Oncology Therapeutic Area Workshop


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Workshop conducted at PhUSE 2013

Awarded as "Best Patient Centric Contribution"

Published in: Health & Medicine

Oncology Therapeutic Area Workshop

  1. 1. Therapeutic Area Workshop Oncology Angelo Tinazzi – Cytel Inc. – on behalf of PhUSE PhUSE 2013 – Bruxelles 14/10/2013
  2. 2. Text Text
  3. 3. Disclaimer The information contained in this presentation is based on research of personal PhUSE Wiki authors. PhUSE Wiki authors may or may not be experts in the field of the specific disease. Neither PhUSEwiki.org nor the PhUSE guarantee for the correctness of the displayed information. Text Text
  4. 4. Overview Introduction • Current/Future Role of SAS Programmers • PhUSE Wiki Oncology • Short Overview of Disease • Signs/Symptoms • Treatment Options
  5. 5. Overview Oncology (cont.) • Endpoints – Tools used • Data Challenges • SDTM and ADaM • Regulatory Setting • FDA Guideline • EMA Guideline • References
  6. 6. Standards help to collaborate, the PhUSE Wiki helps to understand CDASH/annotated CRF SDTM ADaM PhUSE Wiki Protocol, CRF, SAP Text Text SAS Programming Standardized Analysis
  7. 7. Aim of PhUSE (TA-)Wiki THE central place to share knowledge and information Basics • Background Information • Etiology • Pathophysiology • Statistics • Symptoms • Treatment options Specific Standardisation • TA-specific • Regulatory Setting • Endpoints • Assessment tools • (Data) Challenges Text Text • SDTM mapping • Tumore Response • Anti-Cancer Medications • Survival Fup • ADaM concepts • TTE Endpoints • References
  8. 8. PhUSE (TA-)Wiki
  9. 9. PhUSE (TA-)Wiki
  10. 10. PhUSE (TA-Onco)Wiki
  11. 11. Oncology - Basics Definition (short) • Cancer is a term used for diseases in which abnormal cells divide without control and are able to invade other tissues. Cancer cells can spread to other parts of the body through the blood and lymph systems. • Oncology is a branch of medicine that specializes in the diagnosis and treatment of cancer. It includes medical oncology (the use of chemotherapy, hormone therapy, and other drugs to treat cancer), radiation oncology (the use of radiation therapy to treat cancer), and surgical oncology (the use of surgery and other procedures to treat cancer).
  12. 12. Oncology - Basics Text Text Invasive colorectal cancer Apoptosis is the process of programmed cell death Cancer are caused by a series of mutations Source: http://en.wikipedia.org Chest x-ray showing lung cancer in the left lung
  13. 13. Oncology - Basics Epidemiology • Cancer is a leading cause of disease worldwide with about 13 million new cancer cases occurred worldwide • Just five cancer sites –lung, female breast, colon-rectum, stomach and prostate – accounted for half (48%) of the world’s total cancer diagnoses in 2008 • Men are more often affected than women. Source: Cancer Research UK http://www.cancerresearchuk.org
  14. 14. Oncology - Basics Risk Factors •The most common risk factors for cancer:  Tobacco  Sunlight  Ionizing radiation  Certain chemicals and other substances  Some viruses and bacteria  Certain hormones  Family history of cancer  Alcohol  Poor diet, lack of physical activity, or being overweight
  15. 15. Oncology - Basics Type of Cancer •Solid Tumors Cancer involving solid tumor, typically originates in a specific body organ, such a lung, breast, ovarian, etc. Types of solid tumors includes sarcomas, carcinomas, adenocarcinomas, blastomas, carcinoid tumors •Hematologic malignancies Arrise in the bloodforming cells; typically present as systemic disease, as blood and lymphatic organs located throughout the body are affected. Types of Hematologic malignancies includes leukemias, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), multiple myeloma (MM)
  16. 16. Oncology - Basics Type of Cancer Source: US NCI – www.cancer.gov
  17. 17. Oncology - Basics Diagnosis •Not easy to diagnose •Symptoms only appears as the mass grow or ulceration E.g. mass effects from lung cancer can cause blockage of the bronchus resulting in cough or pneumonia •Metastasis when cancer spread to other locations •Screening (Periodic Assessment) •Mammography for Breast Cancer •PSA for Prostate Cancer •Sigmoidoscopy or Colonscopy for Colorectal Cancer •Pap test for Cervix
  18. 18. Oncology - Basics Diagnosis •Primary vs Metastatic vs Recurrent Cancer •Resistant/Refractory Cancer •Location of the Cancer •Stage (TNM): extent of the disease and whether or not the cancer has spread in the body (metastasis) •Histology: type of normal tissue the tumor cells most closely resemble •Grading: cells differentiation/proliferation
  19. 19. Oncology - Basics Treatment •The treatment plan depends mainly on the type of cancer, the stage of the disease, age and general health •Treatment to Cure or Control or Reduce Symptoms •The treatment plan may change over time •The treatment plan includes •Surgery (local therapy removes or destroys cancer) •Radiation (to shrink or destroy a tumor) •Systemic Therapies •Vaccines to prevent and ‘cure’
  20. 20. Oncology - Basics Treatment Systemic Therapies Drugs or substances are used (through the bloodstream) to destroy cancer cells all over the body. The therapies kill or slow the growth of cancer cells that may have spread beyond the original tumor: •Chemotherapy •Biological therapy •Monotherapy vs Combination therapies •Adjuvant vs Neo-Adjuvant Treatment
  21. 21. Oncology - Basics Treatment Therapies with molecular/biological target •Use of Biomarkers to target the population E.g. drugs used in the therapy target specific markers - Herceptin in breast cancer with HER2++ - Gefitinib in lung cancer with mutant EGFR
  22. 22. Oncology - Basics Treatment Indications: Type of cancer + Line of therapy 3rd line XXXXX Treatment in relapsed YYYYY cancer patients
  23. 23. Oncology - Basics Treatment •Because cancer treatments often damage healthy cells and tissues, side effects are common:  Type and extent of the treatment.  Side effects may not be the same for each person, and they may change from one treatment session to the next.
  24. 24. Oncology - Basics Summary • • • • One Disease/Several Diseases Not easy to diagnose Complex pattern of therapies Challenging disease therefore challenging in programming
  25. 25. Oncology – Specific Clinical Trials in Oncology • Placebos are never used in place of treatment when an existing standard therapy exists. • Patient recruitment is more complicated.” • Longer follow-up
  26. 26. Oncology – Specific Clinical Trials in Oncology • Phase I • Toxicity • Optimal Dose Determination • Initial Drug Activity • PK • Phase II • Activity Signals / Tumor Response • Confirmation about tollerability
  27. 27. Oncology – Specific Clinical Trials in Oncology • Phase III • To show better clinical risk/benefit profile based on the efficacy and safety data analysis. • Efficacy through survival endpoints
  28. 28. Oncology – Specific Phase I in Oncology In alternative • Accelerated Titration • Intra-Patient Titration • Continuation Reassessment Method (CRM)
  29. 29. Oncology – Specific Phase I in Oncology • A peculiarity of Oncoloy • The concept of DLT (Dose Limiting Toxicity) and DLT period • Extended lab (hematology/chemistry) assessments • Nadir / Time to Nadir • Recovery / Time to Recovery • „Screening“ for future indication to develop (Phase II)
  30. 30. Oncology - Specific Primary Efficacy Outcome Measures • Overall Survival (OS) is the gold standard • Several surrogate endpoints can be used in place of OS • Best Overall Response (BOR) • Objective Response Rate • Duration of Response • Time to Progression (TTP) / Disease Free Survival (DFS) • Progression Free Survival (PFS)
  31. 31. Oncology - Specific Primary Efficacy Outcome Measures Quality of Life (EORTC QLQ-C30) and indication specific questionnaires http://groups.eortc.be/qol/eortc-modules
  32. 32. Oncology - Specific Primary Efficacy Outcome Measures •Standardised Tumor response evaluation: •RECIST for solid tumors •CHESON for Acute Myeloid Leukemia •Modified version •Modified PFS for Prostate Cancer (PCWG2) •mRECIST for Hepatocellular Carcinoma
  33. 33. Oncology - Specific Efficacy Analysis • Primarly survival analysis (Cox Model) • Graphical Representation • Kaplan Meier Plot • Forest Plot • Waterfall Plot • Sensitivity Analysis E.g. for incorrect periodicity of tumor assessment
  34. 34. Oncology - Specific Efficacy Analysis •Use of Covariates (some examples)
  35. 35. Oncology - Specific The concept of cycle • Commonly defined as a Number of days (or weeks), e.g. 21 / 28 days (3/4 weeks), where treatment is repeted • Different type of schedule • With combinations studies drugs might have a different schedule • The sequence of treatment is repeated (recycled) under certain condition usually safety and/or efficacy related.
  36. 36. Oncology - Specific Exposure assessment • Usually described by means of DoseIntensity and Relative Dose-Intensity • Cumulative dose (mg/sqm) / Treatment duration (weeks) • Dose Modifications e.g.: • Delays • Reductions • Overdoses • Omissions
  37. 37. Oncology - Specific Laboratory data and the CTCAE Grade Very often Laboratory results comes from local labs For some of the hematology, chemistry and coagulation parameters, a categorisation of the value is possibleNCI-CTCAE criteria • Each lab value is assigned a grade between 1 and 4 • The grade depends on the actual value and the normal ranges defined by the labs where the sample was analyzed • The classification can be mono or bi-directional • Hypo • Hyper • Hypo and Hyper • •
  38. 38. Oncology - Specific CTCAE Grade for laboratory data
  39. 39. Oncology - Specific Tumor response evaluation with RECIST • Tumor response measures the changes in tumor mass, growth (progression) or shrinkage (response) • Lesion classified as target (measurable) or nontarget (non-measurable) • Periodically assessed with CT-SCAN (every 6/8 weeks) • Progression evaluated vs Nadir (best ‘response’ prior to current assessment) • Response evaluated vs Baseline • Best Overall Response as the best response assessed since the subject is on-study (on-treatment) Applicable to Solid Tumors
  40. 40. Oncology - Specific Tumor response evaluation with RECIST Applicable to Solid Tumors
  41. 41. Oncology - Specific Data Challenges • Use of Local Labs • Advers Events and Treatment Emergent Definition • Periodic Tumor Assessments • Tumor Assesment and Treatment having different schedule • Blinded Tumor Assessments (Independent Review) • Follow-up when OS is primary endpoint • Use of Biomarkers in the analysis
  42. 42. Oncology - Specific Summary • • • • Choice of endpoints depends on several factors Efficacy evaluation of response is standardised and validated for solid tumors and for certain non-solid tumors (e.g. AML) Revised standard for specific cancer-type Peculiarity in handling Safety and Exposure
  43. 43. Oncology - Standardisation CDISC •SDTM version 3.1.3 contains oncology specific data domains for tumor response evaluation •TU: Tumor Identification •TR: Tumor Results •RS: Tumor Response •Upcoming version of SDTM •PR: Procedures •SS: Subject Status (Follow-up) •TS: Trial Design Assessment RG02: “CDISC Journey on Solid Tumor Studies using RECIST” Kevin Lee, ; PhUSE 2013
  44. 44. Oncology - Standardisation CDISC ADaM • No specific oncology-standard have been developped • ADTTE for most of efficacy endpoints (time-to-event) including composite endpoints
  45. 45. Oncology - Standardisation CRF  SDTM  ADaM  TLF PFS as a composite endpoints EVENT CENSOR Progression From Tumor Assessment / Response Death From Survival Follo-up Last Tumor Assessment From Tumor Assessment / Response
  46. 46. Oncology - Standardisation CRF  SDTM  ADaM  TLF PFS as a composite endpoints
  47. 47. Oncology - Standardisation CRF  SDTM  ADaM  TLF PFS as a composite endpoints
  48. 48. Oncology - Standardisation CDISC – Oncology Open Questions • [SDTM] Where to store prior anti-cancer therapiesCommon approach is to store them in CM with appropriate CMCAT and CMSCAT • [SDTM] Prior Cancer history stored in several different domain e.g. MH, CM, SUPPQUAL of MH, sponsor domains • [SDTM] Follow-up in DSLack of details • [SDTM] The use of Oncology Domains to store non-efficacy information • [ADaM] Cycles date as TRxxSDT/TRxxEDT?
  49. 49. Oncology - Standardisation CDISC – Coming Version (SDTM 3.1.4) • PR Procedures For Prior prior/post anti-cancer treatments • SS Subject Status For survival follow-up • TD Trial Disease Assessments For efficacy schedule of assessments
  50. 50. Oncology - Standardisation Analysis Display (Survival Estimates)
  51. 51. Oncology - Standardisation Analysis Display (Forest Plot)
  52. 52. Oncology - Standardisation Analysis Display (Tumor Shrinkage)
  53. 53. Oncology – Regulatory Regulatory Setting (FDA) FDA Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2007) General regulatory requirements for efficacy Detailed description of endpoints and how they can be used in various clinical settings • Pros and Cons • Protocol and SAP design requirements • Data Collection for Tumor Measurement
  54. 54. Oncology – Regulatory Regulatory Setting (FDA) • Issues to consider in PFS analysis • • • • Progression and Censoring Date How to handle Missing Data Lesions evaluation Sensitivity Analysis
  55. 55. Oncology – Regulatory Regulatory Setting (EMA) • ……… Guideline on the evaluation of anticancer medical products in man All stages of clinical drug development Appendices covering methodologial aspects related to: • Use of Progression Free Survival (PFS) and Disease Free Survival (DFS) in confirmatory trials • Confirmatory Studies in Haematological Malignancies • Condition specific Guidance such as NSCLC, Prostate The EMA is also planning to provide an additional appendix for Quality of Life/Patient Reported Outcome.
  56. 56. Oncology - Bibliography
  57. 57. Oncology - Bibliography Regulatory Guidance
  58. 58. Oncology - Bibliography Oncology Specific
  59. 59. Oncology - Bibliography Oncology and Programming
  60. 60. Oncology – Bibliography (PhUSE 2013) Oncology and Programming
  61. 61. Oncology Overall Summary •Cancer one diseases, several diseases •Complex study endpoints derivation in efficacy but also in safety •Unsual concepts e.g. a „cycle“ is not a „visit“ •If you get involved in a Oncology-study you may take a look at the PhUSE Wiki before you start
  62. 62. PhUSE (TA-Onco)Wiki What next •Seeking for feedback •Structure, Sections, Topics covered •Enough or more details •Link to source or source •Seeking for contributions •Complete sections, provide missing details •Review •Maintenance
  63. 63. PhUSE (TA-Onco)Wiki What next to develop •Identify tumor type specific characteristics from the data and analysis point of view •E.g. What make different colorectal cancer from lung cancer? •Key requirements for submission •E.g. Differences between indications, type of cancer and / or line of therapy •Complete the following area: •Phase II and Phase III design •Statistical Analysis •Quality of Life •Any missing important item?
  64. 64. Oncology Everyone is invited to contribute! http://www.phusewiki.org For further information: wikiadmin@phusewiki.org angelo.tinazzi@cytel.com
  65. 65. Oncology Any questions?