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Postęp w onkologii - nowe techniki, nowe leki

Postęp w onkologii - nowe techniki, nowe leki. Radosław Mądry Katedra i Klinika Onkologii Uniwersytety Medycznego im. K. Marcinkowskiego w Poznaniu. Cancer Treatment Today. Surgery Radiation Systemic treatment: Cytotoxic Chemotherapy Hormone therapy Immunotherapy Non-cytotoxic therapy.

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Postęp w onkologii - nowe techniki, nowe leki

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  1. Postęp w onkologii - nowe techniki, nowe leki Radosław Mądry Katedra i Klinika Onkologii Uniwersytety Medycznego im. K. Marcinkowskiego w Poznaniu

  2. Cancer Treatment Today • Surgery • Radiation • Systemic treatment: • Cytotoxic Chemotherapy • Hormone therapy • Immunotherapy • Non-cytotoxic therapy

  3. Stanley B. Kaye Progress in the treatment of ovarian cancer. Lessons from Homologous Recombination 10th International Symposium Advanced Ovarian Cancer: Optimal Therapy. Update Valencia, Hiszpania, 6 Marca 2015

  4. Long Term Survival (%) 1970 2008 • Leukemia in children 0 80 • Leukemia in adults 0 45 • Bone cancer 5 60 • Testicular cancer 0 80 • Breast cancer 40 85 • Non-small cell lung cancer 0 15 • Colon cancer 30 60 • Hodgkin’s disease 10 85

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

  6. Drug Development • Identification of new agents • Preclinical requirements:efficacy, toxicology (ICH) • Formulation, manufacturing • Regulatory (government) review(IND submission) • Phase I, II, III clinical trials • Regulatory (government) review(NDS = new drug submission)

  7. Anticancer Drug Discovery • Mechanism based • Rational synthesis or discovery of agents targeting mechanisms of malignant behavior. Then test in laboratory models • Screening/Compound based • Screen new chemical entities for activity in cancer models in the laboratory. Then discover mechanisms of action.

  8. Screening/CompoundBased Discovery • Majority of available anticancer drugs have been identified by screening • Sources: plants (vincas, taxanes) microbes (doxorubicin) chemicals (cisplatin) • Most act by interfering with molecular process of cell division. Therefore, many normal tissues will be affected.

  9. Preclinical Requirements A new drug must have completed the following prior to patient testing: • Demonstration of efficacy in tumor models • Toxicology testing: 2 species (rodent and non-rodent) • Formulation and manufacturing • Animal pharmacokinetics • Mechanism of action studies

  10.  Target level  Maximum tolerated dose  Spectrum of activity  Cellular level  Dose-limiting toxicities  Schedule dependency  Efficacy  Route of administration  Cross resistance  Combination therapies Preclinical Evaluation of Cytotoxic Agents IN VITRO IN VIVO Mechanism of action Stage I Stage II

  11. Human Tumor in Nude Mouse

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

  13. Clinical Trials • Phase I • Phase II • Phase III

  14. Phase I Trials:Important issues What kind of purpose (goals) To determine the appropriate dose for phase II evaluation Dose Limiting toxicity (DLT) Those toxic effects that by nature of their severity limit further dose escalation Maximum-tolerated dose (MTD) That dose producing a certain frequency of DLT within the treated population Eisenhauer EA et al, J Clin Oncol 2000; 18: 684-692

  15. Phase I Design:Selection of Starting Dose • Based on mouse toxicity: • 0.1 Mouse Equivalent LD10 (MELD10) • In instances where dog toxicity show this dose to be toxic, 1/3 Toxic Dose Low (TDL) in dogs is selected as starting dose

  16. Severe toxicity 3 pts Recommended dose 3 pts 3 pts Dose 3 pts 3 pts 3 pts Phase I Trials • Find highest safe dose (1 level below MTD) • Identify side effects Dose escalating by modified Fibonacci

  17. Modified Fibonacci Escalation

  18. Phase II Trials • Screen drug for activity in cancer patients • Use recommended dose • Test it in 15-30 patients with same tumor type • Look for objective tumor shrinkage: Partial or Complete Response

  19. RECIST Guidelines:Response Criteria • Target lesions ( LD /  LD baseline) • CR • PR: 30%  (50% surf. area and 65% volume) • SD • PD: 20%  (44% surf. area and 73% volume) • Non-target lesions • CR (including markers) • Non-CR • PD

  20. New Response Evaluation Criteria in Solid Tumors: Revised RECIST Guidelines (version 1.1)E.A. Eisenhauer, et al.European Journal of Cancer 2009; 45: 228-247

  21. RECIST 1.1 Measurable lesions defined by unidimensional measurement Tumor burden based on sum of diameters Categories of response: CR PR (30% decrease in sum from baseline) SD PD (20% increase in sum from nadir) Courtesy of E.A. Eisenhauer

  22. Summary

  23. Maximum % Change in Tumor Shrinkage (Stage 1)Investigator Assessment Randomized set; adjusted mean change. Only patients with baseline and at least one post-baseline measurement are included.

  24. Inhibitory PARP u chorych na raka jajnika będących nosicielami mutacji BRCA1/2

  25. What is Efficacy? • Response  Efficacy • Efficacy is improved: • Cure rates • Survival • Quality of life: i.e. meaningful symptom palliation • “Response” is a measure of biologic effect which may be a marker for efficacy

  26. 2014

  27. Phase III TrialsOnce a new agent has shown activity in phase II, comparative trials are usually designed. New agent can be given alone or in combination • Objectives: Compare “new” to “standard” • Endpoints: Survival, toxicity, quality of life. • Sample Size: 200-2000 patients

  28. Phase III Trials: Definitive Tests of Efficacy • Large studies to detect “significant” differences in outcomes of interest: • Cure, survival, quality of life • Randomized design: • Allows unbiased assessment of treatment effect • Sample Size: • Determines power with which one can detect postulated differences

  29. How Much Improvement in Efficacy? • Critical question which drives: • Trial design and sample size • Eventual change in practice • Patients and physicians (staff) differ on degree of improvement which must be seen to choose a more toxic therapy. • If patients views are accepted: many trials are too small (underpowered).

  30. Bez korzyści

  31. Bez korzyści

  32. 2014

  33. ORR = objective response rate; PD = progressive disease; PFS = progression-free survival; aEpithelial ovarian, primary peritoneal or fallopian tube cancerbStratification factors: selected chemotherapy; prior anti-angiogenic therapy; platinum-free interval (<3 vs 3–6 months)cOr 10 mg/kg q2w. d15 mg/kg q3w, permitted on clear evidence of PD

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