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Lenalidomide Safety AssessmentStudy MDS-003, 002

Robert Knight, MDVice President Clinical Research Oncology

Celgene Corporation

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Safety in Del 5q Patients(120-Day Update)

Study MDS-003

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Lenalidomide ExposureDel 5q (MDS-003) 148 received ≥ 1 dose of 10 mg 105/148 received ≥ 24 wk Median exposure

– 10 mg continuous (n = 103): 43.7 wk (0.4 - 68.0)

– 10 mg cyclic (n = 45): 44.7 wk (2.0 - 69.9)

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day

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DLTs Grade 4 neutropenia Platelet count < 30,000/µL≥ Grade 3 non-hematologic toxicity

Lenalidomide Dose-Adjustment for DLTDel 5q (MDS-003)

Dose reductionStarting dose level 1 210 mg qd 5 mg qd 5 mg qod

Most dose adjustments were for neutropenia and/or thrombocytopenia.

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Dosing by Week on StudyDel 5q (MDS-003)

§ Highest frequency dose selected for each patient as their dose within each 4-wk period.

1-4 5-8 9-12 13-16 17-20 21-240

20

40

60

80

100Interrupted5 mg QD10 mg 5 mg QOD

Med

ian

time

to re

spon

se

Study week

Patie

nts,

%

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Grade 3/4 Hematologic AEs ≥ 2%Del 5q (MDS-003)

Patients, %N = 148

Grade 3 Grade 4Neutropenia 16.9 40.5Thrombocytopenia 41.9 10.1Febrile neutropenia 4.7 0.7Anemia 3.4 4.1Hemorrhagic events 3.4 0.7

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Clinically Significant CytopeniaDel 5q (MDS 003) (12-31-04)

Nadir platelet counts/µLN = 148

≤ 10,000 > 10,000 - ≤ 20,000

> 20,000 -

≤ 50,000Patients, n (%) 9 (6.8) 16 (10.8) 50 (33.7)Platelet transfusions, bleeding

Clinically significant 3 (2.0) 3 (2.0) 2 (1.3)Clinically insignificant 6 (4.0) 9 (6.8) 4 (2.7)

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Grade 3/4 Hematologic AEs ≥ 2%Del 5q (MDS-003)

Patients, %N = 148

Grade 3 Grade 410 contn = 103

10 cyclicn = 45

10 contn = 103

10 cyclicn = 45

Neutropenia 17.5 15.6 50.5 17.8Thrombocytopenia 44.7 35.6 6.8 17.8Febrile neutropenia 3.9 6.7 0 2.2Anemia 1.9 6.7 4.9 2.2Hemorrhagic events 1.9 6.7 0 2.2

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day

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CS-9Median ANC/Platelets by Week for TI RespondersDel 5q (MDS-003)

0 4 8 12 16 20 24 28 32 36 40 44 480

1

2

3

4 ANCPlatelets

0

100

200

300

400

BL/Scrn Wk

AN

C (1

09 /L)

Platelets (109/L)

CS-10Median ANC/Platelets by Week for TI Non RespondersDel 5q (MDS-003)

0 4 8 12 16 20 24 28 32 36 40 44 480

1

2

3

4 ANCPlatelets

0

100

200

300

400

BL/Scrn Wk

AN

C (1

09 /L)

Platelets (109/L)

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Grade 3/4 Non Hematologic AEs ≥ 3%Del 5q (MDS-003)

Patients, %N = 148

Grade 3 Grade 4Fatigue 6.1 0.0Pneumonia 6.1 2.0Nausea 4.7 0.0Back pain 4.1 0.7Diarrhea 4.1 0.0Hypokalemia 3.4 0.0Pyrexia 3.4 0.0

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day

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Serious AEs > 2%Del 5q (MDS-003)

Patients, %N = 148

All serious AEs

Suspecteddrug related

Pneumonia 9 4Neutropenia 8 6Pyrexia 4 3Febrile neutropenia 4 3Thrombocytopenia 4 3Dehydration 4 0Acute leukemia 4 0Anemia 3 1Congestive heart failure 3 < 1Sepsis 3 < 1Diarrhea 3 0Vomiting 3 < 1

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day

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Patient Disposition Del 5q (MDS-003)

Patients, n (%)10 mg

N = 148Median time on study 47 wksDiscontinued study medication 69 (47)Primary reason for discontinuations

AE 26 (18)Inadequate therapeutic effect 26 (18)Patient withdrew consent 3 (2)Death 9 (6)Other 5 (3)

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AEs Leading to Discontinuation Del 5q (MDS-003) (n/N = 26/148)

Reasons for discontinuation – Thrombocytopenia 8 (5.4%)– Neutropenia 4 (2.7%)– Rash 4 (2.7%)– Pneumonia 2 (1.4%)

All other AEs leading to discontinuations were reported in 1 patient each

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CS-15Deaths on Study or ≤ 30 Days After Drug Termination Del 5q (MDS-003)

Patients, n (%)N = 148

Deaths 11 (7)Suspected as drug related 3 (2)

Neutropenia/pneumonia 1Neutropenia/Klebsiella sepsis 1Pancytopenia/sepsis 1

Not suspected 8 (5)CHF 3Ischemic colitis/CHF/multiorgan failure 1Sudden death 1Intestinal perforation at colonoscopy 1Acute leukemia 1Traumatic SAH/subdural hematoma 1

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day

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Safety in Non-Del 5q Patients(12-31-04)

Study MDS-002

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Grade 3/4 AEs > 3%Non Del 5q (MDS-002)

Patients, %N = 215

Grade 3 Grade 4Thrombocytopenia 19.5 4.7Anemia 5.6 1.9Neutropenia 6.5 21.9Atrial fibrillation 4.2 0.5Cardiac failure congestive 4.2 0.0Diarrhea 3.3 0.0Fatigue 3.7 0.0Pneumonia 4.7 0.0Rash 4.2 0.0

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MDS On-Study DeathsMDS-001, 002, 003 (Pooled)

n/N = 26/408 (6%)– 5 (1%) suspected as drug related

Median age (min, max) at time of death– 80 (62, 93)

Time to death from MDS diagnosis– Median, yr (range): 2.8 (1 - 12)

18DV per client

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Safety Conclusions Favorable safety profile Neutropenia/thrombocytopenia

– Most common AEs – Manageable with dose interruption/reduction– Frequency in non del 5q ~ half of del 5q – Consistent with putative mechanism of action

Non hematologic AEs were mild and infrequent

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Dosing Regimen ConclusionsMDS-001 established 10 mg starting dose

MDS-002 (non del 5q) and MDS-003 (del 5q) used a starting dose of 10 mg, with dose adjustments based on clinical and laboratory findings

Durable TI responses, in a high proportion of del 5q patients, with readily managed AEs