1. Accenture Life Sciences
Rethink  Reshape  Restructure… for better patient outcomes
CDISC Journey in Lymphoma using Cheson 2007 Kevin Lee CDISC NJ meeting April 17th, 2014

2. Disclaimer
Any views or opinions presented in this presentation are solely those of the author and do not necessarily represent those of the company.

3. Agenda Introduction of Oncology Introduction of Lymphoma Studies
Introduction of Cheson
CDISC SDTM
CDISC ADaM
Conclusion
Questions

4. Cancer Trivia
The word ‘cancer’ is related to the Greek word “crab” because its finger-like projections were similar to the shape of the crab
In 2010, the economic cost of the disease worldwide was estimated at $1.16 trillion.
One in eight deaths in the world are due to cancer.
Cancer is the leading cause of death in developed countries.
WHO predicts new cancer cases of 14 million in 2012 to 22 million in 2030 and cancer deaths from 8.2 million a year to 13 million annually.
There are 28 million cancer survivors worldwide.
Men who have never married are up to 35% more likely to die from cancer than those who are married.

5. FDA New Drug Approval 2012 37 Approval 12 Oncology (32 %) 2013

6. Oncology Study
How are the oncology studies different from other studies?
Tumor measurements and their response to drug
Toxicity (Lab and AE)
Time to Event Analysis
What tumor studies and response guidelines?
Solid Tumor : RECIST 1.1
Lymphoma : Cheson 2007
Leukemia : IWCLL 2008

7. What is Lymphoma Cancer that starts in lymph nodes Type of Lymphoma
Hodgkin lymphoma (HL) : lymphoma in the presence of a specific type of abnormal cell called a Reed-Sternberg cell
Non-Hodgkin lymphoma (NHL) : lymphoma not in the presence of a specific type of abnormal cell called a Reed-Sternberg cell
Guidelines for response : Cheson 2007

8. Cheson 2007 History Lesions (tumors)
IWG (International Working Group) 1999 and Cheson 2007
Lesions (tumors)
Type :
Enlarged Lymph Nodes (long axis > 15 mm or its greatest perpendicular axis > 10 mm by CT scan)
Nodal Masses
Extra Nodal Masses (> 10 mm )

9. Lymphatic System
A Nodal Mass is the conglomerate of several enlarged nodes touching one another which are not distinguished from individual nodes any more.

10. Extra Nodal Site
Extra nodal – a lymphoma that is detected outside of lymphatic system.

11. Cheson 2007
Two-dimensional measurement - product of longest diameter and its greatest perpendicular axis (e.g., 40 mm * 15 mm = 600 mm^2)

12. What is to measure in Lymphoma according to Cheson 2007
Tumor measurements in CT / MRI
Lymph Node, Nodal Masses and Extra Nodal Masses
PET scan on lesions (to distinguish viable tumor from fibrosis)
Bone Marrow Assessment
Spleen and Liver Enlargement Assessment

13. Target Lesions according to Cheson 2007
Normally 6 lesions
lymph nodes or nodal masses
Two perpendicular diameters should be clearly measurable
Quantitative measurements
Longest diameter and its greatest transverse perpendicular diameter
Products of the diameters
Sum of the products of the diameters (SPD) up to 6 target lesions

14. Non-Target Lesions according to Cheson 2007
All other lesions beside target lesions
Extra nodal (i.e., Liver, Spleen)
Quantitative measurements
Longest diameter and its greatest transverse perpendicular diameter
Products of the diameters
Qualitative measurements – present, absent, increased or decreased.

15. New Lesions according to Cheson 2007
Any lesions that are newly found at post-baseline
Either quantitative or qualitative measurements

16. Lesions at baseline Lesions Measurable Lymph Node or Nodal Masses
Non-Measurable or Extra Nodal Masses
Targets
Non-Targets

17. Response Criteria
Complete Response(CR) : Disappearance of all evidence of disease
Partial Response(PR) : Regression of measurable disease and no new sites
Progressive Diseases (PD) : Any new lesions or any increase by 50% from nadir in SPD
Stable Disease (SD) : Fail to CR/PR or PD
Not Evaluable (NE)

18. Complete Response (CR)
Nodal Masses
Typically FDG-avid lymphoma - if PET is positive in screening, PET is negative for all lesions.
Variably FDG-avid lymphoma - all the lymph nodes/nodal masses regress to normal size (<= 15 mm in their greatest transverse diameter or < 10 mm in short axis if their greatest transverse diameter is between 10 and 15)
Spleen and Liver – Not palpable, nodules disappeared
Bone Marrow – Infiltrate cleared; if indeterminate by morphology, immunohistochemistry should be negative

19. Partial Response (PR) Nodal Masses
A 50% decrease in the sum of the product of diameters (SPD) of six target lesions
No increase in any lesions
Typically FDG-avid lymphoma - if PET is positive in screening, PET is positive at least one lesion.
Variably FDG-avid lymphoma - all the lymph nodes/nodal masses regress.
Spleen and Liver – Not palpable, nodules regressed by 50 % in SPD.
Bone Marrow – Irrelevant

20. Progressive Disease (PD)
Nodal Masses
Any new lesions (more than 15 mm in any axis)
An increase by 50% in SPD from nadir of any involved lesions
An increase by 50% in the longest diameter from nadir of any involved lesions
Positive PET.
Spleen and Liver – nodules increase by 50 % in SPD.
Bone Marrow – New or recurrent involvement

21. CDISC Domains or Datasets for Lymphoma Studies
SDTM
TU : Tumor Identification
TR : Tumor Results
RS : Response
LB / FA : Bone Marrow
PE : Liver and Spleen Palpable assessment
ADaM
-TTE : Time to Event Analysis Datasets

22. Efficacy Evaluation in Lymphoma
Primary
Overall Survival : Death as event.
Progression-free survival : Disease Progression or death as a event. preferred end point in Lymphoma studies.
Secondary
Event-free survival
Overall Response Rate : Phase II trials of novel new agents
Time to Progression
Disease Free Survival

23. Example Randomized and open label Phase II Study
Lymphoma following Cheson 2007
5 cycles
3 target and 2 non-target lesions at screening
Primary Efficacy – Overall Survival and Progression Free Survival

24. SDTM TU (Tumor Identification)
USUBJID
TULINKID
TUTESTCD
TUTEST
TUORRES
TULOC
TUMETHOD
T01
TUMIDENT
Tumor Identification
TARGET NODAL
PELVIC LYMPH NODE
CT SCAN
T02
AXILARY LYMPH NODE
T03
CERVICAL LYMPH NODE
NT01
NON-TARGET EXTRA NODAL
LIVER
NT02
SPLEEN
FDGPET
Key points to note:
Subject 001 has 3 target and 2 non-targets
TU.TULINKID is connected TR.TRLINKID using RELREC.

25. SDTM TR at Screening Key points to note:
USUBJID
TRGRID
TRLINKID
TRTESTCD
TRTEST
TRCAT
TRORRES
TRORRESU
VISIT
TRMETHOD
Target
T01
LDIAM
Longest Diameter
Measurement 20 mm
Screening
CT SCAN
LPERP
Longest Perpendicular 15
AREA
Area
300
mm^2
TUMSTATE
Tumor State
Qualitative
POSITIVE
FDGPET
SUMAREA
Sum of Products of Perpendicular Diameters
2560
Non-Target
NT01
PRESENT
NT02
Key points to note:
Area and Sum of Area were collected
SPD at screening for 001 is 2,560 mm^2

26. SDTMTR at Cycle 1 Key points to note:
USUBJID
TRGRID
TRLINKID
TRTESTCD
TRTEST
TRCAT
TRORRES
TRORRESU
VISIT
TRMETHOD
Target
T01
LDIAM
Longest Diameter
Measurement 15 mm
Visit 1
CT SCAN
LPERP
Longest Perpendicular 10
AREA
Area
150
TUMSTATE
Tumor State
Qualitative
NEGATIVE
FDGPET
SUMAREA
Sum of Products of Perpendicular Diameters
1200
Non-Target
NT01
PRESENT
NT02
Key points to note:
SPD at visit 1 for 001 is 1,200, more than 50 % decrease.
FDGPET is “negative” from “positive”.

27. Bone Marrow - SDTM LB and FA
USUBJID
LBCAT
LBSPEC
LBSPID
LBTEST
LBORRES
LBORRESU
VISIT
HEMATOLOGY
BONE MARROW
BR01
Bone Marrow Infiltrate 35 %
Screening 9
Visit 1
USUBJID
FACAT
FASPID
FATEST
FAORRES
VISIT
BONE MARROW
BIOPSY
BR01
Bone Marrow Biopsy Results
POSITIVE
Screening
Visit 1
Key points to note:
LB.LBSPID is connected to FA.FASPID
We can also use BR (Biopsy) domain following SDTM terminology
Row 1: Bone Marrow Infiltration (i.e., 35%) and its result (i.e., POSITIVE) are collected, so the example has infiltration number in LB and results in FA.

28. Liver and Spleen Palpable Assessment - SDTM PE
USUBJID
PECAT
PEMETHOD
PETESTCD
PETEST
PEORRES
VISIT
PHYSICAL EXAMINATION
PALPATION
SPLEENEN
Spleen Enlargement
YES
Screening NO
Visit 1
LIVEREN
Liver Enlargement
Key points to note:
Subject 001 was palpable at Screening, but not palpable at Visit 1

29. SDTM RS (Response) Key points to note:
USUBJID
RSTESTCD
RSTEST
RSCAT
RSORRES
VISIT
RSDTC
RSSEQ
OVRLRESP
Overall Response
CHESON 2007 PR
Cycle 1 1 SD
Cycle 2 2
Cycle 3 3 PD
Cycle 4 4
Cycle 5 5
Key points to note:
Overall Response for each visit was collected.

30. Response Assessment at given visit
Response (RS)
Tumor measurement in SPD by CT SCAN (TU)
Tumor Assessment by PET (TU)
Bone Marrow Infiltrate (LB, FA)
Spleen and Liver Enlargement (PE)

31. ADaM : Overall Survival (OS)
USUBJID
TRTP
PARAM
AVAL
STARTDT
ADT
CNSR
EVNTDESC
Study Drug 1
Overall Survival (Days)
452 1
PROGRESSION DISEASE
Control
338
LOST TO FOLLOW-UP
212
DEATH
463
COMPLETED STUDY 67
Key points to note:
DEATH is NOT censored.

32. ADaM : Progression Free Survival (PFS)
USUBJID
TRTP
PARAM
AVAL
STARTDT
ADT
CNSR
EVNTDESC
Study Drug 1
Progression Free Survival (Days)
452
PROGRESSION DISEASE
Control
338 1
LOST TO FOLLOW-UP
212
DEATH
463
COMPLETED STUDY 67
Key points to note:
In PFS, DEATH and PD are NOT censored.

33. Conclusion Standard for Lymphoma Studies
Cheson 2007 : Tumor Measurements and Responses
CDISC SDTM : submission data
CDISC ADaM : analysis data

34. 2014 Summer Preview Blockbuster Movies
Webinar : FDA Electronic submission Guidance
PharmaSUG (June 1st to 4th)
CDISC Electronic Submission

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36. Questions and Discussion
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