title: Safety and Pharmacodynamics of the PDE4 Inhibitor Roflumilast in Advanced B-cell Malignancies.
abstract: Purpose:In this study, we aimed to validate our extensive preclinical data on phosphodiesterase 4 (PDE4) as actionable target in B-cell malignancies. Our specific objectives were to determine the safety, pharmacokinetics, and pharmacodynamics (PI3K/AKT activity), as well as to capture any potential antitumor activity of the PDE4 inhibitor roflumilast in combination with prednisone in patients with advanced B-cell malignancies.Experimental Design:Single-center, exploratory phase Ib open-label, nonrandomized study. Roflumilast (500 mcg PO) was given daily for 21 days with prednisone on days 8 to 14. Additional 21-day cycles were started if patients tolerated cycle 1 and had at least stable disease.Results:Ten patients, median age 65 years with an average of three prior therapies, were enrolled. The median number of cycles administered was 4 (range, 1-13). Treatment was well tolerated; the most common ≥grade 2 treatment-related adverse events were fatigue, anorexia (≥25%), and transient ≥ grade 2 neutropenia (30%). Treatment with roflumilast as a single agent significantly suppressed PI3K activity in the 77% of patients evaluated; on average, patients with PI3K/AKT suppression stayed in trial for 156 days (49-315) versus 91 days (28-139 days) for those without this biomarker response. Six of the nine evaluable patients (66%) had partial response or stable disease. The median number of days in trial was 105 days (range, 28-315).Conclusions:Repurposing the PDE4 inhibitor roflumilast for treatment of B-cell malignancies is safe, suppresses the oncogenic PI3K/AKT kinases, and may be clinically active.Clin Cancer Res; 23(5); 1186-92. ©2016 AACR.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.|Institute for Drug Development, Cancer Research and Therapy Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Kevin
authors.initials: K
authors.lastname: Kelly
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.|Institute for Drug Development, Cancer Research and Therapy Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Alex
authors.initials: A
authors.lastname: Mejia
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Avvaru N
authors.initials: AN
authors.lastname: Suhasini
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: An-Ping
authors.initials: AP
authors.lastname: Lin
authors.affiliation: College of Pharmacy, University of Texas Health Science Center at San Antonio and UT Austin, Texas.
authors.forename: John
authors.initials: J
authors.lastname: Kuhn
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.|Institute for Drug Development, Cancer Research and Therapy Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Anand B
authors.initials: AB
authors.lastname: Karnad
authors.affiliation: Institute for Drug Development, Cancer Research and Therapy Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas.|Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Steven
authors.initials: S
authors.lastname: Weitman
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas. aguiarr@uthscsa.edu.|Institute for Drug Development, Cancer Research and Therapy Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas.|Greehey Children's Cancer Research Institute, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas.|South Texas Veterans Health Care System, Audie Murphy VA Hospital, San Antonio, Texas.
authors.forename: Ricardo C T
authors.initials: RC
authors.lastname: Aguiar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines / Q000008:administration & dosage* / Q000009:adverse effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000187:drug effects / Q000235:genetics*; D003521:Cyclopropanes / Q000008:administration & dosage / Q000009:adverse effects; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000081082:Phosphoinositide-3 Kinase Inhibitors
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003521:Cyclopropanes; D019869:Phosphatidylinositol 3-Kinases; D058988:Phosphodiesterase 4 Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; C424423:Roflumilast; C517355:PDE4A protein, human