Clinical Trial: Phase II Pazopanib Study in Advanced Dermatofibrosarcomas

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: A Phase IIa Open Multicenter, Trial, of Treatment With Pazopanib (Multi Tyrosine Kinase Inhibitor) in Dermatofibrosarcomas (DFSP), Unresectable Locally Advanced (Potential

Brief Summary: In relation to the activation of PDGF-mediated signalization due to the fusion gene COL1A1-PDGFb in DFSP, imatinib (800mg/day) has shown activity in advanced DFSP and has became the reference treatment option for these patients. Yet the activity observed does not allow for a downstaging compatible with successful resection in a number of patients and does not prevent subsequent tumour progression in case of residual tumour.Pazopanib in relation to 1) its multi tyrosine kinase inhibiting activity (VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-β and c-kit with IC50 values of 10, 30, 47, 71, 84, and 74 nM, respectively) involving in particular PDGFR, and VEGFR which has been shown to be activated in DFSP, 2) its antitumour activity in sarcomas patients, and 3) its acceptable safety profile, is a logical candidate for therapeutic trials in DFSP both in patients not expected to derive a sufficient benefit from imatinib and in patients failing imatinib mesylate. Moreover, using quantitative RT-PCR and immunohistochemistry we have recently demonstrated high levels of VEGF and VEGFR2 expression in dermatofibrosarcoma.

Detailed Summary:

Dermatofibrosarcoma protuberance (DFSP) is a rare soft tissue sarcoma of intermediate malignant potential. Treatment relies on a wide local excision with negative margin and with frequent need of reconstructive surgery. A translocation between chromosomes 17 and 22 that places the platelet-derived growth factor-B (PDGFB) under the control of the collagen 1A1 promoter is present in > 90 % of the cases leading to an up regulation of PDGF-β expression and activation of the tyrosinase kinase PDGFRβ. Imatinib mesylate has been approved in unresectable and metastatic DFSP due to its activity on PDGFR. This study will evaluate the benefit of pazopanib, a multikinase inhibitor in advanced DFSP. Administration of pazopanib per os 800mg/ qd during 6 months until stable response according to primary endpoint , and for a period of study not exceeding one year.In case of progression evaluated according to the primary endpoint after a period of treatment superior to one month, or in the absence of response at 3 months, the patient will be withdrawn from study, in order to get alternative therapeutics. These patients will be considered as failures for analysis. After a 6-month treatment period, and reaching a stable response, treatment continuation decision will be based on the operability of patients.

Administration of pazopanib per os 800mg/ qd during 6 months until stable response according to primary endpoint, with 3 monthly successive examinations, and for a period of study not exceeding 18 months.In case of progression evaluated according to the primary endpoint after a period of treatment superior to one month, or in the absence of response at 3 months, the patient will be withdrawn from study, in order to get alternative therapeutics. These patients will be considered as failures for analysis. After a 6-month treatment period, and reaching a stable response, treatme
Sponsor: Assistance Publique - Hôpitaux de Paris

Current Primary Outcome: Decrease of at least 30% of the biggest diameter measured clinically at 6 months preceded by clinical response [ Time Frame: at 3 months ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • For measure of tumour volume : Measure of radiologic response (" MULTIBARETTE " MDCT scanner) using RECIST criteria and OMS (WHO) [ Time Frame: at 3 months ]
  • For measure of tumour volume : Measure of the volume of the tumour (" MULTIBARETTE " MDCT scanner) in each centre [ Time Frame: at 3 months ]
  • For measure of tumour volume : Research of translocation COL1A1-PDGFB by FISH (paraffin) and caryotype on fresh tissue (centralisation in F PEDEUTOUR laboratory, Nice) [ Time Frame: at 3 months ]
  • Prognostic factors of tumoral response : Semi-quantitative measure of apoptosis on surgical piece and of senescence [ Time Frame: at inclusion, M1, M3 and M6 ]
  • Expression of the phosphorylated form of the receptors of PDGFB and VEGF and of the MAPK. [ Time Frame: at inclusion, M1, M3 and M6 ]
  • Prognostic factors of tumoral response :Clinical and biologic safety Common Terminology Criteria forAdverse Events v3.0 (CTCAE) [ Time Frame: at every visit except M0 ]
  • Prognostic factors of tumoral response :Evaluation of QOL, EORTC QLQ-C30 [ Time Frame: M0, M3, M6, M9, M12, M15 and M18 ]


Original Secondary Outcome: Same as current

Information By: Assistance Publique - Hôpitaux de Paris

Dates:
Date Received: January 28, 2010
Date Started: July 2010
Date Completion:
Last Updated: June 30, 2016
Last Verified: June 2016