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A pilot study of sirolimus (S) in subjects with Cowden syndrome (CS) with germ-line mutations in PTEN.
Developmental Therapeutics - Clinical Pharmacology and Experimental Therapeutics
2013 ASCO Annual Meeting
J Clin Oncol 31, 2013 (suppl; abstr 2532)
Author(s): Takefumi Komiya, Gideon Michael Blumenthal, Marc S. Ballas, Roopa Dechowdhury, Michell Manu, Suzanne Fioravanti, Thomas J Hornyak, Stephen Wank, Douglas Weinstein, Jennifer Morris, Stephen M. Hewitt, Regan Memmott, Phillip A. Dennis, Betsy Morrow; National Cancer Institute, Bethesda, MD; U.S. Food and Drug Administration, Silver Spring, MD; Bristol-Myers Squibb, Wallingford, CT; Maryland Oncology Hematology, Silver Spring, MD; Dermatology, University of Maryland School of Medicine, Baltimore, MD; National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD; Laboraory of Pathology, National Cancer Institute, Gaithersburg, MD; Tissue Array Research Program, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD; Johns Hopkins University, Baltimore, MD; Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
Background: CS is characterized by germline PTEN mutations. Because tumors from CS patients show increased activation of the PI3K/Akt/mTOR pathway, mTOR inhibitor such as S might have activity in such patients. Methods: Eligibility: subjects with germline PTEN mutation who meet international diagnostic criteria for CS, age 18, ECOG PS 0-2, and adequate organ function. Subjects were treated with a 56-day course of daily oral S (2 mg). Objective: Inhibition of the mTOR pathway in benign skin/GI lesion, as assessed by IHC (P-AKT, Total S6, P-S6, P-4E-BP1, score 0-4), changes in benign or malignant tumor by CT/MRI/PET, digital dermoscopy/endoscopy, and changes in cerebellar testing by modified SARA (Neurology 2006). Protocol was amended to allow up to 20 subjects. Results: A total of 18 pts/16 families were enrolled. Median age 42 (range 19-69). Male/Female: 9/9. Involvement in skin, thyroid, GI polyps, breast, CNS, and all of the five organs was observed in 18, 15, 13, 8, 18, 5 subjects, respectively. 7 had h/o malignancies: 3 renal cell, 4 breast, 3 thyroid, 4 others. 3 cerebellar gangliocytomas and 2 others were measurable by CT or MRI. PTEN mutations: 6 families in Exon 1-2, 1 in Exon 4, 9 in Exon 5-8. All but one (D24H) were truncating mutations. 11 of 16 pts who completed a 56-day course reported subjective improvement in energy, mood, focus or skin lesion. Pts with Ex6-8 mutation (n=4) had a median SUV decrease of 29.4%. Regression of skin and GI lesions was observed by dermoscopy or endoscopy. Cerebellar evaluation showed a significant improvement in a total SARA score at 1 month (n=9, p=0.034). 3 pts were treated for only 28 days due to voluntary withdrawal. IHC analysis in skin and GI benign lesions showed a decrease in average P-S6K, P-S6, Total S6, P-S6/Total S6 in response to S. P-S6K/Total S6 ratios at d14 and d56 were significantly lower than at baseline (p=0.0026, 0.0391, respectively). The most common AEs (all grades >25%) were LFTs/Hb (39%), fatigue/hypercholesterolemia (28%). Grade 3 AEs: 1 pt hypophosphatemia/lymphopenia. Conclusions: A 56-day course of S was well tolerated in subjects with CS and was associated with improvement in symptoms, skin/GI lesions, cerebellar function and decreased mTOR signaling. Clinical trial information: NCT00971789.
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Meeting: 2013 ASCO Annual Meeting Abstract No: 2531 First Author: A. M. Gonzalez-Angulo