41st
`
`Annual Meeting of the
`
`American Society of Clinical Oncology
`
`May 13-17, 2005
`
`Orlando, Florida
`
`2005 Annual Meeting Proceedings Part I
`
`(a supplement to the Journal of Clinical Oncology)
`
`ASC®
`
`Copyright 2005 American Society of Clinical Oncology
`
`Roxane Labs., Inc.
`Exhibit 1006
`Page 001
`
`Roxane Labs., Inc.
`Exhibit 1006
`Page 001
`
`

`
`Editor: Steven M. Grunberg, MD
`
`Publisher and Managing Editor: Lisa Greaves
`Editorial Assistant: Elissa Fuchs
`
`Administrative Associate: Adell Cokley
`
`Director of Production: Victoria Vaughn
`
`Production Manager: Dana Monzi
`
`Executive Editor: Deborah Whippen
`
`Requests for permission to reprint abstracts should be directed to Intellectual Property
`Rights Manager, American Society of Clinical Oncology, 330 John Carlyle St., Suite 300,
`Alexandria, VA 22314. Tel: 703-299-0150; fax 703-518-8157; e-mail permissions@asco.org.
`Editorial correspondence and production questions should be addressed to Managing Editor,
`Annual Meeting Proceedings, American Society of Clinical Oncology, 330 John Carlyle St., Suite
`300, Alexandria, VA 22314. Tel: 703-519-1437; fax 703-5 18-8157 ; e-mail abstracts@asco.org.
`
`Copyright © 2005 American Society of Clinical Oncology. All rights reserved. No part of this
`publication may be reproduced or transmitted in any form or by any means, electronic or
`mechanical, including photocopy, recording, or any information storage and retrieval system,
`without written permission by the Society.
`
`The American Society of Clinical Oncology assumes no responsibility for errors or
`omissions in this document. The reader is advised to check the appropriate medical literature
`and the product information currently provided by the manufacturer of each drug to be
`administered to verify the dosage, the method and duration or administration, or
`contraindications. It is the responsibility of the treating physician or other health-care
`professional, relying on independent experience and knowledge of the patient, to determine
`drug, disease, and the best treatment for the patient.
`
`Abstract management and indexing provided by Database Publishing Group, Inc.,
`Cambridge, MA. Composition services and print production provided by Cadmus Professional
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`
`Roxane Labs., Inc.
`Exhibit 1006
`Page 002
`
`Roxane Labs., Inc.
`Exhibit 1006
`Page 002
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`

`
`Developmental Therapeutics: Molecular Therapeutics
`
`1935
`
`Integrated Education Session, sat, 11:15 AM - 12:30 PM
`3004
`Determining relevant biomarkers from tissue and serum that may predict
`response to single agent Iapatinib in trastuzumab refractory metastatic breast
`cancer. K. L. Blackwell, H. Burstein, M. Pegram, A. M. Storniolo, V. M.
`Salazar, J. E. Maleski, X. Lin, N. Spector, S. H. Stein, M. S. Berger; Duke
`Univ Medcl Ctr, Durham, NC; Dana-Farber Cancer Inst, Boston, MA; Univ
`of CA, Los Angeles, Los Angeles, CA; Indiana Univ Cancer Ctr, Indianapolis,
`IN; GIaxoSmithKline, Collegeville, PA; GlaxoSmlthKllne, Research Triangle
`Park, NC
`tyrosine kinase inhibitor that potently
`Background: Lapatinib is an oral
`inhibits both ErbB1 and ErbB2 tyrosine kinase activity. Results of two
`Phase II
`trials in metastatic breast cancer (MBC) suggest activity of
`Iapatinib in trastuzumab (T) pretreated patients. The main objective of this
`report was a combined biomarker analysis from these two large studies to
`evaluate correlations between clinical parameters, tissue/serum biomarker
`expression and response to Iapatinib. Methods: Eligible patients had MBC
`with disease progression following T-containing regimens in the 15’ phase II
`study and were anthracycline, taxane, capecitabine and T exposed in the
`2"“ phase II study. Tumor tissues were obtained on each patient from the
`time of most recent biopsy. Using standard IHC techniques, tumors were
`stained for: ErbB1-4, |GF1R, truncated ErbB2 (p95), heregulin and p-Erk
`1/2. Sequential quanitation of extra-cellular domain (ECD) for both ErbB1
`and ErbB2 were obtained. Results: Investigator reported efficacy data on
`the first 81 patients from the combined trials demonstrates a total of 19
`patients progression-free at 16 weeks of which 7 achieved an objective
`response (CR or PR). The mean T exposure in the 15‘ study was 46 weeks
`and in the 2"“ study 84 weeks. As of Dec 2004, both studies have
`completed accrual with a total of 215 patients. For the initial 37 tumors
`analyzed, IHC data indicate only 6/37 patients overexpressed both ErbB1
`and ErbB2. To date, over 100 tumortissues have been collected and tested
`for ErbB1-4, |GF1R, p95, heregulin, and p-Erk 1/2. Initial data suggest
`that expression levels of ER, PR and ErbB1 may be related to Iapatinib
`response in T pre-treated patients. Declines of ErbB2 ECD at both week 4
`and week 8 appear to predict response to Iapatinib. A multivariate analysis
`for response predictors,
`including all collected tumors, sequential ECD
`levels and clinical parameters will be performed. Conclusions: Inhibition of
`both ErbB1 and ErbB2 with Iapatinib represents a promising approach in
`the treatment of MBC. This analysis of potential predictive molecular
`phenotypes for response to Iapatinib in T-resistant tumors will be the most
`extensive to date.
`
`Oral Presentation, Sun, 1:00 PM - 4:00 PM
`3006
`Pharmacodynamic analysis of target receptor tyrosine kinase activity and
`apoptosis in GIST tumors responding to therapy with SU11248. D. W. Davis,
`D. J. Mcconkey, J. V. Heymach, J. Desai, S. George, J. Jackson, C. L. Bello,
`C. Baum, D. R. Shalinsky, G. D. Demetri; Univ of Texas MD Anderson
`Cancer Ctr, Houston, TX; Dana-Farber Cancer Inst, Boston, MA; Pfizer
`Global Research and Development, La Jolla, San Diego, CA
`Background: Most GIST lesions contain activating mutations in the receptor
`tyrosine kinases, KIT andlor PDGFR. SU11248 is an oral, multitargeted
`tyrosine kinase inhibitor of KIT, PDGFR, and VEGFR-1, -2 and -3 active
`against imatinib-resistant GIST. We report here effects of SU11248 on
`endothelial and tumor compartments in GIST. Methods: Paired tumor
`biopsies were obtained from 19 GIST patients (pts) undergoing phase 1/2
`therapy with SU11248 (Proc. ASCO 22:A3001, 2004). Biopsies were
`collected at baseline before and after at
`least 14d of treatment with
`SU11248 in the first cycle of treatment. Biopsies were examined using
`immunofluorescence coupled with laser scanning cytometry to quantify
`endothelial and tumor cell apoptosis, microvessel density (MVD), and the
`phosphorylation of PDGR—B and other RTKs. Results: Eight of 19 pairs of
`tumor samples came from patients who had clinical benefit (CB), defined
`as either partial response (PR) by RECIST criteria or stable disease (SD) for
`>6 months and 11 from pts with progressive disease (PD). Compared with
`baseline, tumors from pts with CB had a significant decrease of 15.0:0.03
`% (SD; p=0.016, t-test) in phosphorylated PDGFR-B activity in the tumor
`cell compartment whereas tumors in non-responders had an increase in
`PDGFR-[3 activity of 11.0:O.17%. Two pts had PR and six had SD,
`corresponding to a 23 and 11% decrease in phosphorylated PDGFR-B
`activity, respectively (p<0.05). Overall, tumors in pts with CB displayed a
`3.6- and 6-fold (p<0.05) increase in endothelial and tumor cell apoptosis,
`respectively. In contrast, tumors in pts with PD had little or no change in
`endothelial and tumor cell apoptosis from baseline. conclusions: PDGFR-[3
`phosphorylation was significantly decreased in tumor biopsies from GIST
`pts treated with SU11248 who had CB but not
`in those who had PD.
`Activities of other target RTKs are under
`investigation and will be
`presented. These data demonstrate that SU11248 inhibits PDGFR-B
`activity in addition to other RTKs in GIST. We hypothesize that SU11248
`exerts direct antitumor and indirect antiangiogenic effects in GIST as the
`basis for its anticancer efficacy.
`
`Oral Presentation, Sun, 1:00 PM - 4:00 PM
`3005
`Pharmacodynamic study of BAY 43-9006 in patients with metastatic renal cell
`carcinoma. P. J. 0’Dwyer, M. Rosen, M. Gallagher, B. Schwartz, K. T.
`Flaherty; Univ of Pennsylvania, Philadelphia, PA; Bayer Pharmaceuticals
`Corp, West Haven, CT
`Background: BAY 43-9006 (BAY) is a novel signal transduction inhibitor
`that prevents tumor cell proliferation and angiogenesis through blockade of
`the RafIMEKlERK pathway at the level of Rat kinase and the receptor
`tyrosine kinases VEGFR-2 and PDGFR-B.
`In preclinical models BAY
`administration is associated with decreased microvessel density and area
`in colon and breast cancer xenografts. We investigated alterations in tumor
`perfusion and vascular permeability associated with BAY using dynamic
`contrast-enhanced MRI (DCE-MRI). Methods: BAY was given from day 1 to
`28 of a 28 day cycle at 400 mg bid. DCE-MRI was performed at baseline
`and after a median of 6.1 weeks (range 2.7—10.9 weeks). The rate constant
`for gadolinium transfer from the vasculature to the interstitium (Ktrans)
`and volume fraction of the tissue extracellular and extravascular space (Ve)
`were calculated for an index lesion for each patient and were normalized for
`the arterial input function. Response was assessed with CT scans after 12
`weeks, then every 8 weeks for four months, then every 12 weeks using WHO
`criteria. Results: 17 renal cell carcinoma patients (pts) (median age 59, PS
`0-1) have been enrolled on this pharmacodynamic study and 16 under-
`went baseline and follow-up MR|s. Data are available from both scans for
`12 patients. 65% of patients had clear cell histology and had a median of 1
`prior therapy (range 0-6). As in previous studies, BAY was wel|—to|erated at
`this dose and schedule. Responses using WHO criteria included 7 partial
`responses (ORR 41%), 7 minor responses (25—50% reduction), 2 stable
`disease and 1 progression prior to 12 weeks. Median time to progression
`has not been reached, but is at least 10.8 months. Among the 12 patients
`with data from both DCE-MRls, Ktrans declined by 60.9% on average
`(95% CI 45.5-76.4%), and Ve declined by 23.4% (95% Cl 4.8—41.9%).
`Both high Ktrans at baseline, and percent decline in Ktrans, correlated with
`time to progression. conclusions: BAY 43-9006 is wel|—to|erated as a
`single-agent and is associated with significant alterations in measures of
`vascular permeability and tumor perfusion in patients with renal cell
`carcinoma. Preliminary evidence is adduced that therapeutic efficacy is a
`consequence of angiogenesis inhibition.
`
`Oral Presentation, Sun, 1:00 PM - 4:00 PM
`3007
`A phase I study with tumor molecular pharmacodynamic (MPD) evaluation of
`dose and schedule of the oral mTOR-inhibitor Everolimus (RAD001) in patients
`(pts) with advanced solid tumors.
`J. Tabernero, F. Rojo, H. Burris, E.
`Casado, T. Macaru/la, S. Jones, 8. Dimitrijevlc, K. Hazell, N. Shand, J.
`Baselga, for the study group; Vall d’Hebron Univ Hosp, Barcelona, Spain;
`Sarah Cannon Cancer Ctr, Nashville, TN; Novartis Oncology, Basel,
`Switzerland
`
`inhibits
`rapamycin,
`Background: Everolimus (E), an oral derivative of
`mTOR, a protein kinase downstream of PI3K and Akt,
`involved in the
`regulation of cell growth, proliferation and survival. In preclinical models,
`the administration of E is associated with reduction of mTOR downstream
`phosphory|ated(p)-S6 (p—S6) and p-4E-BP1, and occasionally with in-
`crease in upstream p-Akt. This study explores safety, PK and MPD changes
`in tumor at different doses and schedules of E to define the recommended
`dose for further development. Methods: Pts with advanced solid tumors
`were treated in successive cohorts of E: weekly 20, 50 and 70 mg or daily 5
`and 10 mg. Dose escalation depended on dose limiting toxicity (DLT) rate
`during the first 4-week period. Pre— and on-treatment steady—state (24hr
`post-dose and, for the weekly schedule, 5 days post-dose) tumor biopsies
`were obtained from each pt. Tumor tissue was evaluated by immunohisto—
`chemistry (IHC) for p-S6, p—4E-BP1 and p-Akt expression by a pathologist
`blinded for the biopsy sequence. Results: 33 pts have been treated with
`6-8 pts in each cohort. Grade 3 DLT occurred in 5 pts comprising
`stomatitis (1 pt at 10 mg daily, 2 at 70 mg weekly), neutropenia and
`hyperglycemia (1 pt each at 70 mg weekly). There were one partial
`response (colon cancer) and 2 stabilizations of >4 months (renal cell and
`breast cancer). MPD studies (see table) demonstrated an almost complete
`inhibition of p-S6 at all doses and schedules (p=0.001). Preliminary
`results suggest a dose-related decrease in p-4E-BP1 and increase in p-Akt
`expression with maximal effect at 10 mg daily and 250 mg weekly.
`Conclusions: This phase I study shows that E, at the doses and schedules
`studied, results in intratumoral inhibition of mTOR signaling. Based on the
`toxicity profile and the MPD findings, a dosage of 10 mg daily can be
`recorrimended for further phase ll-Ill development with E as a single agent.
`
`Schedulemose
`Dally 5 mg (n=3)
`Daily 10 mg (n=6)
`Weekly 20 mg (n=5)
`weekly 250 mg (n=6)
`
`Meat‘:i:-"Sg/‘l);1ilIbl- Mean
`100
`92.5
`96.7
`100
`
`'
`
`48
`58.2
`5.9
`63.6
`
`Irihibi- Meantp;'I:lg/3ctiva-
`22.2
`45.5
`327
`63.1
`Roxane Labs., Inc.
`Exhibit 1006
`Page 003
`
`Roxane Labs., Inc.
`Exhibit 1006
`Page 003