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Innovative clinical trial designs

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The dream of any physician and consequently every patient is to receive the right treatment in the right time with cost effectiveness. To achieve this goal, the 3 pillars: evidence based medicine, clinical research innovation & resources utilization should be integrated efficiently.
In this presentation, I'll try to comprehensively review the following:
1- How are we used to perform clinical trials in Oncology?
2- Does it fits in today’s needs?
3- Integration of biology knowledge in shaping drug development
4- New Clinical trial designs “Can they offer solution for accelerating drug development?”
5- The supporting infrastructure role in clinical trial execution

Publié dans : Santé & Médecine

Innovative clinical trial designs

  1. 1. Innovative Clinical Trial Designs: How to maximize the benefit? Emad Shash, MBBCh., MSc., MD. Medical Oncology Department National Cancer Institute Cairo University
  2. 2. What are we going to discuss today! Evidence Based Medicine Resources Utilization Clinical Research Innovation • How are we used to perform clinical trials in Oncology? • Does it fits in today’s needs? • Integration of biology knowledge in shaping drug development • New Clinical trial designs “Can they offer solution for accelerating drug development?” • The supporting infrastructure role in clinical trial execution Right Patient Right Treatment Right Time Cost Effectiveness
  3. 3. Evolution Theory Adaptation is always and should be according to Needs
  4. 4. Experimental design for Scurvy “James Lind 1716-1794” 12 classical SCURVY Sailors Vinegar Diluted sulfuric acid Cider Sea Water Nutmeg & Garlic 2 Oranges & 1 Lemon Normal diet + supplementation (6 experimental groups)
  5. 5. Phases of Clinical Trials “what we are used to do” Phase I Drug given to 20-100 healthy volunteers (although patients in some cases) Duration 1mth – 1 year Cost $100K to $500K Following studied here • PK/PD • Food interaction • Safety • Dose escalation/MTD • Safety • Early evidence of efficacy Drug given to 100-500 patient volunteers Duration 1 – 2 years Cost $10M to $100M Following studied here • Efficacy • Safety • Establish dose for Phase III Drug given to 1000-5000 patient volunteers Duration 3 – 4 years Cost $10M to $500M Following studied here • Confirmation of Efficacy • Safety Drug is launched in the market. 1000’s of patients Many years No specific amount Additional post marketing testing of patients for drug • Safety & Efficacy • Support use of the approved indication • Finding new therapeutic opportunities • Extended use to different classes of patients • 1000s of patients Phase II Phase III Phase IV
  6. 6. Stages of drug development “Time & Money Consumption” Source: “An Overview of the Drug Development Process”, by Ross Tonkens, M.D. Phase I Phase IIIRESOURCES ≅15 Years ≅30 M – 700 M
  7. 7. Continuous Decline in Healthcare & Research Spending
  8. 8. What are we going to discuss today! Evidence Based Medicine Resources Utilization Clinical Research Innovation • How are we used to perform clinical trials in Oncology? • Does it fit our today’s needs? • Integration of biology knowledge in shaping drug development • New Clinical trial designs “Can they offer solution for accelerating drug development?” • The supporting infrastructure role in clinical trial execution
  9. 9. Molecularly Targeted therapy Versus Conventional therapy Patient DrugBiomarker Efficacy
  10. 10. Schwaederle M et al. JCO 2015 Better Biology Understanding & Treatment Outcome Optimization Matching patients with drugs based on specific biomarkers PubMed search January 1, 2010, and December 31, 2012 570 phase II single- agent studies 32,149 patients
  11. 11. NSCLC Pathology: From Traditional View to more sub-molecular categorization
  12. 12. Advanced NSCLC: Evolution of Treatment 2000 - 2006 2006 - 2009 2010 2011 – 2017…….. EGFR mutation ALK rearrangement K-ras mutation B-raf, HER2 mutation ROS1, RET Immunotherapy Non-Squamous Squamous Targeting an Oncogenic Driver EGFR mutation Non-Squamous Squamous Non-Squamous Squamous NSCLC Targeting EGFRTreating according histologyNSCLC
  13. 13. Time elapsed from discovery to practice change
  14. 14. The biomarker and drug development cycle Patients-industry-Drug developers- Translational researchers Regulators Payers Analytical validation Clinical validation Clinical utility Market access Health care deliveryTR Drug developers Patients-Payers-Regulators- Industry Time & Money Consumption while patients are waiting!!
  15. 15. Can we accelerate time? & Still get the maximal benefit!
  16. 16. What are we going to discuss today! Evidence Based Medicine Resources Utilization Clinical Research Innovation • How are we used to perform clinical trials in Oncology? • Does it fit in today’s needs? • Integration of biology knowledge in shaping drug development • New Clinical trial designs “Can they offer solution for accelerating drug development?” • The supporting infrastructure role in clinical trial execution
  17. 17. Umbrella Trial • Different targeted agents investigated in parallel in the same tumor type and within independent cohorts of patients • Defined by specific molecular aberrations that could predict sensitivity to the investigational agent under assessment
  18. 18. Histology based clinical trial design To evaluate multiple molecular aberrations
  19. 19. Le Tourneau et al. Lancet Oncol 2015 Paoletti et al. CCO 2015 Molecularly targeted therapy based on tumor molecular profiling versus conventional therapy for advanced cancer (SHIVA) Trial: Proof-of-Concept
  20. 20. Le Tourneau et al. Lancet Oncol 2015 Molecularly targeted therapy based on tumor molecular profiling versus conventional therapy for advanced cancer (SHIVA) Trial: Proof-of-Concept Molecularly targeted agent group (n=99) Treatment at physician's choice group (n=96) Age (years) 61 (54–69) 63 (54–69) Sex Female 60 (61%) 69 (72%) Male 39 (39%) 27 (28%) Previous lines of treatment 3 (2–5) 3 (2–5) Royal Marsden Hospital score 0 or 1 51 (52%) 48 (50%) 2 or 3 48 (48%) 48 (50%) Molecular pathway altered Hormone receptor pathway 40 (40%) 42 (44%) PI3K/AKT/mTOR pathway 46 (46%) 43 (45%) RAF/MEK pathway 13 (13%) 11 (11%)
  21. 21. Adapted from: Le Tourneau et al. Lancet Oncol 2015 Molecularly targeted therapy based on tumor molecular profiling versus conventional therapy for advanced cancer (SHIVA) Trial: Proof-of-Concept 0 5 10 15 20 25 Breast adenocarcinoma Colorectal cancer Sarcoma Adenocarcinoma of unknown primary Non-adenoid cystic carcinoma salivary gland tumour Neuroendocrine tumour Cutaneous melanoma Ependymoma Germline tumour Distribution By Tumor Type Treatment at Physican Choice Moleculary Targeted Group 0 5 10 15 20 25 30 35 40 45 50 Hormone receptor pathway PI3K/AKT/mTOR pathway RAF/MEK pathway Distribution By Molecular Abberation Moleculary Targeted Group Physician Choice Group Distribution of molecular alterations in the PI3K/AKT/mTOR pathway Distribution of molecular alterations in the RAF/MEK pathway
  22. 22. Molecularly targeted therapy based on tumor molecular profiling versus conventional therapy for advanced cancer (SHIVA) Trial: Proof-of-Concept Le Tourneau et al. Lancet Oncol 2015 Progression-free survival Intent to treat population PI3K/AKT/mTOR pathway RAF/MEK pathway
  23. 23. Molecularly targeted therapy based on tumor molecular profiling versus conventional therapy for advanced cancer (SHIVA) Trial: Proof-of-Concept Le Tourneau et al. Lancet Oncol 2015 Progression-free survival Intent to treat population PI3K/AKT/mTOR pathway RAF/MEK pathway • It is the first to test, with a randomized control, the idea of whether off-label use of commercial drugs for matched molecular biomarkers confers a clinical benefit. • The results suggest that off-label use of molecularly targeted agents in this manner should be restricted. • Instead, patients should be encouraged to participate in well-designed next-generation clinical trials that use an iterative and scientific approach to build on findings from trials such as SHIVA • Irrespective of these limitations, SHIVA offers robust evidence for deficiencies in assigning therapy based on the various loose associations between biomarkers and inhibitors that are often provided in commercial clinical diagnostic reports.
  24. 24. Basket Trial • Histology-independent trial design • Patients with cancers of different histology enrolled in the clinical trial based on the presence of a specific molecular aberration
  25. 25. Histology-independent aberration-specific clinical trial design
  26. 26. EXAMPLE: NCI MPACT BASKET TRIAL KummarS, et al., ASCO Annual Meeting 2014 poster
  27. 27. CREATE EORTC TRIAL • Six Cohorts of rare solid tumors and anaplastic large cell lymphoma • ALK and/or MET alterations are considered to play a role of the carcinogenesis process of these tumors Clinical trial information: NCT01524926
  28. 28. EORTC 90101 MET Driven (PRCC1 Cohort) Schoffski et al. LBA AACR 2016
  29. 29. EORTC 90101 MET Driven (PRCC1 Cohort) Schoffski et al. LBA AACR 2016
  30. 30. Basket of trials
  31. 31. BASKET TRIAL: PROS AND CONS • Pros • Determining potential tumor efficacy of a single targeted agent in different cancer types with the same gene abnormality • Cons • Risk of overlooking the impact of tumor histology type. In fact, different tumor responses by targeting the same mutation in several cancer types could be observed. (e.g. BRAF in melanoma versus BRAF in colorectal cancer: RR 50%-60% versus <5%)
  32. 32. ADAPTIVE TRIALS (1) The principle of this trial is based on modifying parameters (dose, sample size, drug, schedule …) of a clinical trial evaluating a treatment in accord with observed outcomes in participants.
  33. 33. ADAPTIVE TRIALS (2) Deepak et al. New Eng J Med 2016
  34. 34. ADAPTIVE TRIALS (3) Deepak et al. New Eng J Med 2016
  35. 35. Park et al. New Eng J Med 2016 I-SPY 2 I-SPY 2 trial Multicenter, adaptive phase 2 trial of neoadjuvant therapy for: • High risk clinical stage II or III breast cancer evaluated multiple new agents added to standard chemotherapy  To assess the effects on rates of pathological complete response
  36. 36. Park et al. New Eng J Med 2016 Neratinib (HKI-272; Puma Biotechnology) • an irreversible small-molecule inhibitor of the ErbB and the human epidermal Growth factor receptor (HER) kinase family (epidermal growth Factor receptor, HER2, and HER4) • It has shown promising activity against HER2-positive metastatic breast cancer. • There is also evidence of preclinical activity against HER2negative tumor cells
  37. 37. Probability Distributions for Selected Biomarker Signatures Park et al. New Eng J Med 2016 Eligible women were categorized according to • 8 biomarker Subtypes on the basis of • Human epidermal growth factor receptor 2 (HER2) status • Hormone-receptor status • Risk according to a 70-geneprofile
  38. 38. Final Posterior and Predictive Probabilities of Neratinib Efficacy with Regard to 10 Biomarker Signatures * The status of high-risk category 2 on the 70-gene profile was determined with the use of the MammaPrint assay Park et al. New Eng J Med 2016
  39. 39. Final Posterior and Predictive Probabilities of Neratinib Efficacy with Regard to 10 Biomarker Signatures * The status of high-risk category 2 on the 70-gene profile was determined with the use of the MammaPrint assay Park et al. New Eng J Med 2016 • Neratinib reached the pre-specified efficacy threshold with regard to the HER2-positive, hormone-receptor–negative signature • Neratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone- receptor–negative breast cancer.
  40. 40. ADAPTIVE TRIAL DESIGN: PROS AND CONS • Pros • Faster evaluation of the drug • Modification of drug, dosage and sample size during the trial according to the observed results • Cons • Practical difficulties during the performance of the trial • The clinicians are not familiar with the essential statistical part of this approach • Active and dynamic follow-up of the trial is needed
  41. 41. WHAT ARE THE CHALLENGES OF THE NEW CLINICAL TRIAL DESIGNS? • To show significant benefit in overall survival • Rapidly evolving and not validated technics in use for tumor sequencing (NGS, circulating tumors cells, circulating tumor DNA…) • High number of screened patients is needed A strong infrastructure behind is needed to execute such trials with quality assurance
  42. 42. What are we going to discuss today! Evidence Based Medicine Resources Utilization Clinical Research Innovation • How are we used to perform clinical trials in Oncology? • Does it fit our today’s needs? • Integration of biology knowledge in shaping drug development • New Clinical trial designs “Can they offer solution for accelerating drug development?” • The supporting infrastructure role in clinical trial execution
  43. 43. The current fragmented approach of Drug & Biomarker related Development Screening patients Enrolling patients Collecting tissue Analyzing tissue Collecting real-life data Screening patients Enrolling patients Collecting tissue Analyzing tissue Collecting real-life data Screening patients Enrolling patients Collecting tissue Analyzing tissue Collecting real-life data Company A Company B Company C
  44. 44. QA/QC validated platforms & services Collected data Towards data-driven healthcare Faster access to effective care Business risk reduction Innovative trial designs / Trial access Regulatory pathway / Market access supported by adaptive licensing Biomarker analytical and clinical validation Treatment guideline development
  45. 45. QA/QC validated platforms & services Collected data Towards data-driven healthcare Faster access to effective care Business risk reduction Innovative trial designs / Trial access Regulatory pathway / Market access supported by adaptive licensing Biomarker analytical and clinical validation Treatment guideline development
  46. 46. • Clinical infrastructure • Quality Assurance in RT(QART) • Imaging• Translational Research Unit • Biobank Sample tool KEOSYS platform ORTA, VISTA, Safe, PRISMA QART VODCA platform EORTC Infrastructure as an “Example” supporting new generation clinical trials
  47. 47. Conclusion • We need to adapt in our trials according to the accelerating needs • Networking between institutions to render molecular tumor board accessible to the majority of centers and consequently to clinical trials and new drugs • More collaboration with pharmaceutical companies due to the need of drugs (including off label drugs) with the different mechanisms of action to be used in precision medicine at the right time for the patient • Validation Role of biomarkers and/or molecular imaging in determining mainly the negative predictive value of an evaluated drug • We need the infrastructure that can support such complex trials
  48. 48. “In the long history of humankind (and animal kind, too) those who learned to collaborate and improvise most effectively have prevailed.” Charles Darwin 1809-1882 Thank You

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