The document provides an introduction to clinical trials for cancer drug development. It discusses moving potential new therapies from preclinical testing in animal models through the different phases of clinical trials in humans. Phase I trials determine safety and dosing, phase II screens for anti-tumor activity, and phase III tests for efficacy in larger patient populations through randomized controlled trials. Ethical review and informed consent are required throughout the clinical trial process to protect patient safety and rights.

1. Introduction to Clinical Trials Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium ESO student course, Ioannina, 2010

5. From Lab….. To Clinical Trials…. To Standard Practice Laboratory data Effective Therapy

11. Human Tumor in Nude Mouse

12. Moving a New Therapy from the Lab to the Clinic Clinical Evaluation Laboratory Experiments River of Unknowns

16. Modified Fibonacci Escalation Dose Level Theory Example starting Dose x 1 level 2 2 x level 1 2 level 3 1.67 x level 2 3.3 level 4 1.5 x level 3 5 level 5 1.4 x level 4 6.7 level 6 1.33 x level 5 8.8 level 7 1.33 x level n-1 -

18. Complete Response: WHO Adapted from World Health Organization, 1980. Primary Tumor Nodes Metastases Disappearance of all clinical, radiologic and biologic signs of tumor Treatment

19. Partial Response: WHO Treatment Decrease of the multiple of two tumor diameters by at least 50% Adapted from World Health Organization, 1980.

20. Progression: WHO Increase of the multiple of two tumor diameters by at least 25% Adapted from World Health Organization, 1980. Treatment

21. Example Calculation PD calculated from lowest sum on study

24. Example Calculation PD calculated from lowest sum on study

25. Unidimensional vs. WHO Criteria: Response Rates in 4,613 Patients from 14 Studies/Data Sets

26. New R esponse E valuation C riteria in S olid T umours: Revised RECIST Guidelines (verion 1.1) E.A. Eisenhauer, et al. European Journal of Cancer 2009; 45: 228-247

28. For example: Response classification same… Time point Response: Patients with Target (+/- non-target) Disease: Target lesions Non-Target lesions New Lesions Overall response CR CR No CR CR Non-CR/Non-PD No PR CR Not evaluated No PR PR Non-PD or not all evaluated No PR SD Non-PD or not all evaluated No SD Not all evaluated Non-PD No NE PD Any Any PD Any PD Any PD Any Any Yes PD

29. Summary: What HAS changed in RECIST 1.1 RECIST 1.0 RECIST 1.1 Measuring tumor burden 10 targets 5 per organ For response: 5 targets (2 per organ) Lymph node Measure long axis as for other lesions. Silent on normal size Measure short axis. Define normal size. Progression definition 20% increase in sum 20% increase and at least 5 mm absolute increase Non-measurable disease PD “ must be unequivocal” Expanded definition to convey impact on overall burden of disease. Examples. Confirmation required Required when response primary endpoint—but not PFS New lesions -- New section which includes comment on FDG PET interpretation

36. Survival Advantage at 3 years Required by Patients vs Staff to Accept Toxic Treatment % Survival Advantage Threshold Number of subjects From Brundage et al, 1997

37. Acceptance Thresholds: By 50% or More of Staff

38. Acceptance Thresholds: By 50% or More of Patients

39. Studies with non-Cytotoxics “Targeted therapy”

41. Moving a New Therapy from the Lab to the Clinic Differences between cytotoxic and non-cytotoxic agents Clinical Evaluation Laboratory Experiments River of Unknowns

42. Preclinical Data: Cytotoxic Agent Dose Effect -- anti-tumor toxicity --

43. Antitumor Effect: Tumor Regression Time tumor Size control increasing doses new agent

45. Preclinical Data: Non- Cytotoxic

46. Antitumor Effect: Growth Delay

53. Complex signalling pathways in oncology Hanahan D, Weinberg RA. Cell 2000;100:57–70 DR4, DR5 Difficult to target Src IGF-II, HGF, Ang2 Growth factor receptors Growth factor receptor ligands  5  1  v  3 EGFR, ErbB2, VEGFR-2,IGF-1R, MET, KIT, RET, Tie2

54. R esponse E valuation C riteria I n S olid T umours RECIST guidelines