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

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

Agenda 1.Introduction of Oncology 2.Introduction of Lymphoma Studies 3.Introduction of Cheson 4.CDISC SDTM 5.CDISC ADaM 6.Conclusion 7.Questions 3

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. 4

FDA New Drug Approval 2012 –37 Approval –12 Oncology (32 %) 2013 –27 Approval –8 Oncology (30 %) 5

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

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

Cheson 2007 History –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 ) 8

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

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

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

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 12

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 13

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. 14

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

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

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) 17

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 18

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 19

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 20

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 21

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 22

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

SDTM TU (Tumor Identification) USUBJI D TULIN KID TUTESTC D TUTESTTUORRESTULOCTUMETHO D T01TUMIDENTTumor Identification TARGET NODAL PELVIC LYMPH NODE CT SCAN T02TUMIDENTTumor Identification TARGET NODAL AXILARY LYMPH NODE CT SCAN T03TUMIDENTTumor Identification TARGET NODAL CERVICAL LYMPH NODE CT SCAN NT01TUMIDENTTumor Identification NON-TARGET EXTRA NODAL LIVERCT SCAN NT02TUMIDENTTumor Identification NON-TARGET EXTRA NODAL SPLEENCT SCAN T01TUMIDENTTumor Identification TARGET NODAL PELVIC LYMPH NODE FDGPET T02TUMIDENTTumor Identification TARGET NODAL AXILARY LYMPH NODE FDGPET T03TUMIDENTTumor Identification TARGET NODAL CERVICAL LYMPH NODE FDGPET 24 Key points to note: Subject 001 has 3 target and 2 non-targets TU.TULINKID is connected TR.TRLINKID using RELREC.

SDTM TR at Screening USUBJ ID TRGRI D TRLIN KID TRTE STCD TRTESTTRCATTROR RES TROR RESU VISITTRME THOD TargetT01LDIAMLongest Diameter Measure ment 20mmScreeningCT SCAN TargetT01LPERPLongest Perpendicular Measure ment 15mmScreeningCT SCAN TargetT01AREAAreaMeasure ment 300mm^2ScreeningCT SCAN TargetT01TUMST ATE Tumor StateQualitati ve POSITI VE ScreeningFDGP ET TargetSUMAR EA Sum of Products of Perpendicular Diameters Qualitati ve 2560mm^2Screening Non- Target NT01TUMST ATE Tumor StateQualitati ve PRESE NT ScreeningCT SCAN Non- Target NT02TUMST ATE Tumor StateQualitati ve PRESE NT ScreeningCT SCAN 25 Key points to note: Area and Sum of Area were collected SPD at screening for 001 is 2,560 mm^2

SDTMTR at Cycle 1 USUBJ ID TRGRI D TRLIN KID TRTE STCD TRTESTTRCATTROR RES TROR RESU VISITTRME THOD TargetT01LDIAMLongest Diameter Measure ment 15mmVisit 1CT SCAN TargetT01LPERPLongest Perpendicular Measure ment 10mmVisit 1CT SCAN TargetT01AREAAreaMeasure ment 150mmVisit 1CT SCAN TargetT01TUMST ATE Tumor StateQualitati ve NEGATI VE Visit 1FDGP ET TargetSUMAR EA Sum of Products of Perpendicular Diameters Qualitati ve 1200mmVisit Non- Target NT01TUMST ATE Tumor StateQualitati ve PRESE NT Visit 1CT SCAN Non- Target NT02TUMST ATE Tumor StateQualitati ve PRESE NT Visit 1CT SCAN 26 Key points to note: SPD at visit 1 for 001 is 1,200, more than 50 % decrease. FDGPET is negative from positive.

Bone Marrow - SDTM LB and FA USUBJI D LBCATLBSPECLBSPIDLBTESTLBORR ES LBOR RESU VISIT HEMATO LOGY BONE MARROW BR01Bone Marrow Infiltrate 35%Screening HEMATO LOGY BONE MARROW BR01Bone Marrow Infiltrate 9%Visit 1 27 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. USUBJIDFACATFASP ID FATESTFAORRESVISIT BONE MARROW BIOPSY BR01Bone Marrow Biopsy ResultsPOSITIVEScreening BONE MARROW BIOPSY BR01Bone Marrow Biopsy ResultsPOSITIVEVisit 1

Liver and Spleen Palpable Assessment - SDTM PE USUBJI D PECATPEMETHODPETESTCDPETESTPEOR RES VISIT PHYSICAL EXAMINATION PALPATIONSPLEENENSpleen Enlargement YESScreening PHYSICAL EXAMINATION PALPATIONSPLEENENSpleen Enlargement NOVisit PHYSICAL EXAMINATION PALPATIONLIVERENLiver Enlargement YESScreening PHYSICAL EXAMINATION PALPATIONLIVERENLiver Enlargement NOVisit 1 28 Key points to note: Subject 001 was palpable at Screening, but not palpable at Visit 1

SDTM RS (Response) USUBJI D RSTESTC D RSTESTRSCATRSORRESVISITRSDTCRSSE Q OVRLRESPOverall ResponseCHESON 2007 PRCycle OVRLRESPOverall ResponseCHESON 2007 SDCycle OVRLRESPOverall ResponseCHESON 2007 PRCycle OVRLRESPOverall ResponseCHESON 2007 PDCycle OVRLRESPOverall ResponseCHESON 2007 PDCycle Key points to note: Overall Response for each visit was collected.

Response Assessment at given visit 30 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)

ADaM : Overall Survival (OS) USUBJI D TRTPPARAM AVA L STARTDTADTCNSREVNTDESC Study Drug 1 Overall Survival (Days) PROGRESSION DISEASE ControlOverall Survival (Days) LOST TO FOLLOW-UP ControlOverall Survival (Days) DEATH Study Drug 1 Overall Survival (Days) COMPLETED STUDY Study Drug 1 Overall Survival (Days) PROGRESSION DISEASE 31 Key points to note: DEATH is NOT censored.

ADaM : Progression Free Survival (PFS) USUBJIDTRTPPARAM AVAL STARTDTADTCNSREVNTDESC Study Drug 1 Progression Free Survival (Days) PROGRESSION DISEASE ControlProgression Free Survival (Days) LOST TO FOLLOW-UP ControlProgression Free Survival (Days) DEATH Study Drug 1 Progression Free Survival (Days) COMPLETED STUDY Study Drug 1 Progression Free Survival (Days) PROGRESSION DISEASE 32 Key points to note: In PFS, DEATH and PD are NOT censored.

Conclusion Standard for Lymphoma Studies 1.Cheson 2007 : Tumor Measurements and Responses 2.CDISC SDTM : submission data 3.CDISC ADaM : analysis data 33

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

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