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SARC011/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
mb
er
of
pa
tie
nts
Patient Enrollment-Ewing’s
68 eligible Ewing’s patients- data from Nov 1st, 2008
Patient Enrollment by week
Accrual/Week
31 2
5364 5 4
6 75
97 6
3 4 3 3 2 3 41
646
25810 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
010
21 1 1 1
01210
2 23
123 3
4
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
of P
atie
nts
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