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