1 specific target

20 Umbrella trial

21

22 Non-small cell lung cancer - subtyping Erlotinib, gefitinib crizotinib

23

24 Progression-free Survival. Larkin J et al. N Engl J Med 2015;373:23-34.

25 Results - Safety Treatment-related adverse events were observed in 93% of patients, with the most common events being rash (in 55% Grade 3 or 4 adverse events, regardless of attribution, were observed in 72%of patients Grade 3 or 4 treatment-related events were noted in 53%, with the most common events being elevated levels of lipase (in 13% of patients), aspartate aminotransferase (in 13%), and alanine aminotransferase (in 11%). Wolchok et al NEJM 2013

26 How to select patients for immunetherapy? Hypothesis: Whole-exome Sequencing can estimate tumor mutational load and identify immune-profiles to predict clinical benefit of checkpoint blockade therapy Methods to identify which tumor-specific mutant peptides (neoantigens) can elicit anti-tumor T cell immunity that are needed to improve predictions of checkpoint therapy response Massively parallel sequencing data including annotated nonsynonymous somatic variants that have been translated into mutant amino acid changes, as well as patient-specific HLA alleles, can provide a basis for Precision Medicine within immuno-oncology

27 The prevalence of somatic mutations across human cancer types Alexandrov et al. Nature 2013

28 Sharma P and Allison JP. Science 2015

29 Sharma and Allison, Cell 2015

30 Most Frequent Gr. 3 and 4 Events Related or possibly related Almost 50% of these may be disease related L. R. Molife et al. Ann Oncol 2012

31 The Challenge Discrimination between drug related and disease related adverse events Does the patient develop side effects or disease deteoriation? Incorporation of palliative care in the setting of a Phase 1 Trial Enrolling a Phase 1 Trials is giving hope Referring a patients for a specialized palliative unit may remove the hope Timing is important

32 Conclusion The patients identified for FIM are often placed in a narrow and short window between active and palliative therapy Close collaboration between Phase 1 Units and palliative care is required New combinations with immunotherapy are promising Patients selection is crucial for success of the patient and optimal conduct of the study

33 Aknowledgements The patients The staff at the Phase 1 Unit Rigshospital The Capital Region of Copenhagen Innovationsfonden