SARC011/NO21157SARC011/NO21157

Alberto Pappo, M.D.

Texas Children’s Cancer Center

Houston, TX

22

SARC011/NO21157

SARC Global Collaboration: A Phase II trial of R1507, a recombinant human monoclonal antibody to the insulin-like growth factor-1 receptor for the treatment of patients with recurrent or refractory Ewing’s sarcoma, osteosarcoma, synovial sarcoma, rhabdomyosarcoma and other sarcomas

R1507 shows anti-tumor activity in the clinic- Phase I

Patient 7002: •27yo male •Ewing’s sarcoma of chest wall with lung metastasis (1997)•SD → Partial Response after 25 weeks of R1507 at 1 mg/kg/week.

Patient 8012: •28yo female •Ewing’s sarcoma of sacrum with lung metastasis (2003)•PR after 6 weeks of R1507 at 9 mg/kg/week

Restaging Week 25Dec 29, 2006

BaselineJune 19, 2006

Pt. 7002

Restaging Week 6Jan 25, 2007

BaselineDec 8, 2006

Pt. 8012

Determine the ORR to R1507 in pts with recurrent or refractory Ewing sarcoma (secondary cohort) osteosarcoma, synovial sarcoma, rhabdomyosarcoma, and other sarcomas: ASPS, CCS, EMS, DSRCT, MLS

Determine PFS at 18 wks for patients treated with R1507 with progressive, recurrent or refractory ESFT (primary cohort)

SARC011/NO21157 Primary Objectives

SARC 011Secondary Objectives

Determine duration of response, PFS at 18 wks and overall PFS for pts with recurrent or refractory osteosarcoma, synovial sarcoma, rhabdomyosarcoma, and other sarcomas-ASPS, CCS, EMS,DSRCT, MLS.

Determine ORR, response duration, overall PFS in patients with Ewing sarcoma

PK,Tolerability and AE profile of R 1507

PET scan changes Serum Biomarkers

SARC011/NO21157 Exploratory Objectives

Protocol Amendment v3 8-1-08

Reduced the age from ≥ 12 to ≥ 2 years Expanded “others” cohort to 10 patients

for each subtype, then if 1PR an additional 10 patients Alveolar Soft Part Sarcoma Clear Cell Sarcoma Extraskeletal Myxoid Chondrosarcoma Desmoplastic Round Cell Tumor Myxoid Liposarcoma

SARC011/NO21157 Statistical Considerations

Ewing’s Primary cohort Relapse ≤ 24 months AND at least 2 previous

chemo regimen, surgically unresectable 65 patients Two stage design

Ewing’s Secondary cohort (all other Ewing’s patients) Relapse > 24 months (or ≤ 24 months 1 chemo

regimen) 35 patients Two stage design

SARC011/NO21157Statistical Considerations

Osteosarcoma, Rhabdomyosarcoma, Synovial Sarcoma 35 patients Two stage design

Other Sarcomas 20 patients for each of 5 other subtypes Two stage design within each of the 5 subtypes

WHO Criteria

Bi-dimensional measurements Complete response (CR)

Disappearance of all known disease Partial response (PR)

≥ 50% decrease Stable disease (SD)

No 50% decrease & no 25% increase Progressive disease (PD)

≥ 25% increase

Interim Analysis

Open to Recruitment: Ewing’s 1 Ewing’s 2 Rhabdomyosarcoma Other Sarcomas

Closed Osteosarcoma

Undergoing interim analysisSynovial Sarcoma

SARC011/NO21157Patient Enrollment

28 centers are activated and open to enroll patients

n = 189 (177 eligible) Age:

12-86 yrs Gender: (n=190*)

118 Male 72 Female

*includes patient in screening data from Nov 1st, 2008

Cumulative Accrual/ Week

189

0

50

100

150

200

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45

week

nu

mb

er

of

pa

tie

nts

Patient Enrollment-All Cohorts

189 enrolled 177 patients are eligible- data from Nov 1st, 2008

Cumulative Accrual/ Week

68

0

10

20

30

40

50

60

70

80

90

100

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45

week

nu

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Patient Enrollment-Ewing’s

68 eligible Ewing’s patients- data from Nov 1st, 2008

Patient Enrollment by week

Accrual/Week

31 2

53

64 5 4

6 75

97 6

3 4 3 3 2 3 41

64

62

58

10 9

3 4 5 41 1

63 4

13 2

41 1

0

5

10

15

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45

Accrual/Week

0 0 0

2

0 0

32 2 2

01

0

21 1 1 1

01

21

0

2 23

12

3 34

1

4

2 21 1

32 2

12 2

1 1 1

0

2

4

6

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45

All Patients

Ewing’s Patients

Patient Enrollment by month

SARC011 Accrual by month

4

20 2128

14 15 18

33

1116

9

0

10

20

30

40

1 2 3 4 5 6 7 8 9 10 11

month

pat

ien

ts

SARC011 Cumulative Accrual by Month

424

4573 87 102

120153 164 180 189

0

50

100

150

200

250

300

Dec-07

Jan-08

Feb-08

Mar-08

Apr-08

May-08

Jun-08

Jul-08

Aug-08

Sep-08

Oct-08

Number of Patients

Mo

nth

Ewing’s – Only 15% of Enrolled Patients < 18

0

1

2

3

4

5

Num

ber o

f Pati

ents

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80

Age (Years)

Ewing's Patient's Age at Study Entry

Pts under 18

15%

Pts 18 and Older85%

Pts under 18

Pts 18 andOlder

data from Nov 1st, 2008

SARC011/NO21157 Protocol Violations

Patients must have measurable disease Index lesions must not be in prior site of

radiation Index lesions must be ≥ 10mm by spiral CT or

≥ 20mm by conventional techniques Central pathology confirmation required

within 6 weeks Dose of R1507 must not be adjusted unless

there is a 10% change in weight

Where do we need your help?

Ensuring patients are eligibleEnrolling pediatric patientsEnrolling Ewing’s 1 patientsEnrolling patients to the CBPSending samples for central path reviewSending pre study, baseline and efficacy scans to BioimagingEntering data answering queries

SARC011/NO21157Enrollment by Cohort

Cohorts enrolled patients (n=189)

No of patients per cohort

Ewing’s 1 35

Ewing’s 2 33

Osteosarcoma 41

Synovial Sarcoma 19

Rhabdomyosarcoma 28

Other Sarcomas 21

Nov 1, 2008

SARC011/NO21157Enrollment by Others Cohort

Cohorts enrolled patients (n=189)

No of patients per cohort

Other Sarcomas 21

Desmoplastic round cell tumor

8

Extraskeletal Myxoid chondrosarcoma

4

Myxoid liposarcoma 4

Alveolar Soft Part Sacroma

3

2 Clear Cell Sarcoma

Nov 1, 2008

SARC011/NO21157Histologic Diagnosis (n=189)

SS

OGS

EWS-1

EWS-2

MLS

EMC

DSRCT

CCS

ASPS

RMS

EMC: extraskeletal myxoid chondrosarcoma DSRCT: desmoplastic small round cell tumor CCS: clear cell sarcomaASPS: alveolar soft part sarcoma RMS: rhabdomyosarcoma

SS: synovial sarcomaOGS: osteosarcoma EWS-1: Ewing’s sarcoma primaryEWS-2: Ewing’s sarcoma secondaryMLS: myxoid liposarcoma

Nov 1, 2008

SARC011/NO21157 SAEsSAE’s (n=51) No of events*

Pain 8

Infection 7 Thrombocytopenia* 4

Shortness of Breath, Hypoxemia 2

Anemia 2

Adrenal Hemorrhage* 1

Pulmonary Embolism* 1

Dehydration 1

DVT 1

Pleural effusion 1

Acute respiratory failure 1

Inflammation of L knee and stump 1

Laryngeal Obstruction 1

Nausea and Vomiting 1

Nausea and Diarrhea 1

Acute Febrile Illness 1*1 event of Thrombocytopenia, Adrenal Hemorrhage and Pulmonary embolism attributed to drug

Nov 1, 2008

SARC011/NO21157 SAEsSAE’s (n=51) continued No of events*

Hyperglycemia 1

Acute Renal Failure 1

L Spontaneous Pneumothorax 1

L Frontal Hematoma 1

Fatigue 1

Hypercalcemia 1

Pyelonephritis 1

Pneumonia 1

Urinary Urgency 1

GU Hemorrhage 1

Postural Hypotension 1

Stomach Outlet Obstruction 1

Spinal Cord compression 1

Fluid collection around L Femoral Prosthesis 1

Increasing Dyspnea 1

Respiratory Distress 1

Bleeding of the metastases of the pleura 1

Nov 1, 2008

Thank you

Background slides

27

SARC011/NO21157 Background

n=605

Pappo et al.JCO, 17, 3487, 1999

Rhabdomyosarcoma

Med age 8y [0-20y]

The outcome for patients with recurrent sarcomas is uniformly poor

28

The outcome for patients with recurrent sarcomas is uniformly poor

1

Ewing Sarcoma

Jürgens

ASCO 2007Asbtract 10012

SARC011/NO21157 Background

292

Osteosarcoma

n=575

Median age at Diagnosis15.5 y [2.2 -68.2y]

Kempf-Bielack et al.JCO, 23, 559, 2005

SARC011/NO21157 Background

The outcome for patients with recurrent sarcomas is uniformly poor

30

SARC 011Background

R 1507 is a IGF-1 MoAb of the IgG1 subclass that binds the extracellular domain of IGF-1R and inhibits receptor activation

Main adverse events in about 40% of patients included GI, and fatigue but NO DLT

4/59 HAHA (3 preexisting) 9 mg/kg weekly. Half life 7 days Responses:

2/7 PR EWS 5/19 SD