Direct Impact

Concepts for which they have direct influence:

desmoid tumors
aggressive fibromatosis
inhibitor pf-03084014
notch response
phase trial
performed baseline
tumor biopsies

Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors/Aggressive Fibromatosis. Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tu

Abstract

Background:Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive, slow-growing soft-tissue tumors. The disease can be either asymptomatic or be associated with severe loss of organ function and significant morbidity.Treatment with the selective small-molecule Gamma-secretase inhibitor PF-03084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early phase clinical trial.The Notch pathway is a key regulator of cell differentiation, proliferation and apoptosis; aberrant signaling via the Notch pathway is associated with carcinogenesis.Objectives:Primary: Determine the response rate (Complete Response (CR)+Partial Response (PR)) of PF-03084014 in patients with desmoid tumors/aggressive fibromatosisSecondary: Assess symptom measures at baseline and on study; perform genotyping for germline and somatic mutations in adenomatous polyposis coli gene (APC) and catenin-beta 1 (CTNNB1) genes; correlate clinical response to therapy with genotyping data; and assess modulation of the Notch pathway by evaluating notch response genes in tumor biopsies at baseline and after drug administrationEligibility:Age greater than or equal to18; histologically confirmed desmoid tumor not amenable to curative resection or definitive radiation therapy that has progressed after receiving at least one line of standard treatment; adequate organ functionWillingness to provide blood samples and 10 unstained slides or a tumor block for genetic research studiesStudy Design:This is an open-label Phase II trial of PF-03084014; study drug will be administered orally at 150 mg twice a day in 21-day cyclesOptional tumor biopsies for research purposes will be performed at baseline prior to study treatment and at the beginning of cycle 7 (+/- one cycle)Restaging scans (magnetic resonance imaging (MRI) with diffusion weighting) will be performed at baseline, at the end of cycles 1 and 6, and then every 6 cyclesHealth-related quality of life (HRQOL)/symptom questionnaires will be administered at baseline and at each Clinical Center visit Detailed Description Background:Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive, slow-growing soft-tissue tumors. The disease can be either asymptomatic or be associated with severe loss of organ function and significant morbidity.Treatment with the selective small-molecule Gamma-secretase inhibitor PF-03084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early phase clinical trial.The Notch pathway is a key regulator of cell differentiation, proliferation and apoptosis; aberrant signaling via the Notch pathway is associated with carcinogenesis.Objectives:Primary: Determine the response rate (Complete Response (CR)+Partial Response (PR)) of PF-03084014 in patients with desmoid tumors/aggressive fibromatosisExploratory: Assess symptom measures at baseline and on study; perform genotyping for germline and somatic mutations in adenomatous polyposis coli gene (APC) and catenin-beta 1 (CTNNB1) genes; correlate clinical response to therapy with genotyping data; and assess modulation of the Notch pathway by evaluating notch response genes in tumor biopsies at baseline and after drug administrationEligibility:Age greater than or equal to18; histologically confirmed desmoid tumor not amenable to curative resection or definitive radiation therapy that has progressed after receiving at least one line of standard treatment; adequate organ functionWillingness to provide blood samples and 10 unstained slides or a tumor block for genetic research studiesStudy Design:This is an open-label Phase II trial of PF-03084014; study drug will be administered orally at 150 mg twice a day in 21-day cyclesOptional tumor biopsies for research purposes will be performed at baseline prior to study treatment and at the beginning of cycle 7 (+/- one cycle)Restaging scans (computed tomography (CT) scan of the known site of disease) will be performed at baseline and then every 6 cycles (+/- one cycle)Optional magnetic resonance imaging (MRI) scans may be performed prior to start of study treatment, end of cycle 1, and every 6 cycles (at the same times as the CT scans)Health-related quality of life (HRQOL)/symptom questionnaires will be administered at baseline and at restaging. Background:Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive, slow-growing soft-tissue tumors. The disease can be either asymptomatic or be associated with severe loss


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