Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors/Aggressive Fibromatosis
Condition: Desmoid Tumors; Aggressive Fibromatosis
MeSH terms: Fibromatosis, Aggressive; Fibroma; Aggression
Study type: Interventional
Phase: Phase 2

Summary: 
      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 fibromatosis

        -  Secondary: 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 administration

      Eligibility:

        -  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 function

        -  Willingness to provide blood samples and 10 unstained slides or a tumor block for
           genetic research studies

      Study 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 cycles

        -  Optional 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 cycles

        -  Health-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 fibromatosis

        -  Exploratory: 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 administration

      Eligibility:

        -  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 function

        -  Willingness to provide blood samples and 10 unstained slides or a tumor block for
           genetic research studies

      Study 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 cycles

        -  Optional 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
    

Intervention name(s): PF-03084014
Intervention type(s): Drug
Intervention description(s): Treatment with the selective small-molecule >=-secretase inhibitor PF- 3084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early-phase clinical trial.
Intervention MeSH terms: Nirogacestat
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Desmoid Tumor; Aggressive Fibromatosis; Gamma-secretase Inhibitor; Notch Pathway