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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 in...
R1507 shows anti-tumor activity
in the clinic- Phase I
Patient 7002:
•27yo male
•Ewing’s sarcoma of chest
wall with lung m...
 Determine the ORR to R1507 in pts with
recurrent or refractory Ewing sarcoma
(secondary cohort) osteosarcoma, synovial
s...
SARC 011
Secondary Objectives
 Determine duration of response, PFS at 18
wks and overall PFS for pts with recurrent
or re...
 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 s...
SARC011/NO21157
Statistical Considerations
 Ewing’s Primary cohort
 Relapse ≤ 24 months AND at least 2 previous
chemo re...
SARC011/NO21157
Statistical Considerations
 Osteosarcoma, Rhabdomyosarcoma,
Synovial Sarcoma
 35 patients
 Two stage de...
WHO Criteria
Bi-dimensional measurements
 Complete response (CR)
 Disappearance of all known disease
 Partial response ...
Interim Analysis
 Open to Recruitment:
 Ewing’s 1
 Ewing’s 2
 Rhabdomyosarcoma
 Other Sarcomas
 Closed
 Osteosarcom...
SARC011/NO21157
Patient Enrollment
 28 centers are activated and open to enroll
patients
 n = 189 (177 eligible)
 Age:
...
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
numbero...
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 ...
Patient Enrollment by week
Accrual/Week
3
1 2
5
3
6
4 5 4
6 7
5
9
7 6
3 4 3 3 2 3 4
1
6
4
6
2
5
8
10 9
3 4 5 4
1 1
6
3 4
1...
Patient Enrollment by month
SARC011 Accrual by month
4
20 21
28
14 15 18
33
11
16
9
0
10
20
30
40
1 2 3 4 5 6 7 8 9 10 11
...
Ewing’s – Only 15% of Enrolled
Patients < 18
0
1
2
3
4
5
NumberofPatients
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80...
SARC011/NO21157
Protocol Violations
 Patients must have measurable disease
 Index lesions must not be in prior site of
r...
Where do we need your help?
Ensuring patients are eligible
Enrolling pediatric patients
Enrolling Ewing’s 1 patients
E...
SARC011/NO21157
Enrollment by Cohort
Cohorts enrolled
patients (n=189)
No of patients per cohort
Ewing’s 1 35
Ewing’s 2 33...
SARC011/NO21157
Enrollment by Others Cohort
Cohorts enrolled
patients (n=189)
No of patients per cohort
Other Sarcomas 21
...
SARC011/NO21157
Histologic Diagnosis (n=189)
SS
OGS
EWS-1
EWS-2
MLS
EMC
DSRCT
CCS
ASPS
RMS
EMC: extraskeletal myxoid chond...
SARC011/NO21157 SAEs
SAE’s (n=51) No of events*
Pain 8
Infection 7
Thrombocytopenia* 4
Shortness of Breath, Hypoxemia 2
An...
SARC011/NO21157 SAEs
SAE’s (n=51) continued No of events*
Hyperglycemia 1
Acute Renal Failure 1
L Spontaneous Pneumothorax...
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 p...
28
The outcome for patients with recurrent sarcomas
is uniformly poor
1
Ewing Sarcoma
Jürgens
ASCO 2007
Asbtract 10012
SAR...
292
Osteosarcoma
n=575
Median age at Diagnosis
15.5 y [2.2 -68.2y]
Kempf-Bielack et al.
JCO, 23, 559, 2005
SARC011/NO21157...
30
SARC 011
Background
 R 1507 is a IGF-1 MoAb of the IgG1 subclass that
binds the extracellular domain of IGF-1R and
inhibi...
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SARC 011 - Connective Tissue Oncology Society

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SARC 011 - Connective Tissue Oncology Society

  1. 1. SARC011/NO21157 Alberto Pappo, M.D. Texas Children’s Cancer Center Houston, TX
  2. 2. 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
  3. 3. 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 25 Dec 29, 2006 Baseline June 19, 2006 Pt. 7002 Restaging Week 6 Jan 25, 2007 Baseline Dec 8, 2006 Pt. 8012
  4. 4.  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
  5. 5. SARC 011 Secondary 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
  6. 6.  PET scan changes  Serum Biomarkers SARC011/NO21157 Exploratory Objectives
  7. 7. 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
  8. 8. 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
  9. 9. SARC011/NO21157 Statistical 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
  10. 10. 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
  11. 11. Interim Analysis  Open to Recruitment:  Ewing’s 1  Ewing’s 2  Rhabdomyosarcoma  Other Sarcomas  Closed  Osteosarcoma  Undergoing interim analysis Synovial Sarcoma
  12. 12. SARC011/NO21157 Patient 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
  13. 13. 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 numberofpatients Patient Enrollment-All Cohorts 189 enrolled 177 patients are eligible- data from Nov 1st , 2008
  14. 14. 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 numberofpatients Patient Enrollment-Ewing’s 68 eligible Ewing’s patients- data from Nov 1st , 2008
  15. 15. Patient Enrollment by week Accrual/Week 3 1 2 5 3 6 4 5 4 6 7 5 9 7 6 3 4 3 3 2 3 4 1 6 4 6 2 5 8 10 9 3 4 5 4 1 1 6 3 4 1 3 2 4 1 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 3 2 2 2 0 1 0 2 1 1 1 1 0 1 2 1 0 2 2 3 1 2 3 3 4 1 4 2 2 1 1 3 2 2 1 2 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
  16. 16. Patient Enrollment by month SARC011 Accrual by month 4 20 21 28 14 15 18 33 11 16 9 0 10 20 30 40 1 2 3 4 5 6 7 8 9 10 11 month patients SARC011 Cumulative Accrual by Month 4 24 45 73 87 102 120 153 164 180 189 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 Month
  17. 17. Ewing’s – Only 15% of Enrolled Patients < 18 0 1 2 3 4 5 NumberofPatients 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 Older 85% Pts under 18 Pts 18 and Older data from Nov 1st , 2008
  18. 18. 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
  19. 19. Where do we need your help? Ensuring patients are eligible Enrolling pediatric patients Enrolling Ewing’s 1 patients Enrolling patients to the CBP Sending samples for central path review Sending pre study, baseline and efficacy scans to Bioimaging Entering data answering queries
  20. 20. SARC011/NO21157 Enrollment 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
  21. 21. SARC011/NO21157 Enrollment 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 2Clear Cell Sarcoma Nov 1, 2008
  22. 22. SARC011/NO21157 Histologic 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 sarcoma ASPS: alveolar soft part sarcoma RMS: rhabdomyosarcoma SS: synovial sarcoma OGS: osteosarcoma EWS-1: Ewing’s sarcoma primary EWS-2: Ewing’s sarcoma secondary MLS: myxoid liposarcoma Nov 1, 2008
  23. 23. SARC011/NO21157 SAEs SAE’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
  24. 24. SARC011/NO21157 SAEs SAE’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
  25. 25. Thank you
  26. 26. Background slides
  27. 27. 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. 28. 28 The outcome for patients with recurrent sarcomas is uniformly poor 1 Ewing Sarcoma Jürgens ASCO 2007 Asbtract 10012 SARC011/NO21157 Background
  29. 29. 292 Osteosarcoma n=575 Median age at Diagnosis 15.5 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. 30. 30
  31. 31. SARC 011 Background  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

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