title: Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis).
abstract: Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the γ-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Geraldine
authors.initials: G
authors.lastname: O'Sullivan Coyne
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Khanh T
authors.initials: KT
authors.lastname: Do
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Baris
authors.initials: B
authors.lastname: Turkbey
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Eric
authors.initials: E
authors.lastname: Polley
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Robert
authors.initials: R
authors.lastname: Meehan
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Rasa
authors.initials: R
authors.lastname: Vilimas
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Horneffer
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Lamin
authors.initials: L
authors.lastname: Juwara
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Ann
authors.initials: A
authors.lastname: Lih
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Amul
authors.initials: A
authors.lastname: Choudhary
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Mitchell
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Helman
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
authors.affiliation: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Yvonne Horneffer, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, and Alice P. Chen, National Cancer Institute, National Institutes of Health, Bethesda; and Rasa Vilimas and Lamin Juwara, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors.forename: Alice P
authors.initials: AP
authors.lastname: Chen
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000328:Adult; D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D018222:Desmoid Tumors / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000071066:Patient Reported Outcome Measures; D066066:Response Evaluation Criteria in Solid Tumors; D019233:Retreatment; D063189:Symptom Assessment; D013764:Tetrahydronaphthalenes / Q000009:adverse effects / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D014633:Valine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D013764:Tetrahydronaphthalenes; D051176:beta Catenin; D053829:Amyloid Precursor Protein Secretases; D014633:Valine; C550722:nirogacestat