CDISC journey in Leukemia studies using IWCLL 2008

1

CDISC Journey in Leukemia

Studies using IWCLL 2008 Kevin Lee

Agenda

1. Introduction of Oncology

2. Introduction of Leukemia Studies

3. Introduction of Chronic Lymphocytic

Leukemia and IWCLL 2008

4. Leukemia Specific CDISC SDTM / ADaM

5. Leukemia Study Example

6. Conclusion

7. Questions 2

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.

• In 2013, an estimated 119,386 people in US were living with Chronic

Lymphocytic Leukemia.

• 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.

3

FDA CDER NMEs and BLAs Approval

• 2012

–39 Approval

–13 Oncology (33 %)

• 2013

–27 Approval

–8 Oncology (30 %)

• 2014 ( as of the end of October)

–34 Approval

–6 Oncology (18%)

Note: based on the reports of NMEs and BLAs approved by CDER

4

Oncology Study

• How are the oncology studies different from other studies?

– Tumor measurements and their response to drug

– Oncology type specific measurements (e.g., liver and

spleen Enlargement, Bone Marrow Infiltrate and so on)

– 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, IWAML 2003, NCCN Guideline

2012 on ALL, CML ESMO Guidelines

5

What is Leukemia

• Cancer that usually begin in the bone marrow and result in

high numbers of abnormal white blood cells(lymphocytes).

• Type of Leukemia

– Acute Lymphoblastic Leukemia(ALL) - a rapid increase in the number of

immature white blood cells.

– Acute Myeloid Leukemia (AML) - a rapid increase in the number of

abnormal white blood cells in bone marrow that interfere with the

production of normal blood cells.

– Chronic Lymphocytic Leukemia (CLL) - excessive buildup of relatively

mature, but still abnormal, white blood cells

– Chronic Myeloid Leukemia (CML) - the increased and unregulated

growth of predominantly myeloid cells in the bone marrow and the

accumulation of these cells in the blood.

6

http://en.wikipedia.org/wiki/Myeloid

http://en.wikipedia.org/wiki/Bone_marrow

Guidelines for Responses in

Leukemia Studies

Acute Lymphoblastic Leukemia(ALL) –

NCCN(National Comprehensive Cancer

Network) Guideline version1.2012

Acute Myeloid Leukemia (AML) – IWAML

2003

Chronic Lymphocytic Leukemia (CLL) –

IWCLL 2008

Chronic Myeloid Leukemia (CML) - CML

ESMO Guideline 7

Introduction of Chronic Lymphocytic

Leukemia (CLL)

Lymphocytic – if the cancerous change

takes place in marrow that forms

lymphocytes

Myelogenous – if the cell change takes

place in marrow that forms red blood cells.

8

Chronic Lymphocytic Leukemia (CLL)

Process

9

Mutation of stem cells in Bone

Marrow

Abnormal WBC (CLL

cells) are formed

CLL cells increase in bone marrow

CLL cells increase in blood

Introduction of IWCLL ( International

Workshop on Chronic Lymphocytic Leukemia)

• History

–IWCLL 1996 and 2008

• Diagnosis of CLL

–Blood : > 5 * 109 B lymphocytes/L (5000 / uL) in

blood.

–Immunophenotype (flow cytometry) of

Lymphocytes:

• A presence of T-cell antigen CD5

• A presence of B-cell surface CD19, CD20, CD23

• Low surface immunoglobin CD20, CD79b 10

Tumor Identification and Measurement

according to IWCLL

11

• Enlarged Lymph Nodes (long

axis > 15 mm)

• Two-dimensional

measurement - product of

longest diameter and its

greatest perpendicular axis

(e.g., 40 mm * 15 mm = 600

mm^2) - up to 5

What are to measure for response

criteria according to IWCLL 2008

• Tumor measurements in CT / MRI

–Lymph Node

• Lymphocytes Assessment

• Spleen and Liver Enlargement Assessment

• Bone Marrow Assessment

• Blood Count Assessment – Neutrophils,

Platelets, and Hemoglobin.

12

Additional measurements according

to IWCLL 2008

• Immunophenotype (flow Cytometry)

Assessment

• Performance Status by ECOG(Eastern

Cooperative Oncology Group)

• Staging – assessment of disease progress for treatment plan

–Rai : 0 (Low risk), 1&2 (Intermediate risk), 3

(High risk)

–Binet : A, B, C

13

Response Criteria

• Complete Response(CR) :

• Partial Response(PR) :

• Progressive Diseases (PD) :

• Stable Disease (SD) : Fail to CR/PR or PD

• Not Evaluable (NE)

14

Complete Response (CR)

• Group A

– Lymph Nodes – all <= 15 mm in longest diameter

– Blood Lymphocytes < 4.0 * 109 /L (4,000 /uL)

– Spleen – Not palpable

– Liver – Not palpable

– Bone Marrow

• Normocelullar for age

• < 30% Lymphocytes

• No Lymphoid nodules

• Group B - Blood Counts

– Neutrophils > 1.5 * 109 /L (1,500 /uL)

– Platelets > 100 * 109 /L (100,000 /uL)

– Hemoglobin > 11.0 g/dL

• Note : All of the criteria has to be met 15

Partial Response (PR)

• Group A

– Lymph Nodes : Sum of products decreases >= 50%, no increase in

any lymph node and no new enlarged lymph nodes

– Blood Lymphocytes : Decrease >= 50% from baseline

– Spleen : Decrease >= 50%

– Liver : Decrease >= 50%

– Bone Marrow : 50% reduction in marrow infiltrate or B-lymphoid

nodules presence


– Neutrophils > 1.5 * 109 /L (1,500 /uL) or increase >= 50%

– Platelets > 100 * 109 /L (100,000 /uL)or increase >= 50%

– Hemoglobin > 11.0 g/dL or increase >= 50%

• At least Two of Group A and one of Group B should be met

16

Progressive Disease (PD)

• Group A

– Lymph Nodes : Sum of products increase>= 50% or new

enlarged lymph nodes

– Blood Lymphocytes : Increase >= 50%

– Spleen : Increase >= 50%

– Liver : Increase >= 50%


– Platelets : Decrease >= 50% or < 100* 109 /L

– Hemoglobin : Decrease of > 2 g/dL or < 10 g/dL

• At least one from Group A or Group B

17

CDISC Domains or Datasets for Leukemia

Studies

• SDTM

– TU : Tumor Identification

– TR : Tumor Results

– PE /FA : Liver and Spleen Enlargement

– LB / FA : Bone Marrow

– LB : Lymphocytes, Neutrophils, Platelets, and Hemoglobin

– RS : Response

• ADaM

– -TTE : Time to Event Analysis Datasets

18

Efficacy Evaluation in Leukemia

• For physically fit patients

–Overall Survival : Death as event.

–Overall Response Rate

• For patients with reduced physical fitness

–Time to Progression

–Health-related quality of life

19

Example

• Randomized and open label Phase II Study

• Leukemia following IWCLL 2008

• Primary Efficacy – Overall Response Rate

20

SDTM TU (Tumor Identification) USUBJI

D

TULIN

KID

TUTESTC

D

TUTEST TUORRES TULOC TUMETHO

D

001-01-

001

T01 TUMIDENT Tumor

Identification

TARGET

NODAL

PELVIC

LYMPH NODE

CT SCAN

001-01-

001

T02 TUMIDENT Tumor

Identification

TARGET

NODAL

AXILARY

LYMPH NODE

CT SCAN

001-01-

001

T03 TUMIDENT Tumor

Identification

TARGET

NODAL

CERVICAL

LYMPH NODE

CT SCAN

21

Key points to note: • Subject 001 has 3 target • TU.TULINKID is connected TR.TRLINKID using RELREC.

SDTM TR at Screening USUBJ

ID

TRGRI

D

TRLIN

KID

TRTE

STCD

TRTEST TRCAT TROR

RES

TROR

RESU

VISIT TRME

THOD

001-01-

001

Target T01 LDIAM Longest

Diameter

Measure

ment

20 mm Screening CT

SCAN

001-01-

001

Target T01 LPERP Longest

Perpendicular

Measure

ment

15 mm Screening CT

SCAN

001-01-

001

Target T01 AREA Area Measure

ment

300 mm^2 Screening CT

SCAN

001-01-

001


Diameter

Measure

ment

25 mm Screening CT

SCAN

001-01-

001


Perpendicular

Measure

ment

20 mm Screening CT

SCAN

001-01-

001


ment


SCAN

001-01-

001

Target SUMAR

EA

Sum of

Products of

Perpendicular

Diameters

Measure

ment

2560 mm^2 Screening

22

Key points to note: • Area and Sum of Area were collected • SPD at screening for 001 is 2,560 mm^2

SDTM TR at Cycle 1 USUBJ

ID

TRGRI

D

TRLIN

KID

TRTE

STCD

TRTEST TRCAT TROR

RES

TROR

RESU

VISIT TRME

THOD

001-01-

001


Diameter

Measure

ment

15 mm Screening CT

SCAN

001-01-

001


Perpendicular

Measure

ment

10 mm Screening CT

SCAN

001-01-

001


ment


SCAN

001-01-

001


Diameter

Measure

ment

15 mm Screening CT

SCAN

001-01-

001


Perpendicular

Measure

ment

10 mm Screening CT

SCAN

001-01-

001


ment


SCAN

001-01-

001

Target SUMAR

EA

Sum of

Products of

Perpendicular

Diameters

Measure

ment

1200 mm^2 Screening

23

Key points to note: • SPD at visit 1 for 001 is 1,200, more than 50 % decrease.

Bone Marrow - SDTM LB and FA

USUBJI

D

LBCAT LBSPEC LBSPID LBTEST LBORR

ES

LBOR

RESU

VISIT

001-01-

001

HEMATO

LOGY

BONE

MARROW

BR01 Percentage of

Cellularity

75 % Screening

001-01-

001

HEMATO

LOGY

BONE

MARROW

BR01 Percentage of

Cellularity

65 % Cycle 1

24

Key points to note: • LB.LBSPID is connected to FA.FASPID

• We can also use BR (Biopsy) domain • If nodules are present in Bone Marrow, they are collected in TR and TU.

USUBJID FACAT FASP

ID

FATEST FAORRES VISIT

001-01-001 BONE MARROW

BIOPSY

BR01 Bone Marrow Cellularity HYPERCEL

LULAR

Screening


BIOPSY

BR01 Bone Marrow Cellularity NORMOCEL

LULAR

Cycle 1


BIOPSY

BR01 B-Lymphoid Nodule PRESENT Screening


BIOPSY

BR01 B-Lymphoid Nodule ABSENT Cycle 1

Liver Palpable Assessment - SDTM PE

and FA at Screening & Visit 1 USUB

JID

PECAT PESPID PEMETH

OD

PETESTC

D

PETEST PEOR

RES

VISIT

001-01-

001

PHYSICAL

EXAMINATION

LP01 PALPATION LIVEREN Liver

Enlargement

YES Screening

001-01-

001

PHYSICAL

EXAMINATION

LP01 PALPATION LIVEREN Liver

Enlargement

NO Cycle 1

25

Key points to note: •PE.PESPID and FA.FASPID are linked thru RELREC •The liver of Subject 001 was palpable at Screening, but not at Visit 1. Its size decreased from 16 to 10 cm.

USUB

JID

FACAT FASPID FATEST FAORRE

S

FAOR

RESU

VISIT

001-01-

001

SPLEEN AND LIVER

MEASUREMENT

LP01 Measurement of Liver

Enlargement

16 cm Screening

001-01-

001

SPLEEN AND LIVER

MEASUREMENT

LP01 Measurement of Liver

Enlargement

10 cm Cycle 1

Spleen Palpable Assessment - SDTM

PE and FA at Screening & Visit 1 USUB

JID

PECAT PESPID PEMETH

OD

PETESTC

D

PETEST PEOR

RES

VISIT

001-01-

001

PHYSICAL

EXAMINATION

SP01 PALPATION SPLEENEN Spleen

Enlargement

YES Screening

001-01-

001

PHYSICAL

EXAMINATION

SP01 PALPATION SPLEENEN Spleen

Enlargement

YES Cycle 1

26

Key points to note: •PE.PESPID and FA.FASPID are linked thru RELREC •The spleen of Subject 001 was palpable at Screening and visit 1. Its size decreased from 15 to 14 cm.

USUB

JID

FACAT FASPID FATEST FAORRE

S

FAOR

RESU

VISIT

001-01-

001

SPLEEN AND LIVER

MEASUREMENT

SP01 Measurement of

Spleen Enlargement

15 cm Screening

001-01-

001

SPLEEN AND LIVER

MEASUREMENT

SP01 Measurement of

Spleen Enlargement

14 cm Cycle 1

SDTM LB for Leukemia Blood counts

USUBJID LBCAT LBTESTC

D

LBTEST LBORRE

S

LBORR

ESU

VISIT

001-01-001 HEMATOLOGY LYM Lymphocytes 6,000 /uL Screening

001-01-001 HEMATOLOGY NEUT Neutrophils 1,400 /uL Screening

001-01-001 HEMATOLOGY PLAT Platelets 90,000 g/dL Screening

001-01-001 HEMATOLOGY HGB Hemoglobin 13 /uL Screening

….

001-01-001 HEMATOLOGY LYM Lymphocytes 4,500 /uL Cycle 1

001-01-001 HEMATOLOGY NEUT Neutrophils 1,600 /uL Cycle 1

001-01-001 HEMATOLOGY PLAT Platelets 100,500 g/dL Cycle 1

001-01-001 HEMATOLOGY HGB Hemoglobin 13 /uL Cycle 1

27

Key points to note: •Lymphocytes counts decreased from 6,000 to 4,500 /uL •Neutrophils counts increased from 1,400 to 1,600 /uL •Platelets counts increased from 90,000 to 100,500 /uL •Hemoglobin counts did not change •Lab blood counts improved to PR (red-circled) according to response criteria

Response Assessment at Visit 1

28

Partial Response at Visit 1

Tumor measurement

decreases more than 50%

Bone Marrow Cellularity

decrease by 13%

Liver size decrease about

37%

Spleen size decrease about

7%

Lymphocytes decrease 33%

Neutrophils counts increase

to 1,600 /uL

Platelets counts increase to 100,500/uL

Hemoglobin counts does not

change

SDTM RS (Response) – overall response at

each visit

USUBJI

D

RSTESTC

D

RSTEST RSCAT RSORRES VISIT RSDTC RSSE

Q

001-01-

001

OVRLRESP Overall Response IWCLL

2008

PR Cycle

1

2011-03-

01

1

001-01-

001


2008

SD Cycle

2

2011-06-

01

2

001-01-

001


2008

PR Cycle

3

2011-09-

01

3

001-01-

001


2008

PD Cycle

4

2011-12-

01

4

001-01-

001


2008

PD Cycle

5

2012-03-

01

5

29

Key points to note: • Using Tumor measurement, Bone Marrow Checkup, Spleen/Live assessment and Blood counts, overall Response for each visit was measured and collected. •Usually, Responses were measured and collected by investigator, not programmatically.

Response Assessment at given visit

30

Response (RS)

Tumor measurement in SPD by CT SCAN (TR)

Bone Marrow (LB, FA)

Spleen and Liver

Enlargement (PE, FA)

Blood Counts (LB)

ADaM : Objective Response Rate

31

Key points to note: • Best overall response for each subject is obtained overall response from all the visits.

USUBJID TRTP PARAMCD PARAM AVISIT AVALC

001-01-001 Study Drug BESTRESP Best Overall Response End of Study PR

001-01-001 Study Drug OBJRESP Objective Response End of Study Y

001-01-002 Control BESTRESP Best Overall Response End of Study SD

001-01-002 Control OBJRESP Objective Response End of Study N

001-01-003 Control BESTRESP Best Overall Response End of Study SD

001-01-003 Control OBJRESP Objective Response End of Study N

001-01-004 Study Drug BESTRESP Best Overall Response End of Study PR

001-01-004 Study Drug OBJRESP Objective Response End of Study Y

001-01-005 Study Drug BESTRESP Best Overall Response End of Study PD

001-01-005 Study Drug OBJRESP Objective Response End of Study N

Conclusion

• Standard for Leukemia Studies

1. IWCLL 2008 : CLL Measurements

2. CDISC

• SDTM : submission data

• ADaM : analysis data

32

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CDISC journey in Leukemia studies using IWCLL 2008