Results of a phase I study of idelalisib, a PI3Kδ inhibitor, in patients with relapsed or refractory mantle cell lymphoma (MCL).
ABSTRACT Idelalisib, an oral inhibitor of PI3Kδ, was evaluated in a 48-week phase I study (50-350 mg qd or bid) enrolling 40 patients with relapsed/refractory mantle cell lymphoma (MCL). Primary outcome was safety and dose-limiting toxicity (DLT). Secondary outcomes were pharmacokinetic parameters, pharmacodynamic effects, overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR). Patients without DLT and no evidence of disease progression after 48 weeks enrolled in the extension study. Patients had median age of 69 years (52-83) and received median of 4 prior therapies (1-14); 17/40 (43%) were refractory to their most recent treatment. Median duration of idelalisib treatment was 3.5 months (range, 0.7-30.7), with 6 (15%) continuing extension treatment. Common grade ≥3 adverse events (AEs) included (total%/grade ≥3%) diarrhea (40/18), nausea (33/5), pyrexia (28/0), fatigue (25/3), rash (23/3), decreased appetite (20/15), upper respiratory infection (20/0), pneumonia (13/10), and ALT or AST elevations (60/20). Nine (25%) patients discontinued therapy due to AEs. ORR was 16/40 (40%), with CR in 2/40 (5%) patients. Median DOR was 2.7 months, median PFS was 3.7 months, and 1-year PFS was 22%. These data provide proof of concept that targeting PI3Kδ is a viable strategy and worthy of additional study in MCL. This study is registered at Clinicaltrials.gov, identifier: NCT00710528.
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ABSTRACT: Mantle cell lymphoma is a heterogeneous subtype of non-Hodgkin lymphoma. Conventional treatment with immunochemotherapy followed by autologous stem cell transplantation or intensive immunochemotherapy alone has improved outcomes, but the disease remains incurable. Recent advances in basic and translational research have significantly enhanced our understanding of disease pathogenesis and have sparked the development of novel therapies. Novel agents include the proteasome inhibitor bortezomib, the immunomodulatory agent lenalidomide, the phosphatidylinositol-4,5-bisphosphate 3-kinase pathway inhibitor idelalisib and the Bruton tyrosine kinase inhibitor ibrutinib. Preliminary results from clinical trials, especially from studies of ibrutinib, have proven these agents to be effective. In ongoing studies, these agents are being integrated into conventional immunochemotherapy regimens to hopefully improve patient outcomes.British Journal of Haematology 06/2014; 167(1). DOI:10.1111/bjh.13000 · 4.96 Impact Factor
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ABSTRACT: The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: email@example.com.Hospital pharmacy 12/2014; 49(11):1009-13. DOI:10.1310/hjp4911-1009
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ABSTRACT: Idelalisib (also known as GS-1101, CAL-101, IC489666 and Zydelig) is a phosphoinositide 3-kinase delta (PI3Kδ) inhibitor that has recently been approved for the treatment of several hematological malignancies. Given its use in human diseases, we needed a clear picture of how idelalisib binds to and inhibits PI3Kδ. Our data showed that idelalisib is a potent and selective inhibitor of the kinase activity of PI3Kδ. A kinetic characterization clearly demonstrated ATP-competitive inhibition, and several additional biochemical and biophysical assays showed that the compound binds reversibly and non-covalently to the kinase. A crystal structure of idelalisib bound to the p110δ subunit of PI3Kδ furthers our understanding of the binding interactions that confer the potency and selectivity of idelalisib. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.Journal of Biological Chemistry 01/2015; 290(13). DOI:10.1074/jbc.M114.634683 · 4.60 Impact Factor