Workshop conducted at PhUSE 2013 Awarded as "Best Patient Centric Contribution"

1. Therapeutic Area Workshop
Oncology
Angelo Tinazzi – Cytel Inc. – on behalf of PhUSE
PhUSE 2013 – Bruxelles 14/10/2013

2. Text
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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.
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4. Overview
Introduction
• Current/Future Role of SAS Programmers
• PhUSE Wiki
Oncology
• Short Overview of Disease
• Signs/Symptoms
• Treatment Options

5. Overview
Oncology (cont.)
• Endpoints – Tools used
• Data Challenges
• SDTM and ADaM
• Regulatory Setting
• FDA Guideline
• EMA Guideline
• References

6. Standards help to collaborate,
the PhUSE Wiki helps to understand
CDASH/annotated CRF
SDTM
ADaM
PhUSE Wiki
Protocol,
CRF,
SAP
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SAS
Programming
Standardized
Analysis

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
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• SDTM mapping
• Tumore
Response
• Anti-Cancer
Medications
• Survival Fup
• ADaM concepts
• TTE Endpoints
• References

8. PhUSE (TA-)Wiki

9. PhUSE (TA-)Wiki

10. PhUSE (TA-Onco)Wiki

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. Oncology - Basics
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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. 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. 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. 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. Oncology - Basics
Type of Cancer
Source: US NCI – www.cancer.gov

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. 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. 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. 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. 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. Oncology - Basics
Treatment
Indications: Type of cancer + Line of therapy
3rd line XXXXX Treatment in relapsed YYYYY cancer patients

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. Oncology - Basics
Summary
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One Disease/Several Diseases
Not easy to diagnose
Complex pattern of therapies
Challenging disease therefore challenging in
programming

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. 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. 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. Oncology – Specific
Phase I in Oncology
In alternative
• Accelerated Titration
• Intra-Patient Titration
• Continuation
Reassessment Method
(CRM)

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. 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. Oncology - Specific
Primary Efficacy Outcome Measures
Quality of Life (EORTC QLQ-C30) and indication specific
questionnaires
http://groups.eortc.be/qol/eortc-modules

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. 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. Oncology - Specific
Efficacy Analysis
•Use of Covariates (some examples)

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. 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. 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
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38. Oncology - Specific
CTCAE Grade for laboratory data

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. Oncology - Specific
Tumor response evaluation with RECIST
Applicable to Solid Tumors

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. Oncology - Specific
Summary
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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. 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. Oncology - Standardisation
CDISC ADaM
• No specific oncology-standard have
been developped
• ADTTE for most of efficacy
endpoints (time-to-event) including
composite endpoints

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. Oncology - Standardisation
CRF  SDTM  ADaM  TLF
PFS as a composite endpoints

47. Oncology - Standardisation
CRF  SDTM  ADaM  TLF
PFS as a composite endpoints

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. 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. Oncology - Standardisation
Analysis Display (Survival Estimates)

51. Oncology - Standardisation
Analysis Display (Forest Plot)

52. Oncology - Standardisation
Analysis Display (Tumor Shrinkage)

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. Oncology – Regulatory
Regulatory Setting (FDA)
• Issues to consider in PFS analysis
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Progression and Censoring Date
How to handle Missing Data
Lesions evaluation
Sensitivity Analysis

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. Oncology - Bibliography

57. Oncology - Bibliography
Regulatory Guidance

58. Oncology - Bibliography
Oncology Specific

59. Oncology - Bibliography
Oncology and Programming

60. Oncology – Bibliography (PhUSE 2013)
Oncology and Programming

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. 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. 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. Oncology
Everyone is invited to contribute!
http://www.phusewiki.org
For further information:
wikiadmin@phusewiki.org
angelo.tinazzi@cytel.com

65. Oncology
Any questions?