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Pharmacyclics Inc. Message Board

  • jgmtruth jgmtruth Mar 25, 2013 9:53 AM Flag

    One more time AACR 2013 April 6-10 2013 ibrutinib

    Presentation Abstract

    Abstract Number: LB-141
    Presentation Title: Potent single agent activity of Ibrutinib (PCI-32765) in patients with chronic lymphocytic leukemia (CLL): clinical and translational results from an ongoing phase II study
    Presentation Time: Monday, Apr 08, 2013, 1:50 PM - 2:05 PM
    Location: Room 144, Washington Convention Center
    Author Block: Adrian Wiestner, Sarah Herman, Rashida Mustafa, Janet Valdez, Jade Jones, Nakhle Saba, Andrew Lipsky, Diane C. Arthur, Gerald Marti, Francine Thomas, Irina Maric, Stefania Pittaluga, Xin Tian, Susan Soto, Georg Aue, Mohammed Z. Farooqui. National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD, NIH, National Cancer Institute (NCI), Lab of Pathology, Center for Cancer Research (CCR), Bethesda, MD, NIH, Radiology and Imaging Services (RIS), Clinical Research Center (CRC), Bethesda, MD, NIH, Department of Laboratory Medicine (DLM), CCR, Bethesda, MD, NIH, NCI, Laboratory of Pathology, Bethesda, MD, NIH, NHLBI, Office of Biostatistics Research, Bethesda, MD

    Presentation Abstract

    Abstract Number: 923
    Presentation Title: Ibrutinib inhibits malignant cell adhesion and migration and reduces tumor burden in lymph node and bone marrow in a murine model of mantle cell dissemination and progression
    Presentation Time: Sunday, Apr 07, 2013, 1:00 PM - 5:00 PM
    Location: Hall A-C, Poster Section 38
    Poster Board Number: 21
    Author Block: Betty Y. Chang1, Michelle Francesco1, Susanne Steggerda1, Stella Chang1, Padmaja Magadala1, Lucy Jawed2, Patricia Thiemann2, Joseph J. Buggy1. 1Pharmacyclics Inc. Research Dept, Sunnyvale, CA; 2Pharmacyclics Inc. Preclinical Development, Sunnyvale, CA
    Abstract Body:
    Introduction:
    Ibrutnib is a potent and selective Btk inhibitor that covalently modifies
    Cys481 in Btk and inhibits B cell antigen receptor (BCR) signaling. Ibrutinib is currently in a Phase II study in patients with relapsed or refractory mantle cell lymphoma (MCL). In MCL Presentation Abstract

    Abstract Number: 2215
    Presentation Title: Pharmacogenomic investigation of Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765): drug sensitivity in diffuse large B-cell lymphoma (DLBCL) within a tumor microenvironment-aligned high-throughput screen
    Presentation Time: Monday, Apr 08, 2013, 1:00 PM - 5:00 PM
    Location: Hall A-C, Poster Section 42
    Poster Board Number: 24
    Author Block: Cuc Davis1, Tineke Casneuf1, Willem Lightenberg1, Richard Rickles2, Winnie Tam2, Matthias Versele1, Steven McClue1, Sriram Balasubramanian3, Joseph Buggy3, Kate Sasser1, Brett Hall1. 1Janssen Pharmaceutical Companies of Johnson & Johnson, Spring House, PA; 2Zalicus Inc., Cambridge, MA; 3Pharmacyclics, Inc., Sunnyvale, CA
    Abstract Body: Ibrutinib (PCI-32765) is an orally administered small molecule that covalently binds to Cys-481 of Bruton’s tyrosine kinase (BTK). Ibrutinib has demonstrated promise across several types of B-cell malignancies and is currently in Phase 2/3 clinical testing. Preclinical studies have established three key mechanisms following blunting of proximal B cell receptor (BCR) signaling through BTK inhibition: (1) suppression of pro-survival pathways, (2) diminished integrin activation and (3) attenuation of chemotactic response. Single agent ibrutinib Phase 1/2 clinical trials have revealed high clinical response rates in both naïve and relapsed or refractory chronic lymphocytic leukemia (CLL), as well as, relapsed or refractory mantle cell lymphoma (MCL) patients (Byrd, et al. 2012 ASH; Wang, et al. 2012 ASH; Advani, et al. 2010 JCO). Response rates in a phase 2 diffuse large B cell lymphoma (DLBCL) clinical trial appeared to be more prevalent in “activated B-cell” (ABC) over “germinal center B-cell like” (GCB) DLBCL patients (Staudt et al., ASH 2012). To gain a further understanding of ibrutinib response and inform optimal therapeutic combinations in DLBCL, we established a combination high throughput pharmacology screen (cHTS) with ibrutinib. Ibrutinib was evaluated alone and in combination with 99 targeted compounds, across 17 (12 GCB; 5 ABC) DLBCL cell lines. To better align with human biology, DLBCL cell lines were screened in the presence of human marrow stromal cell conditioned media (hMSC-CM) and B-cell receptor stimulation via anti-IgG/anti-IgM antibodies. Interestingly, 8/17 (47%) DLBCL cell lines were intolerant to any external BCR stimulation, so those lines were screened in hMSC-CM without exogenous BCR stimulation. Under our experimental conditions, 11/17 (65%) cell lines displayed some sensitivity (IC50 10 M)]. Consistent with DLBCL clinical responses, the highly sensitive (IC50

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    • Presentation Abstract

      Presentation Title: Rational combination therapy of lymphoma using the BTK inhibitor ibrutinib as a platform
      Presentation Time: Saturday, Apr 06, 2013, 3:15 PM - 3:40 PM
      Location: Ballroom C, Washington Convention Center
      Author Block: Louis M. Staudt. NCI-CCR, Bethesda, MD Presentation Abstract

      Abstract Number: 4543
      Presentation Title: High-throughput combination screening identifies novel drug-drug pairings for a Bruton’s tyrosine kinase inhibitor against the ABC subtype of diffuse large B-cell lymphomas
      Presentation Time: Tuesday, Apr 09, 2013, 1:00 PM - 5:00 PM
      Location: Hall A-C, Poster Section 44
      Poster Board Number: 12
      Author Block: Lesley A. Mathews1, Rajarshi Guha1, Paul Shinn1, Ryan M. Young2, Kian-Huat Lim2, Jonathan Keller1, Dongbo Liu1, Adam Yasgar1, Crystal McKnight1, Matthew B. Boxer1, Damien Y. Duveau1, Jian-kang Jiang1, Sam Michael1, Bryan T. Mott1, Paresma R. Patel3, William Leister1, David J. Maloney1, Christopher A. LeClair1, Ganesha Rai1, Ajit Jadhav1, Brian D. Peyser4, Christopher P. Austin1, Scott Martin1, Anton Simeonov1, Marc Ferrer1, Louis Staudt2, Craig J. Thomas1. 1Division of Preclinical Innovation, National Center for Advancing Transnational Sciences, National Institutes of Health, Rockville, MD; 2Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; 3SAIC-Frederick, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD; 4Information Technology Branch, Developmental Therapeutics Program, National Cancer Institute, National Institutes of Health, Bethesda, MD
      Abstract Body: The vast majority of cancer treatments currently administered to patients consist of combinations of more than one drug via routine infusions that adhere to specific dosing schedules. It is thought that this multi-arm and time dependent approach will kill not only the tumor cells within the primary site, but also any metastatic lesions, and importantly, any circulating tumor cells (CTCs) which may still exist in the blood. Combination therapies have also been developed as a means to reduce general cytotoxic side effects and prevent resistance and recurrence. Our labs have recently developed a high throughput screening platform to test compounds in pair-wise combinations to rapidly and systematically identify additive, synergistic and antagonistic drug combinations. This HTS capability can easily generate hundreds of dose response matrices in a single study and can increase significantly when applied to multiple cell lines. We are using this combination screening platform with in vitro models from both established cell lines and primary patient material, and we expect it will serve as a very valuable tool and a starting point when designing clinical trials after these combinations show promise within in vivo models. In a proof of concept study, we tested combinations of compounds that effectively kill 2 established lines of the ABC sub-type of diffuse large B-cell lymphoma (DLBCL); TMD8 and HBL1. We will present the infrastructure and methods that we have developed to implement the combination screens, visualize data from the combination dose response comparisons and numerically compare combinations in terms of their response matrices. We will also describe how this approach allows us to investigate putative polypharmacological effects that play a role in compound combination responses. Finally, we will show the results of a combination screen with TMD8 and HBL1 cells, including the identification of a novel drug-drug combination for the BTK inhibitor ibrutinib (PCI-32765) which is of both basic and translational interest for the treatment of DLBCL.

      Sentiment: Strong Buy

    • we were just 90 plus on way to a 100 man

    • Thanks jgmtruth
      Appreciate the updates
      AK

    • mwindsweptfarm@comcast.net mwindsweptfarm Mar 26, 2013 7:44 AM Flag

      Ibrutinib is fabulous. We don't have to worry about that letting us down. It's the wall street market swings that have been effecting the stock. Clear sailing very soon. Patience.

      Sentiment: Strong Buy

 
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