Medical Students 2010 - Slide 5 - J.B. Vermorken - Introduction to Clincial Trials


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  • 5. Drug Development: Preclinical Evaluation of Cytotoxic Agents Preclinical evaluation of potentially useful cytotoxic agents comprises in vitro and in vivo analyses. In vitro analysis may include assays designed to evaluate the mechanism of action of compounds against specific mechanistic or molecular targets or activity at the cellular level in terms of cytotoxicity, growth inhibition, or differentiation. Thereafter, Stage I in vivo testing is designed to identify the maximum tolerated dose and dose-limiting toxicities of the compound, in addition to preliminary efficacy findings. Stage II in vivo testing is designed to define the spectrum of activity, schedule dependency, optimal route of administration, potential for cross resistance with other agents, and potential usefulness in combination therapies.
  • 9. Drug Development: Clinical Endpoints: Complete Remission One criterion for evaluating response to chemotherapy involves degrees of remission from the signs of disease. A complete remission is a response to treatment in which all clinical, radiologic, and biologic signs of a tumor have been observed to disappear. All fields demonstrating the primary tumor, node-positive disease, and metastatic disease must be confirmed to be disease-free for designation as a complete remission.
  • 10. Drug Development: Clinical Endpoints: Partial Remission Remission that is less than complete may be designated as partial remission if the tumor bulk has been reduced by at least 50%.
  • 11. Drug Development: Clinical Endpoints: Disease Progression A response designation of disease progression indicates failure of therapy to arrest tumor growth. Specifically, tumor growth must exceed the multiple of two tumor diameters by at least 25%.
  • The ultimate test of any agent is the phase III trial. These are large and seek to address differences in treatments using outcomes such as overall survival, cure rate and quality of life. Issues of bias are minimized by the randomized design. The sample size determines the power with which one can detect differences of interest between treatment arms.
  • Medical Students 2010 - Slide 5 - J.B. Vermorken - Introduction to Clincial Trials

    1. 1. Introduction to Clinical Trials Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edegem, Belgium ESO student course, Ioannina, 2010
    2. 2. Outline <ul><li>Cancer treatment today </li></ul><ul><li>Drug development </li></ul><ul><li>The bridge to the clinic </li></ul><ul><li>Phase I and II trials </li></ul><ul><li>WHO vs RECIST criteria </li></ul><ul><li>Phase III trials for efficacy </li></ul><ul><li>Ethical aspects </li></ul><ul><li>Studies with non-cytotoxics </li></ul><ul><li>Conclusions </li></ul>
    3. 3. Cancer Treatment Today <ul><li>Surgery </li></ul><ul><li>Radiation therapy </li></ul><ul><li>Systemic treatment: </li></ul><ul><ul><li>Cytotoxic chemotherapy </li></ul></ul><ul><ul><li>Hormone therapy </li></ul></ul><ul><ul><li>Immunotherapy </li></ul></ul><ul><ul><li>“ Targeted therapy” </li></ul></ul>
    4. 4. Long Term Survival (%) <ul><li>1970 2008 </li></ul><ul><li>Leukemia in children 0 80 </li></ul><ul><li>Leukemia in adults 0 45 </li></ul><ul><li>Bone cancer 5 60 </li></ul><ul><li>Testicular cancer 0 80 </li></ul><ul><li>Breast cancer 40 85 </li></ul><ul><li>Non-small cell lung cancer 0 15 </li></ul><ul><li>Colon cancer 30 60 </li></ul><ul><li>Hodgkin’s disease 10 85 </li></ul>
    5. 5. From Lab….. To Clinical Trials…. To Standard Practice Laboratory data Effective Therapy
    6. 6. Drug Development <ul><li>Identification of new agents </li></ul><ul><li>Preclinical requirements: efficacy, toxicology (ICH) </li></ul><ul><li>Formulation, manufacturing </li></ul><ul><li>Regulatory (government) review (IND submission) </li></ul><ul><li>Phase I, II, III clinical trials </li></ul><ul><li>Regulatory (government) review (NDS = new drug submission) </li></ul>
    7. 7. Anticancer Drug Discovery <ul><li>Mechanism-based </li></ul><ul><ul><li>Rational synthesis or discovery of agents targeting mechanisms of malignant behavior. Then test in lab models </li></ul></ul><ul><li>Screening/Compound-based </li></ul><ul><ul><li>Screen new chemical entities for activity in cancer models in the laboratory. </li></ul></ul><ul><ul><li>Then discover mechanisms of action. </li></ul></ul>
    8. 8. Screening/Compound Based Discovery <ul><li>Majority of available anticancer drugs have been identified by screening </li></ul><ul><li>Sources: plants (vincas, taxanes) microbes (doxorubicin) chemicals (cisplatin) </li></ul><ul><li>Most act by interfering with molecular process of cell division, thus many normal tissues affected. </li></ul>
    9. 9. Preclinical Requirements <ul><li>A new drug must have the following completed prior to patient testing: </li></ul><ul><li>Demonstrated efficacy in tumor models </li></ul><ul><li>Toxicology: 2 species (rodent and non-rodent) </li></ul><ul><li>Formulation and manufacturing </li></ul><ul><li>Animal pharmacokinetics; mechanism of action studies </li></ul>
    10. 10. Preclinical Evaluation of Cytotoxic Agents <ul><li> Target level  Maximum tolerated dose  Spectrum of activity </li></ul><ul><li> Cellular level  Dose-limiting toxicities  Schedule dependency </li></ul><ul><li> Efficacy  Route of administration </li></ul><ul><li> Cross resistance </li></ul><ul><li> Combination therapies </li></ul>IN VITRO IN VIVO Mechanism of action Stage I Stage II
    11. 11. Human Tumor in Nude Mouse
    12. 12. Moving a New Therapy from the Lab to the Clinic Clinical Evaluation Laboratory Experiments River of Unknowns
    13. 13. Clinical Trials <ul><li>Phase I </li></ul><ul><li>Phase II </li></ul><ul><li>Phase III </li></ul>
    14. 14. Phase I Design: Selection of Starting Dose <ul><li>Based on mouse toxicity: </li></ul><ul><ul><li>0.1 Mouse Equivalent LD10 (MELD10) </li></ul></ul><ul><li>In instances where dog toxicity show this dose to be toxic, 1/3 Toxic Dose Low (TDL) in dogs is selected as starting dose </li></ul>
    15. 15. Phase I Trials <ul><li>Find highest safe dose (1 level below MTD) </li></ul><ul><li>Identify side effects </li></ul>Dose escalating by modified Fibonacci 3 pts 3 pts 3 pts 3 pts 3 pts 3 pts Dose Severe toxicity Recommended dose
    16. 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 -
    17. 17. Phase II Trials <ul><li>Screen drug for activity in cancer patients </li></ul><ul><li>Use recommended dose </li></ul><ul><li>Test it in 15-30 patients with same tumor type </li></ul><ul><li>Look for objective tumor shrinkage: Partial or Complete Response </li></ul>
    18. 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. 19. Partial Response: WHO Treatment Decrease of the multiple of two tumor diameters by at least 50% Adapted from World Health Organization, 1980.
    20. 20. Progression: WHO Increase of the multiple of two tumor diameters by at least 25% Adapted from World Health Organization, 1980. Treatment
    21. 21. Example Calculation PD calculated from lowest sum on study
    22. 22. R esponse E valuation C riteria i n S olid T umors (RECIST) Therasse et al JNCI 2000 <ul><li>Intended for use in clinical trials with primary endpoint of objective response </li></ul><ul><li>Measurable lesion >= 20 mm (10 if spiral CT) </li></ul><ul><li>Unidimensional assessment: Tumor burden assessed by summing longest diameters of all measurable lesions up to 10 (5 per organ) </li></ul><ul><li>Four categories of response: CR*, PR*, SD, PD </li></ul><ul><li>RECIST widely adopted by cooperative groups, industry, academia </li></ul>* Required confirmation
    23. 23. RECIST Guidelines: Response Criteria <ul><li>Target lesions (  LD /  LD baseline) </li></ul><ul><ul><li>CR </li></ul></ul><ul><ul><li>PR: 30%  (50% surf. area and 65% volume) </li></ul></ul><ul><ul><li>SD </li></ul></ul><ul><ul><li>PD: 20%  (44% surf. area and 73% volume) </li></ul></ul><ul><li>Non-target lesions </li></ul><ul><ul><li>CR (including markers) </li></ul></ul><ul><ul><li>Non-CR </li></ul></ul><ul><ul><li>PD </li></ul></ul>
    24. 24. Example Calculation PD calculated from lowest sum on study
    25. 25. Unidimensional vs. WHO Criteria: Response Rates in 4,613 Patients from 14 Studies/Data Sets
    26. 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
    27. 27. What HAS NOT changed in RECIST 1.1 <ul><li>Measurable lesions defined by unidimensional measurement </li></ul><ul><li>Tumor burden based on sum of diameters </li></ul><ul><li>Categories of response: </li></ul><ul><ul><li>CR </li></ul></ul><ul><ul><li>PR (30% decrease in sum from baseline) </li></ul></ul><ul><ul><li>SD </li></ul></ul><ul><ul><li>PD (20% increase in sum from nadir) </li></ul></ul><ul><li>Courtesy of E.A. Eisenhauer </li></ul>
    28. 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. 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
    30. 30. New Lesions (1) <ul><li>Must be unequivocal : not attributable to different scanning technique or non tumor (e.g. “new” bone lesions may be flare) </li></ul><ul><li>When in doubt continue treatment, repeat evaluation </li></ul><ul><li>If scan showing new lesion is of anatomical region which was not included in baseline scans, it is still PD </li></ul><ul><li>Courtesy of E.A. Eisenhauer </li></ul>
    31. 31. New Lesions (2) <ul><li>FDG-PET: sometimes used by investigators to complement CT. If so: </li></ul><ul><ul><li>Negative FDG-PET at baseline and a positive FDG-PET at follow-up means PD </li></ul></ul><ul><ul><li>No FDG-PET at baseline and a positive FDG-PET at follow up: </li></ul></ul><ul><ul><ul><li>It is PD if it corresponds to a new site of disease on CT </li></ul></ul></ul><ul><ul><ul><li>It is equivocal if no new site of disease on CT. Repeat CT to see if new site apparent next scan: if so, PD date will be that of the initial abnormal FDG-PET scan </li></ul></ul></ul><ul><ul><ul><li>It is not PD if corresponds to a pre-existing site of disease on CT that is not progressing on the anatomic images </li></ul></ul></ul>
    32. 32. What is Efficacy? <ul><li>Response  Efficacy </li></ul><ul><li>Efficacy is improved: </li></ul><ul><ul><li>Cure rates </li></ul></ul><ul><ul><li>Survival </li></ul></ul><ul><ul><li>Quality of life: i.e. meaningful symptom pallia tion </li></ul></ul><ul><li>“ Response” is a measure of biologic effect which may be a marker for efficacy </li></ul>
    33. 33. Phase III Trials Once a new agent has shown activity in phase II, comparative trials are usually designed. New agent can be given alone or in combination <ul><li>Objectives : Compare “new” to “standard” </li></ul><ul><li>Endpoints : Survival, toxicity, quality of life. </li></ul><ul><li>Sample Size : 200-2000 patients </li></ul>
    34. 34. Phase III Trials: Definitive Tests of Efficacy <ul><li>Large studies to detect “significant” differences in outcomes of interest: </li></ul><ul><ul><li>Cure, survival, quality of life </li></ul></ul><ul><li>Randomized design: </li></ul><ul><ul><li>Allows unbiased assessment of treatment effect </li></ul></ul><ul><li>Sample Size: </li></ul><ul><ul><li>Determines power with which one can detect postulated differences </li></ul></ul>
    35. 35. How Much Improvement in Efficacy? <ul><li>Critical question which drives: </li></ul><ul><ul><li>Trial design and sample size </li></ul></ul><ul><ul><li>Eventual change in practice </li></ul></ul><ul><li>Patients and physicians (staff) differ on degree of improvement which must be seen to choose a more toxic therapy. </li></ul><ul><li>If patients views are accepted: many trials are too small (underpowered). </li></ul>
    36. 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. 37. Acceptance Thresholds: By 50% or More of Staff
    38. 38. Acceptance Thresholds: By 50% or More of Patients
    39. 39. Studies with non-Cytotoxics “Targeted therapy”
    40. 40. Non-Cytotoxics (“Targeted Therapy”) <ul><li>General term to describe agents which do not directly target DNA. </li></ul><ul><li>Includes agents having targets which are: </li></ul><ul><ul><li>Cellular </li></ul></ul><ul><ul><ul><li>Growth factors and their receptors </li></ul></ul></ul><ul><ul><ul><li>Signaling pathways </li></ul></ul></ul><ul><ul><li>Extracellular </li></ul></ul><ul><ul><ul><li>Matrix </li></ul></ul></ul><ul><ul><ul><li>Vasculature </li></ul></ul></ul>
    41. 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. 42. Preclinical Data: Cytotoxic Agent Dose Effect -- anti-tumor toxicity --
    43. 43. Antitumor Effect: Tumor Regression Time tumor Size control increasing doses new agent
    44. 44. The Bridge to the Clinic for Traditional Cytotoxics <ul><li>Dose-Toxicity and Dose-Effect relationships: often parallel </li></ul><ul><li>Cause regression of established tumors </li></ul><ul><li>Traditionally: </li></ul><ul><ul><li>phase I trials: endpoint is toxicity </li></ul></ul><ul><ul><li>phase II trials: endpoint is response </li></ul></ul><ul><li>These have allowed dose determination and selection of many agents found in randomized trials to be effective i.e. prolong survival </li></ul>
    45. 45. Preclinical Data: Non- Cytotoxic
    46. 46. Antitumor Effect: Growth Delay
    47. 47. The Bridge to the Clinic For Novel Non-Cytotoxics <ul><li>Dose-Toxicity and Dose-Effect relationships: may not be parallel </li></ul><ul><li>May not cause regression of established tumors </li></ul><ul><li>Thus, for newer agents: </li></ul><ul><ul><li>phase I trials: endpoint is uncertain </li></ul></ul><ul><ul><li>phase II trials: endpoint is uncertain </li></ul></ul>
    48. 48. Ethical Committee: Roles and Function <ul><li>To safeguard the rights, safety and well-being of trial subjects </li></ul><ul><li>Documented procedures </li></ul><ul><li>At study start assess: </li></ul><ul><ul><li>Scientific justification for proposed research and use of human subjects </li></ul></ul><ul><ul><li>Weigh potential benefits/risks </li></ul></ul><ul><ul><li>Consent document and process </li></ul></ul><ul><ul><li>Qualifications of investigator and team </li></ul></ul><ul><li>Ongoing review </li></ul>
    49. 49. Summary <ul><li>Journey from the laboratory to clinical practice requires several steps </li></ul><ul><li>Promising new therapies must undergo evaluation in patients: </li></ul><ul><ul><li>Phase I: find dose, side effects </li></ul></ul><ul><ul><li>Phase II: look for hints of activity </li></ul></ul><ul><ul><li>Phase III: definitive tests of efficacy </li></ul></ul><ul><li>All trials must have ethical committee review and patient consent </li></ul>
    50. 51. Declaration of Helsinki: Sample Statements <ul><li>It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject </li></ul><ul><li>Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation </li></ul><ul><li>Appropriate caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected </li></ul><ul><li>The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol </li></ul>
    51. 52. Ethics and Consent <ul><li>History: </li></ul><ul><ul><li>War Crimes </li></ul></ul><ul><ul><li>Tuskagee syphilis study </li></ul></ul><ul><ul><li>Jewish Chronic Hospital study </li></ul></ul><ul><ul><li>Willowbrook study </li></ul></ul>
    52. 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
    53. 54. R esponse E valuation C riteria I n S olid T umours RECIST guidelines
    54. 55. Sorafenib: targets both tumour cell and vascular compartments <ul><li>A multi-kinase inhibitor of </li></ul><ul><ul><li>serine/threonine kinases: C-Raf (Raf-1) and B-Raf-1 </li></ul></ul><ul><ul><li>receptor tyrosine kinases: VEGFR-2, VEGFR-3, PDGFR- β , Flt-3, and c-KIT </li></ul></ul>Wilhelm S, et al. Clin Cancer Res 2004;64:7099–109 Tumour cell Endothelial cell or pericyte (vascular) Angiogenesis: differentiation proliferation migration tubule formation VEGFR-2 PDGFR-  Apoptosis Proliferation PDGF VEGF Survival Ras MEK Apoptosis PDGF VEGF Paracrine stimulation KIT/Flt-3/RET Mitochondria Mitochondria Mcl-1 HIF Sorafenib Sorafenib Sorafenib HIF = hypoxia inducible factor; VEGF = vascular endothelial growth factor VEGFR = VEGF receptor; PDGF = platelet-derived growth factor PDGFR = PDGF receptor; Mcl-1 = myeloid cell leukaemia-1 Raf MEK Ras Nucleus ERK Raf ERK Sorafenib Nucleus
    55. 56. Codes of Conduct: International Standards <ul><li>Nuremberg Code </li></ul><ul><li>Declaration of Helsinki </li></ul><ul><li>Good Clinical Practice </li></ul><ul><li>Adopted by most nations </li></ul>
    56. 57. Elements of Informed Consent <ul><li>Purpose of the trial and that it involves research </li></ul><ul><li>Treatment and how it is assigned. Number of subjects planned </li></ul><ul><li>Duration of study and procedures involve </li></ul><ul><li>Experimental aspects </li></ul><ul><li>Possible benefits and likely risks </li></ul><ul><li>Voluntary nature </li></ul><ul><li>Alternative treatment </li></ul><ul><li>Access to data and confidentiality </li></ul>
    57. 58. Summary (2) <ul><li>Some drugs showing activity in animal studies or phase II turn out to be inactive in phase III </li></ul><ul><li>New agents are now exploiting the scientific discoveries of the last decades: </li></ul><ul><ul><li>Targeting differences between cancer and normal cells </li></ul></ul><ul><ul><li>Targeting blood vessels that support cancer growth </li></ul></ul><ul><li>Many such new agents now being investigated in clinical trials in several areas of the world </li></ul>