Objectives: Establish the safety and the maximum tolerated dose (MTD) of orallyadministered PCI-32765 in patients with recurrent B cell lymphoma. Determine pharmacokinetics (PK) of orally administered PCI-32765 Measure pharmacodynamic parameters to include drug occupancy of Btk, thetarget enzyme, and effect on biological markers of B cell functionSamples for pharmacokinetics and pharmacodynamics will be collected as outlined in theprotocol and shipped to Pharmacyclics, Inc. as specified below. Tissue samples will notbe sent to Pharmacyclics, Inc. Rather, tissue samples will be obtained as outlined below.Biopsy specimens will be required from all patients before initiation of PCI-32765treatment (pre-treatment biopsies). It is anticipated that roughly half of the patientswill have accessible tumor tissue and will be rebiopsied prior to PCI-32765. Thesepatients will also be biopsied 48 hours after the initial PCI-32765 dose. For the otherpatients, formalin fixed and paraffin embedded (FFPE) samples from previous biopsieswill be analyzed.Gene expression profiling using Affymetrix U133plus2.0 arrays will be performed for allcases. For those cases with available fresh frozen pre-treatment biopsy samples, geneexpression profiling will be performed as described by the Staudt laboratory, withassignment to ABC or GCB subgroups based on a Bayesian predictor (Wright et al.PNAS 2003, 100:9991). On these patients, we will also obtain biopsy samples 48 hourspost-treatment and profile gene expression similarly. Comparison with the pre-treatmentsample will allow us to assess the ability of PCI-32765 to inhibit btk. For patients withonly an FFPE biopsy sample, we will use a newly described method that can use RNAfrom FFPE biopsies to accurately predict ABC vs. GCB DLBCL subtypes (Williams etal. J Mol Diag 2010, in press). Briefly, RNA is extracted from FFPE samples with aQiagen FFPE extraction kit followed by amplification using a kit from Nugen, prior tostandard Affymetrix U133Plus2.0 array analysis. We will also perform where possibleanalyses of tumor mutations which include but are not be restricted to CARD11, ITAMand A20.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Basic Sciences
Zip Code
Dunleavy, Kieron; Roschewski, Mark; Wilson, Wyndham H (2012) Lymphomatoid granulomatosis and other Epstein-Barr virus associated lymphoproliferative processes. Curr Hematol Malig Rep 7:208-15
Wilson, Wyndham H; Jung, Sin-Ho; Porcu, Pierluigi et al. (2012) A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica 97:758-65
Degheidy, Heba A; Venzon, David J; Farooqui, Mohammed Z H et al. (2012) Combined normal donor and CLL: Single tube ZAP-70 analysis. Cytometry B Clin Cytom 82:67-77
Royo, C; Navarro, A; Clot, G et al. (2012) Non-nodal type of mantle cell lymphoma is a specific biological and clinical subgroup of the disease. Leukemia 26:1895-8
Roschewski, Mark; Wilson, Wyndham H (2012) EBV-associated lymphomas in adults. Best Pract Res Clin Haematol 25:75-89
Dunleavy, Kieron; Grant, Cliona; Eberle, Franziska C et al. (2012) Gray zone lymphoma: better treated like hodgkin lymphoma or mediastinal large B-cell lymphoma? Curr Hematol Malig Rep 7:241-7
Eberle, Franziska C; Song, Joo Y; Xi, Liqiang et al. (2012) Nodal involvement by cutaneous CD30-positive T-cell lymphoma mimicking classical Hodgkin lymphoma. Am J Surg Pathol 36:716-25
Dunleavy, Kieron; Wilson, Wyndham H (2012) How I treat HIV-associated lymphoma. Blood 119:3245-55
Degheidy, Heba A; Venzon, David J; Farooqui, Mohammed Z H et al. (2011) Methodological comparison of two anti-ZAP-70 antibodies. Cytometry B Clin Cytom 80:300-8
Eberle, Franziska C; Rodriguez-Canales, Jaime; Wei, Lai et al. (2011) Methylation profiling of mediastinal gray zone lymphoma reveals a distinctive signature with elements shared by classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma. Haematologica 96:558-66

Showing the most recent 10 out of 23 publications