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`April 1-5, 2000 San Francisco, CA
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`Univ. ui Minn.
`Bin-Medical
`Library
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`___ 71
`Breckenridge Exhibit 1131
`Breckenridge v. Novartis lPR2017-01592
`Alexandre AACR Abstract
`
`

`

`host-dependent processes promoting cancer cell growth. ZD1839 showed an
`IC.o of 10.3-35.0 ng/ml for EGFR isolated from A431 vulval squamous carcinoma.
`This study evaluated the pharmacokinetics of ZD1839 following oral administra(cid:173)
`tion of single (50mg) and repeated (50-700 mg/day) doses in pis (n~6-10/group)
`with advanced malignancies. 57 pts (median age 55 years, range 28-75) provided
`blood samples included in the phannacokinetic analysis. Blood samples obtained
`up to 6 days after the single 50 mg dose, and at intervals during and for 6 days
`after the multiple-dose phase. were analysed by HPLC. Following the single 50
`mg dose, maximum plasma drug concentrations (mean 45 ng/ml; range 26.9-62.1
`ng/mQ occurred 1-5h post-dose. Concentrations declined biphasically thereafter
`with a mean terminal t"2 of 34h. Exposure (AUCO•24) following single and multiple
`administration, though variable (up to 7-fold at each dose level) increased ap(cid:173)
`proximately proportionally with dose with no apparent change in terminal t'll!' On
`repeated administration, steady-state was achieved by day 7, and there was a 2-
`to 7-fold increase in exposure (AUCO•24)on day 14 relative to day 1. Terminal t'l2
`appeared unaltered. Thus, ZD1839 is suitable for once-daily oral administration
`and potentially biologically relevant concentrations of drug are achievable at the
`dose levels studied. 'IRESSA' is a trademark, the property of the AstraZeneca
`group of companies
`
`#3897 PHASE I STUDY OF CCI-779,A NOVEL RAPAMYCIN ANALOG:
`PRELIMINARY RESULTS. Jerome Alexandre, E. Raymond, H. DepEmbrock, S.
`Mekhaldi. E. Angevin, C. Paillel. A. Hanauske, T. Le Chevalier, B. Escudier, J.
`Frisch, A. Feussner, and J. P Armand, Inst Gustave Roussy. Villejuif cedex,
`France. and Onkologische Tagesklinik, Genetics Institute, Munich. Germany
`CCI-779, a novel rapamycin analog displays antitumor activity without signifi(cid:173)
`cant immunosuppression in animals models. CCI-779 was given as a weekly 30
`min infusion in patients (pts) with advanced solid tumors. Dose escalations were
`made using the modified continuous reassessment method. 15 pts (M/F: 10/5)
`were treated at the doses of 7.5 (1 pt. 15.0 (2 pts), 22.5 (1 pt). 34.0 (3 pts), 45.0
`(3 pts). 60.0 (2 pts), 80 (1 pt). 110 (1 pt. and 165 mg/m2/w (1 pt). So far. no dose
`limiting toxicity was observed. A grade (G) 1-2 skin toxiCity was observed at each
`dose level without any evidence of dose-effect relationship: dryness with mild
`itching (7 pts). eczema-like lesions (3 pts). sub-acute urticaria (1 pt). and aseptic
`follicles (10 pts). In the latest. skin biopsies showed folliculitis and superficial
`peri-capillar dermatitis. 5 pts experienced reactivation of peri-oral herpes lesions.
`G 1-2 mucositis was observed in 9 pts. All pts receiving >8 doses experienced GI
`nails Changes. ThromlXlcytopenia were observed in 4 pts treated at 34 (G3). 45
`(G2). 60 (G3) and 80mg/m2/w (Gl) requiring treatment delay in 3 pts. An asymp(cid:173)
`tomatic increased of triglyceridemia and cholesterolemia levels were observed in
`8 and 4 pts. respectively. Decreases in testoteronemia aSSOCiated with an in(cid:173)
`creased levels of LH and FSH were observed in 5/6 men receiving more than 4
`doses at doses >15mg/m2/w. The immunophenotype of peripheral lymphocytes
`and the mitogen proliferation assays did not show significant immunosuppres(cid:173)
`sion. 13 pts were evaluables for efficacy: 1 partial response in a patient with a
`1L2-IFa resistants metastatic renal cell carcinoma treated with 15mg/m2/w. 3
`minor responses. and 5 stabilization were observed. Accrual is ongoing.
`
`#3898 A PHASE I TRIAL OF GEMCITABINE AND RADIATION IN LOCALLY
`ADVANCED UNRESECTABLE CANCER OF THE PANCREAS. Laurie L Her(cid:173)
`scher, C. M Muir, G. S Kroog, J. A Cook. and J. B Mitchell, National Cancer Inst,
`Bethesda. MD
`Purpose: To determine the maximum tolerated dose (MTD) and dose- limiting
`tOXicities ot gemcitabine with concurrent radiation therapy In patients with unre(cid:173)
`sectable adenocarcinoma of the pancreas delivered as a 30 minute infusion once
`weekly. Patients and Methods: Patients who had locally advanced or locally
`recurrent un resectable pancreatic cancer were eligible. Gemcitabine was admin(cid:173)
`istered as a 30 minute infusion once weekly for a total ot 5 cycles during the
`course of radiation therapy. The starting dose of gemcitablne was 350 mg/m2.
`Doses were escalated by increments of 25% in successive cohorts of three
`patients. Radiation therapy was delivered at 180 cGy/day to a total dose at
`5400-5580 cGy. Results: Nineteen patients were entered on this study through 3
`dose levels (350-550 mg/m2. The maximum tolerated dose was determined to be
`440 mg/m2. The dose-limiting toxicity was neutropenia and thrombocytopenia.
`Conclusion: The maximum tolerated dose of gemcilabine when administered as
`a 30 min infusion once weekly during radiation therapy tor unresectable pancre(cid:173)
`atic cancer was determined to be 440 mg/m2 • The dose-limiting toxiCity was
`cytopenia. Concurrent gemcitabine and radiotherapy is tolerable and may repre(cid:173)
`sent a basis to evolve increasingly effective chemoradiotherapy of pancreatic
`cancer.
`
`RADIOBIOLOGYIRADIATION ONCOLOGY 6: Radiation
`Biology V: Translational Research
`
`#3899 EFFECTS OF RADIATION DOSE AND DOSE RATE ON LYMPHO(cid:173)
`CYTE POPULAnONS. Michael J Pecaut, Radha Dutta-Roy. Michael F Moyers,
`Gregory A Nelson. and DaHa S Gridley, Loma Linda Univ. Lorna Linda, CA. and
`Lorna Linda Univ Med Ctr, Loma Linda, CA
`
`CLINICAL RESEARCH 22
`
`The hazards of interplanetary missions have been stressed in recent reports
`issued by the National Aeronautics and Space Administration and the National
`Research Council. Of concern is the possibility that the low-dosellow-dose rate
`radiation inherent to Solar Particle Events (SPE) and Galactic CosmiC Rays (GCR)
`may enhance tumorigenesis by immunosuppression andlor DNA damage. To
`address the issue of immune suppression, female C57BLl6 mice (n=85) were
`treated with whole-body irradiation from a 6°Cobalt gamma source. Animals were
`exposed to O. 0.5, 1.5, and 3.0 Gy at 1 cGy/min or 80 cGy/min. and euthanized
`4 days later. Splenic 'and peripheral blood lymphocytes underwent flow cytomet(cid:173)
`ric analysis with antibodies against leukocytes (CD45+), T cells (CD3+). B cells
`(CDI9+). helperlinducer T cells (CD4+), cytotoxic T cells (CD8+), and natural
`killer cells (NK 1.1 +). There were significant dose responses in both total cell
`counts and population distributions. In the blood, there were Significant dose
`responses in T cell. helper/inducer T cell. B cell. and NK cell percentages (p <
`0.001). However, only cytotoxiC T and NK cell percentages were affected by the
`dose rate (p < 0.02). Similar dose and dose rate responses were observed in the
`splenocyte percentages, as well as in blood and spleen lymphocyte counts.
`These results suggest that the doses predicted during SPEs can playa significant
`role in radiation-induced immunosuppression. There also appear to be differ(cid:173)
`ences in the ability of T, B, and NK cell populations to recover from radiation
`exposure. Because of these differences in population dynamics, hematopoietic,
`apoptotic, and trafficking mechanisms may all be involved. Studies are in
`progress to determine whether the immunomodulation affects tumor initiation and
`promotion.
`
`#3900 RADIATION EFFECTS OF TOTAL DOSE AND DOSE RATE ON
`COMPONENTS OF THE IMMUNE SYSTEM. Glen M Miller, Michael J Pecaut.
`Melba L Andres, Erik D Zendejas. Gregory A Nelson, and Daila S Gridley, Lama
`Linda Univ, Lorna Linda, CA, and Lorna Linda Univ Sch of Medicine, Lorna Linda,
`CA
`Interest in radiation-induced carcinogenesis has progressed as increased num(cid:173)
`bers of humans are exposed 10 radiation in various environmental, occupational,
`and therapeutic settings. Exposure to radiation can greatly modify immunological
`status and increase risk for cancer. In the present study. C57BLl6 female mice
`(n=85) were exposed to 0.5,1.5. and 3.0 Gy total dose of whole body gamma
`radiation from a 6OCobait source at a low dose rate (1 cGy/min) and a high dose
`rate (80 cGy/min). Four days post-exposure. all mice were euthanized to analyze
`immmunological components for a variety of proliferative and functional proper(cid:173)
`ties. A decline in spleen and thymus mass strongly correlated with total dose
`delivered. Similarly. leukocyte counts in both the blood and spleen were Inversely
`proportional to total dose (p<0.001) but independent of dose rate. In contrast,
`spontaneous blastogenesis results showed a directly proportional dose re(cid:173)
`sponse. Dose and dose rate did not alter splenocyte activation by PHA or ConA,
`T-cell mltogens. However. splenocyte response to the 8-cell mitogen, LPS, was
`negatively correlated with dose (p<O.OOI), independent of dose rate. Regarding
`cytokine production by splenocytes, IL-2 concentrations decreased as the total
`radiation dose increased. Cumulatively, these data suggest that protein synthesis
`of T-cells is affected by dose of radiation, as evidenced by IL-2 secretion, while
`DNA synthesis is unaffected within the same exposures. In summary, the data
`showed that immune components involved in tumor resistance, although highly
`affected by total dose, are not influenced by dose rate in these measures.
`Additional studies are in progress to detemline long term effects of radiation
`exposure on susceptibility to tumorigenesiS.
`
`#3901
`GENOTYPE/PHENOTYPE CORRELATIONS IN RADIATION-IN(cid:173)
`DUCED PAPILLARY THYROID CARCINOMAS: THE CHERNOBYL PARA·
`DIGM. Hartmut M Aabes, S. Klugbauer, D. Hoelzel. E. Lengfelder, and E. P
`Demidchik. Thyroid Cancer Ctr, Minsk, Belarus. and Univ of Munich, Munich,
`Germany
`The incidence of papillary thyroid carcinomas (PTC) increased in children
`exposed to radioactice fallout after the Chemobyl reactor accident. An analysis of
`191 cases revealed various types of RET rearrangements (H4IRET, PTC1; ELE11
`RET, PTC3; GOLGAS/AET, PTC5; HTIFIRET, PTC6; RFG7IRET, PTC7) with dif(cid:173)
`ferent prevalence and a few NTRKI rearrangements. RET rearrangement-positive
`PTC develop rapidly, with a significantly higher prevalence of PTC3 at short
`intervals after irradiation. At longer latency, the prevalence of rearrangements
`declines with a shift from PTC3 to PTCI. The type of rearrangement is indepen(cid:173)
`dent of age at radiation. However. the highest prevalence of PTC3 was found,
`irrespective of age, in the most heavily contaminated parts of Belarus. RET
`rearrangement is connected to a more advanced pT and pN category. In ELEI/
`RET tumors the solid variant of the papillary carcinoma predominates. while
`H4IRET tumors display more frequently the typical papillary pattem. The spec(cid:173)
`trum of radiation-induced gene rearrangements in the cohort of post-Chernobyl
`PTC from radiation-exposed children provides clues to phenotypes and bears
`implications for tumor biology and clinical course.
`
`#3902 MALDI·MASS SPECTROMETRY ANALYSIS OF NOVEL RADIA(cid:173)
`TION-INDUCED PROTEINS
`IN TUMORS AND HUMAN ENDOTHELIAL
`CELLS. M. Stoeckli. P. Chaurand, Elaine Sierra-Rivera. G. Cunningham, R. Cap(cid:173)
`rioli, and D. E Callahan, Vanderbilt Univ Sch of MediCine, Nashville, TN
`Tumor development and expansion requires a well-defined vascular supply to
`provide the tumor with necessary nutrients. Tumor blood vessels respond dlffer-
`
`Proceedings of the American Association for Cancer Research 0 Volume 41 0 Marcn 2000
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`613
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