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Phase II study of pazopanib in patients with relapsed or refractory soft tissue sarcoma. S. Sleijfer, I. Ray-Coquard, Z. Papai, A. LeCesne, M. Scurr, P. Sch ö ffski, F. Collin, L. Pandite, S. Marreaud, A. deBrauwer, J.Y.Blay on behalf of the EORTC Soft Tissue Bone Sarcoma Group

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phase ii study of pazopanib in patients with relapsed or refractory soft tissue sarcoma

Phase II study of pazopanib in patients with relapsed or refractory soft tissue sarcoma

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

EORTC study 62043

introduction
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)
introduction1
Introduction
  • Pazopanib (GW786034) (TKI) targets:
    • VEGF-receptors 1-3
    • c-kit
    • PDGFR α and β
objective
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
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
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
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

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
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%)
slide16

Tumor responses

Leiomyosarcoma (pt 101), PR according to RECIST

Base-line

(25-08-2006)

3 months pazopanib

Slide cut showing the largest tumor

lesion at that time point

(11-12-2006)

slide17

Tumor responses

Hemangiopericythoma, SD according to RECIST

Cystic alterations

6 months pazopanib

(26-02-2007)

Base-line (09-08-2006)

conclusions
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
conclusions1
Conclusions

Pazopanib warrants further investigation in soft tissue sarcomas

(but not in adipocytic sarcomas)

serious adverse events
Serious Adverse Events

* The numbers may not add up to the total as a case may contain different events

adverse events 3
Adverse Events (3)

Non hematological events grade ≥ 2

(likely related + relationship to drug not assessable)

slide27

Leiomyosarcoma (pt 101), PR according to RECIST

3 months pazopanib

Showing the tumor lesion

at the initial cut

(11-12-2006)

Base-line

(25-08-2006)

slide28

Hemangiopericythoma, SD according to RECIST

Cystic alterations

Base-line (09-08-2006)

6 months pazopanib

(26-02-2007)

adverse events 1
Adverse Events (1)

Hematological events

Biochemical events

adverse events 2
Adverse Events (2)

Non hematological events

(unrelated, likely related and relationship to drug not assessable)

conclusions2
Conclusions
  • Pazopanib warrants further investigation in:
  • leiomyosarcoma
  • synovial sarcoma
  • “other eligible sarcoma subtypes”
  • but not in the adipocytic sarcomas