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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. 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

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  1. 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

  2. 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)

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

  4. Objective To screen whether pazopanib exhibits anti-tumor activity warranting further exploration in soft tissue sarcomas, and if so, in which subtypes.

  5. 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

  6. 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)

  7. 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

  8. 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

  9. 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%)

  10. Hematological / biological adverse events

  11. Other adverse events (treatment related)

  12. Cumulative incidence

  13. Cumulative incidence

  14. Cumulative incidence

  15. Progression-free rate at week 12

  16. 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)

  17. Tumor responses Hemangiopericythoma, SD according to RECIST Cystic alterations 6 months pazopanib (26-02-2007) Base-line (09-08-2006)

  18. Time to progression

  19. Overall survival

  20. 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

  21. Conclusions Pazopanib warrants further investigation in soft tissue sarcomas (but not in adipocytic sarcomas)

  22. Baseline characteristics (2)

  23. Baseline characteristics (1)

  24. Serious Adverse Events * The numbers may not add up to the total as a case may contain different events

  25. Adverse Events (3) Non hematological events grade ≥ 2 (likely related + relationship to drug not assessable)

  26. 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)

  27. Hemangiopericythoma, SD according to RECIST Cystic alterations Base-line (09-08-2006) 6 months pazopanib (26-02-2007)

  28. Adverse Events (1) Hematological events Biochemical events

  29. Adverse Events (2) Non hematological events (unrelated, likely related and relationship to drug not assessable)

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

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