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Introduction to Clinical Trials Jan B. Vermorken, MD, PhD Department of Medical Oncology Antwerp University Hospital Edege...
Outline <ul><li>Cancer treatment today </li></ul><ul><li>Drug development </li></ul><ul><li>The bridge to the clinic </li>...
Cancer Treatment Today <ul><li>Surgery </li></ul><ul><li>Radiation </li></ul><ul><li>Systemic treatment:  </li></ul><ul><u...
Long Term Survival (%) <ul><li>1970 2008 </li></ul><ul><li>Leukaemia in children   0 80 </li></ul><ul><li>Leukaemia in adu...
From Lab….. To Clinical Trials…. To Standard Practice Laboratory data Effective Therapy
Drug Development <ul><li>Identification of new agents </li></ul><ul><li>Preclinical requirements: efficacy, toxicology (IC...
Anticancer Drug Discovery <ul><li>Mechanism based </li></ul><ul><ul><li>Rational synthesis or discovery of agents targetin...
Screening/Compound Based Discovery <ul><li>Majority of available anticancer drugs have been identified by screening </li><...
Preclinical Requirements <ul><li>A new drug must have the following completed prior to patient testing: </li></ul><ul><li>...
Preclinical Evaluation of Cytotoxic Agents <ul><li>   Target level   Maximum tolerated dose   Spectrum of activity </li...
Human Tumor in Nude Mouse
Moving a New Therapy from  the Lab to the Clinic Clinical Evaluation Laboratory Experiments River of Unknowns
Clinical Trials <ul><li>Phase I </li></ul><ul><li>Phase II </li></ul><ul><li>Phase III </li></ul>
Phase I Design: Selection of Starting Dose <ul><li>Based on mouse toxicity: </li></ul><ul><ul><li>0.1 Mouse Equivalent LD1...
Phase I Trials <ul><li>Find highest safe dose  (1 level below MTD) </li></ul><ul><li>Identify side effects </li></ul>Dose ...
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...
Phase II Trials <ul><li>Screen drug for activity in cancer patients </li></ul><ul><li>Use recommended dose </li></ul><ul><...
Complete Response: WHO Adapted from World Health Organization, 1980. Primary Tumor Nodes Metastases Disappearance of all c...
Partial Response: WHO Treatment Decrease of the multiple of two tumor diameters by at least 50% Adapted from World Health ...
Progression: WHO Increase of the multiple of two tumor diameters by at least 25% Adapted from World Health Organization, 1...
Example Calculation PD calculated from lowest sum on study
R esponse  E valuation  C riteria  i n  S olid  T umors (RECIST)   Therasse et al JNCI 2000 <ul><li>Intended for use in cl...
RECIST Guidelines: Response Criteria <ul><li>Target lesions (   LD /    LD baseline) </li></ul><ul><ul><li>CR </li></ul>...
Example Calculation PD calculated from lowest sum on study
Unidimensional vs. WHO Criteria:  Response Rates  in 4,613 Patients from 14 Studies/Data Sets
New  R esponse  E valuation  C riteria in  S olid  T umours: Revised RECIST Guidelines (verion 1.1) E.A. Eisenhauer, et al...
What  HAS NOT  changed in RECIST 1.1 <ul><li>Measurable lesions defined by unidimensional measurement </li></ul><ul><li>Tu...
For example: Response classification same… Time point Response: Patients with Target (+/- non-target) Disease: Target lesi...
Summary: What  HAS  changed in RECIST 1.1 RECIST 1.0 RECIST 1.1 Measuring tumor burden 10 targets 5 per organ For response...
New Lesions (1) <ul><li>Must be  unequivocal : not attributable to different scanning technique or non tumor (e.g. “new” b...
New Lesions (2) <ul><li>FDG-PET: sometimes used by investigators to complement CT. If so: </li></ul><ul><ul><li>Negative  ...
What is Efficacy? <ul><li>Response    Efficacy </li></ul><ul><li>Efficacy is improved: </li></ul><ul><ul><li>Cure rates <...
Phase III Trials Once a new agent has shown activity in phase II, comparative trials are usually designed.  New agent can ...
Phase III Trials:  Definitive Tests of Efficacy <ul><li>Large studies to detect “significant” differences in outcomes of i...
How Much Improvement in Efficacy? <ul><li>Critical question which drives: </li></ul><ul><ul><li>Trial design and sample si...
Survival Advantage at 3 years Required by Patients vs Staff to Accept Toxic Treatment % Survival Advantage Threshold Numbe...
Acceptance Thresholds:  By 50% or More of Staff
Acceptance Thresholds:  By 50% or More of Patients
Studies with non-Cytotoxics
“ Non-Cytotoxics” <ul><li>General term to describe agents which do not directly target DNA. </li></ul><ul><li>Includes age...
Moving a New Therapy from  the Lab to the Clinic Differences between cytotoxic and non-cytotoxic agents Clinical Evaluatio...
Preclinical Data: Cytotoxic Agent Dose Effect -- anti-tumor toxicity --
Antitumor Effect: Tumor Regression Time tumor Size control increasing doses new agent
The Bridge to the Clinic for Traditional Cytotoxics <ul><li>Dose-Toxicity and Dose-Effect relationships: often parallel </...
Preclinical Data: Non- Cytotoxic
Antitumor Effect: Growth Delay
The Bridge to the Clinic For Novel Non-Cytotoxics <ul><li>Dose-Toxicity and Dose-Effect relationships:  may not be paralle...
Ethical Committee: Roles and Function <ul><li>To safeguard the rights, safety and well-being of trial subjects </li></ul><...
Summary <ul><li>Journey from the laboratory to clinical practice requires several steps </li></ul><ul><li>Promising new th...
 
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Medical Students 2011 - J.B. Vermorken - INTRODUCTION TO CANCER TREATMENT - Introduction to Clinical Trials

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Medical Students 2011 - J.B. Vermorken - INTRODUCTION TO CANCER TREATMENT - Introduction to Clinical 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, 2011
  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 </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>Non-cytotoxic therapy </li></ul></ul>
  4. 4. Long Term Survival (%) <ul><li>1970 2008 </li></ul><ul><li>Leukaemia in children 0 80 </li></ul><ul><li>Leukaemia 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 lab. 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 palliation </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
  40. 40. “ Non-Cytotoxics” <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>

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