Phase II study of pazopanib in patients with relapsed or refractory
soft tissue sarcoma
EORTC study 62043
S. Sleijfer, I. Ray-Coquard, Z. Papai, A. LeCesne,
M. Scurr, P. Schöffski, F. Collin, L. Pandite,
S. Marreaud, A. deBrauwer, J.Y.Blay
on behalf of the EORTC Soft Tissue Bone Sarcoma Group
This study was financially supported by GlaxoSmithKline
Introduction
Patients with advanced soft tissue sarcoma (STS) have poor prognosis
No standard second-line therapy
VEGF-driven angiogenesis likely involved in pathogenesis of several STS
subtypes:
• VEGF overexpression in many primary subtypes (Potti et al, 2004)
• VEGF overexpression correlates with survival (Yudoh et al, 2001)
• VEGF serum levels correlate with grade (Hayes et al, 2003)
Introduction
Pazopanib (GW786034) (TKI) targets:
• VEGF-receptors 1-3
• c-kit
• PDGFR α and β
Objective
To screen whether pazopanib exhibits anti-tumor activity warranting
further exploration in soft tissue sarcomas,
and if so, in which subtypes.
Study design & regimen
• Phase II: multi-center, open-label, non-randomized study
• Therapeutic regimen:
• Oral pazopanib at 800 mg once daily
• until disease progression or unacceptable toxicity
• Four different tumor strata (heterogeneity STS subtypes (a.o. in pathogenesis
and drug sensitivity)):
• adipocytic STS
• synovial STS
• leiomyosarcoma
• other eligible STS subtypes
Main eligibility criteria
• High or intermediate grade of STS
• Relapsed or refractory disease incurable by surgery or radiotherapy
• Progression (RECIST) within the previous 6 months
• No prior chemotherapy for advanced disease, or no more than 1 combination
therapy or 2 single agents
• Performance status 0–1 and age ≥ 18 years
• Adequate bone marrow, hepatic, and renal function
• Adequately controlled blood pressure (baseline < 150/90 mmHg)
End points
Primary end point
• Progression-free survival rate (PFR) at 12 weeks after start
• A good endpoint for screening non-cytotoxic drugs
Secondary end points
• Progression-free survival, response (RECIST), toxicity (CTCAE vs 3.0)
and overall survival
Statistical design
Statistical design:
• Simon Optimal two-stages design separately applied to each stratum
(P1: 40%; P0: 20%; α=β=0.1)
• EORTC database (Van Glabbeke EJC 2002):
• active second-line drug PFR at 12 wks: 40%
• inactive second-line drug PFR at 12 wks: 20%
Each cohort:
• Step 1: 17 pts
• if > 3 successes: step 2
• Step 2: 37 pts
• if > 11 successes: warrants further investigation
Baseline characteristics
142 patients
Median age: 51 yrs (range: 18-79 yrs)
Males = 72 (50%); females = 72 (50%)
PF 0 = 72 (51%); PF 1 = 70 (49%)
Prior chemotherapy = 140 (98.6%)
(Neo)-adjuvant = 35 (24.6%)
Advanced setting = 84 (59.2%)
Both = 21 (14.8%)
Hematological / biological adverse events
0 10 20 30 40 50 60 70
WBC
ANC
PLA
HGB
Creatinine
Bilirubin
ASAT
ALATGrade 4
Grade 3
Grade 2
Grade 1
Other adverse events (treatment related)
0 10 20 30 40 50
Hypertension
Fatigue
Hypopigmentation
Anorexia
Diarrhea
Nausea
Vomiting
Thrombo-embolism
Hemorrhage
Grade 4
Grade 3
Grade 2
Grade 1
Cumulative incidence
(months)
0 2 4 6 8 10 12
0
10
20
30
40
50
60
70
80
90
100
Grade 1 Grade 2 Grade 3
HypertensionCumulative incidence
Cumulative incidence
(months)
0 2 4 6 8 10 12
0
10
20
30
40
50
60
70
80
90
100
Grade 1 Grade 2 Grade 3
FatigueCumulative incidence
Cumulative incidence
(months)
0 2 4 6 8 10 12
0
10
20
30
40
50
60
70
80
90
100
Grade 1 Grade 2 Grade 3
DiarrheaCumulative incidence
Progression-free rate at week 12
Leiomyosarcoma
Adipocyticsarcoma
Synovialsarcoma
Other typessarcoma
Step 1
Step 2
Step 1
NoStep
2
Step 1
Step 2
Step 1
Step 2
Partialresponse
1 1 2 1
Stable disease
5 7 3 7 9 9 9
Progressivedisease
13 11 16 7 11 16 8
No info yet 1
Not assessabl
e1 1 1 2
Total 19 21 19 16 24 26 17
Progression
-free rate
13/40(32.5%)
3/19(15.8%)
19/40(47.5%)
19/43(44.2%)
Leiomyosarcoma (pt 101), PR according to RECIST
Base-line(25-08-2006)
3 months pazopanibSlide cut showing the largest tumor
lesion at that time point (11-12-2006)
Tumor responses
Hemangiopericythoma, SD according to RECISTCystic alterations
Base-line (09-08-2006)6 months pazopanib
(26-02-2007)
Tumor responses
Time to progression
(months)
0 2 4 6 8 10 12
0
10
20
30
40
50
60
70
80
90
100
Adipocytic Leiomyos. Synovial Other STS
Inactive (hist) Active (hist)
Time to progressionEORTC study 62043 vs historical control
Overall survival
(months)
0 2 4 6 8 10 12
0
10
20
30
40
50
60
70
80
90
100
Adipocytic Leiomyos. Synovial Other STS
Inactive (hist) Active (hist)
Overall survivalEORTC study 62043 vs historical control
Conclusions
Pazopanib is well tolerated
Infrequently grade 3/4 toxicity:
hypertension (7.8%, no grade 4)
fatigue (11.3%, 0.7% grade 4)
diarrhea (5%, no grade 4)
pain (7.7%, 0.7% grade 4)
Other relevant toxicities: mild myelosuppression, mild liver toxicity,
hypopigmentation, nausea, and vomiting
Occurrence of diarrhea seems related to cumulative dose
Occurrence of fatigue and hypertension seems independent of
cumulative dose
Conclusions
Pazopanib warrants further investigation Pazopanib warrants further investigation
in soft tissue sarcomasin soft tissue sarcomas
(but not in adipocytic sarcomas)
Baseline characteristics (2)
Tumor types in “other” stratum Nb pts
fibrosarcoma 6 (14%)
MFH 7 (16.3%)
rhabdomyosarcoma 2 (4.7%)
vascular tumours 7 (16.3%)
tumours of uncertain differentation 7 (16.3%)
MPNST 4 (9.3%)
malignant solitary fibrous tumour 2 (4.7%)
undifferentiated sarcoma NOS 8 (18.6%)
Total 43
Age
Minimum 18.5024
Maximum 79.2964
Median 51.4059
Baseline characteristics (1)
Leiomyo sarcoma
Adipocytic sarcoma
Synovial sarcoma
Other types sarcoma
Total
Male 8 (20%) 12 (63.2%) 24 (60%) 27 (62.8%) 71 (50%)
Female 32 (80%) 7 (36.8%) 16 (40%) 16 (37.2%) 71 (50%)
PS 0 22 (55%) 4 (21.1%) 24 (60%) 22 (51.2%) 72 (50.7%)
PS 1 18 (45%) 15 (78.9%) 16 (40%) 21 (48.8%) 70 (49.3%)
Prior chemo
no 1 (2.5%) 1 (5.3%) 2 (1.4%)
yes, (neo) adjuvant
8 (20%) 3 (15.8%) 14 (35%) 10 (23.3%) 35 (24.6%)
yes, for adv. disease
28 (70%) 13 (68.4%) 15 (37.5%) 28 (65.1%) 84 (59.2%)
yes, both 3 (7.5%) 2 (10.5%) 11 (27.5%) 5 (11.6%) 21 (14.8%)
Serious Adverse Events
* The numbers may not add up to the total as a case may contain different events
Total SAE cases 38
SAE cases containing unrelated events* 20
SAE cases containing related events* 20
Death 4
Life threatening 1
Hospitalization/prolongation of 15
Persistent or significant disability/incapacity -
Other medically important condition 3
Adverse Events (3)
Grade 2 Grade 3 Grade 4 Total
Hypertension 35 (24.82%) 11 (7.80%) 141
Fatigue 11 (7.80%) 6 (4.26%) 141
Hypopigmentation 5 (3.57%) 140
Anorexia 7 (5%) 140
Diarrhea 14 (10%) 4 (2.86%) 140
Nausea 8 (5.71%) 1 (.71%) 140
Vomiting 13 (9.29%) 140
Headache 2 (1.43%) 1 (.71%) 140
Thrombosis/Embolism 1 (.72%) 2 (1.45%) 1 (.72%) 138
Non hematological events grade ≥ 2 (likely related + relationship to drug not assessable)
Leiomyosarcoma (pt 101), PR according to RECIST
3 months pazopanibShowing the tumor lesion at the initial cut(11-12-2006)
Base-line(25-08-2006)
Hemangiopericythoma, SD according to RECISTCystic alterations
Base-line (09-08-2006)
6 months pazopanib (26-02-2007)
Adverse Events (1)
Hematological events
Biochemical events
Grade 1 Grade 2 Grade 3 Grade 4
WBC 34 (23.9%) 19 (13.4%) 1 (.7%)
ANC 20 (14.1%) 14 (9.9%) 4 (2.8%)
Platelets 9 (6.3%) 2 (1.4%) 2 (1.4%)
Hemoglobin
68 (47.9%) 30 (21.1%) 4 (2.8%) 1 (.7%)
Grade 1 Grade 2 Grade 3 Grade 4
Creatinine 23 (16.2%) 4 (2.8%) 2 (1.4%)
Bilirubin 27 (19%) 13 (9.2%) 6 (4.2%) 1 (.7%)
ASAT 47 (33.1%) 9 (6.3%) 5 (3.5%)
ALAT 53 (37.3%) 11 (7.7%) 4 (2.8%)
Adverse Events (2)
Non hematological events (unrelated, likely related and relationship to drug not assessable)
Grade 1 Grade 2 Grade 3 Grade 4
Hypertension 14 (9.9%) 37 (26.2%) 11 (7.8%)
Fatigue 47 (33.3%) 30 (21.3%) 15 (10.6%) 1 (.7%)
Diarrhea 28 (19.9%) 19 (13.5%) 7 (5%)
Nausea 42 (29.8%) 11 (7.8%) 2 (1.4%)
Vomiting 26 (18.4%) 15 (10.6%) 2 (1.4%)
Pain 69 (48.9%) 28 (19.8%) 10 (7%) 1 (.7%)
(months)
0 2 4 6 8 10 12
0
10
20
30
40
50
60
70
80
90
100
Grade 1 Grade 2
HypopigmentationCumulative incidence
Conclusions
Pazopanib warrants further investigation in:
• leiomyosarcoma
• synovial sarcoma
• “other eligible sarcoma subtypes”
• but not in the adipocytic sarcomas