Sandoz Inc.
`Exhibit 1016-0001
`
`Teva – Fresenius
`Exhibit 1016-00001
`
`

`
`558a
`
`TUMOR BIOLOGY/HUMAN GENETICS
`
`Proceedings of ASCOVolume 17 1998
`
`"2138
`PROPHYLACTIG MASTECTOMY (PM) AND OOpHOREGTOMY (PO) IN WOMEN
`UNDERGOING BRCAI/2 TESTING. D. Schrag, K.J. Kalkbrenner, T.L. Light,
`K.A. Schneider, J.E. Garber. Dana FarberCancer institute, Boston, MA.
`Women tested for BRCAI/2 mutations may consider PM and/or PO based
`on the results of genetic testing for predisposing mutations. A cohort of 88
`women with at least 10% risk of inherited breast/ovarian cancer provided
`information about altitudes towards PM and PO before testing and again at
`mean 5.5 months following results disclosure. 46 women had prior
`breesffovarian cancer (CA); 42 women had .not had cancer (NC). Before
`genetic testing, 8 women had had PM, 12 PO and 5 therapeutic
`oophorectomy. At baseline, 37/80 had discussed PM with a physician and
`33/71 had discussed PO 8/80 were considering PM and 24/71 PO.
`Following BRCAdisclosure, 6 women underwent PM (3 CA, 3 NC) and 5
`had PO (2 CA, 3 NC); one woman (NC) had both procedures. Mutations
`were identified in all women having prophylactic surgery following results
`disclosure except for 2 who had PM with indeterminate results but
`abnormal breast biopsies. In addition, 13 were still considering PM (8+,
`4?) and 19 were considering PO (12+, 6?, 1-) For the entire cohort, no
`cancers have been detected at PM; one borderline ovarian cancer was
`found at PO. PM and PO are often considered by women who have BRCAI/2
`mutation testing even with indeterminate test results.
`
`"2140
`PHASE I CHEMOPREVENTION CLINICAL, TRIAL OF CURCUMIN A.L. Cheng, J.K.
`Lin, M.M. Hsu, T.S. Shen, J. Y Ko, J. T. Lin, B.J. Lin, M.S. Wu, H.S. yu, S.H.
`Jee, G.S. Chen, T.M. Chen, C.A. Chen, M.K. Lai, Y.S. Pu, M.H. Pan, Y.J.
`Wang, C.C. Tsai, C.Y Hsieh. National Taiwan University College of Medi,
`cine, Taipei, Taiwan; and Kaohsiung Medical College, Kaohsiung, Taiwan.
`Curcumin (diferuloylmethane), a yellow substance from the root of the
`plant Curcuma Ionga Linn., has been demonstrated to inhibit murine
`carcinogenesis of skin, stomach, intestine and oral cavity. A phase-I clinical
`trial was conducted to examine the toxicology, the pharmacokinetics and
`the biologically effective dose of curcumin in humans. Five types of
`high-risk individual were eligible: 1. recently-resected urinary bladder
`cancer (BC), 2. arsenic Bowen’s disease (BD), 3. uterine cervical intraepi-
`thelial neoplasia (CIN), 4. oral leukoplakia (OL), and 5. intestinal metapla-
`sia of gastric muces..a (IM). The starting dose was 500 rag/day, taken orally
`for 3 months. If no any >-- Grade II toxicity was noted in at least 3 p’ts, the
`dose was escalated successively to 1000 (level I1), 2000 (level 111), 4000
`(level IV), and 8000 rag/day (level V). Lesion sites were biopsied before and
`3 months after taking curcumin. Serum curcumin was quantitated by HPLC
`method. In a total of 25 p’ts enrolled, no treatment-related toxicity was
`noted up to 8000 mg/day (level V). Serum concentration usually peaked at
`1 to 2 hours after oral intake, and gradually declined within 12 hours. The
`average peak serum concentrations after taking 4000 rag, 6000 mg and
`8000 mg of curcumin were 0.41 ___ 0.07 I~M, 0.57 + 0.05 I~M, and
`1.75 -+ 0.80 I~M, respectively. Although 3 of 25 p’ts proceeded to develop
`frank malignancies, histological improvement of the precancerous lesions
`was seen in 1 (level Ill)of the 2 p’ts with BC, 2 (both level IV)of 7 p’ts with
`OL, ! (level II) of 6 p’ts with IM, 1 (level I) of 4 p’ts with CIN, and 2 (level I
`and III) of 6 p’ts with BD. Although curcumin is probably non-toxic even up
`to more than 8000 rag/day, the bulky volume of dCug tablets became a
`limiting factor itself. Therefore, for future phase 11 studies, doses close to
`8000 rag/day may be recommended.
`
`"2139
`LY231514 (MTA): RELATIONSHIP OF VITAMIN METABOLITE PROFILE TO TOXIC-
`flY. C. Niyikiza, J. Walling, D. Thornton, D. Seitz, and R. Allen. Eli Lilly and
`Company, Indianapolis, IN, and Univ of Colorado Health Science Center,
`Denver, CO.
`LY231514 (MTA) is a new generation multitargeted antifolate antimetabo-
`lite with inhibitory activity against thymidylate synth~se, dihydrofolate
`reductase and glycinamide ribonucleotide formyl transferase. Of a total of
`246 patients (pts) in phase !1 trials treated with MTA (600 mg/m2 IV over
`10 minutes once every 21 days) 118 pts also had vitamin metabolites
`measured. Because earlier studies with other antifolates had suggested
`that nutritional status may play a role in the likelihood that a patient will
`experience severe toxicity, levels of the vitamin metabolites homocysteine,
`cystathionine and methylmalonic acid were measured at baseline and once
`each cycle thereafter. A multivariate statistical analysis of the data was
`conducted in order to determine which among a set of pre-specified
`predictors (creatinine clearance, albumin levels, liver enzyme levels, and
`vitamin metabolites) might correlate with toxicity. There was a strong
`correlation between baseline homocysteine levels and the development of
`the following toxicities at any time during the study: CTC Grade 4
`neutropenia (57 pts, p < 0.0001), Grade 4 thrombocytopenia (13 pts,
`p < 0.0001), Grade 3 or 4 mucositis (8 pts, p < 0.0003), and Grade 3 or
`4 diarrhea (8 pts, p < 0.004). Cystathionin.e levels did not correlate with
`hematologic toxicity or mucositis but were moderately correlated with
`fatigue (p < 0.04). Maximum cystathionine levels doubled from baseline
`during treatment with MTA. No correlation between toxicity (CTC Grades as
`defined above) and the remaining pre-specified predictors was seen.
`Toxicity was seen in all patients with homocysteine levels above a threshold
`concentration of 10 I~M. A correlation over time between homocysteine
`levels and CTC Grade 4 neutropenia and thrombocytopenia and CTC Grade
`3 or 4 mucositis was also observed, but only in the first two cycles of
`treatment. Maximum homocysteine levels did not appear to change from
`baseline during treatment with MTA.
`
`"2141
`
`FACTORS INFLUENCING THE DECISION TO UNDERGO BRCAI/2 GENE TESTING: A
`STUDY OF ASHKENAZI JEWISH WOMEN WITH A PERSONAL HISTORY OF BREAST
`CANCER (BC), ENROLLED IN AN ONTARIO CANCER GENETICS NETWORK
`PROTOCOL, K.A. Phillips, J. Hunter, E. Warner, W. Meschino, G. Glendon,
`hL. Andrulis and P.J. Goodwin. Mt Sinai Hospital, Princess Margaret
`Hospital, Toronto-Sunnybrook Regional Cancer Center, North York General
`Hospital, Toronto, Ontario, Canada.
`
`The purpose of this study was to examine the contribution of demographic,
`medical, psychosocial, and cultural/religious factors in decision making
`regarding testing for BRCA1 and BRCA2 mutations, in Canadian Jewish
`women with 8C, unselected for family history. A self-administered question-
`naire was developed and distributed, (after genetic counseling), to 134
`individuals enrolled in a research-based testing program for Ashkenazi
`women. Data for the first 52 participants are presented. The response rate
`was 40 (77%). Respondents had the following demographic features: age
`40-75 years (median = 59), married 83%, had children 92%, post-
`secondary education 55%, practicing Jew 88%, extra health insurance
`77%, media[~ age of BC diagnosis = 50. No patient had ovarian cancer
`(OC). 45% had at least one 1st degree relative with BC or OC (median
`perceived risk for being a gene carrier 50%). 35% had no affected relatives
`(median perceived ri&k for being a carrier = 15%). The 5 factors most
`frequently identified as "definitely an important factor in my decision
`making" were, desire to contribute to research (90%), curiosity (77%),
`potential benefit to other family members (64%), potential for personal
`cancer prevention (59%), and impact on ovarian cancer screening practice
`(41%). 53% and 38% of women respectively, identified a potential change
`in their perspective on prophylactic oophorectomy and mastectomy as at
`least "somewhat important." Main concerns related to insurance discrimi-
`nation (35%), confidentiality (30%), accuracy and interpretability of
`results (33%), potential impact on marriage prospects for family members
`(20%),. and focus on the Jewish community (15%). Potential employer
`discrimination and impact on life planning were "not a factor" for most
`(90%,82%). The focus on factors unrelated to personal physical health is
`notable. The generalisability of these results to women not affected by 8C
`requires further study. Final results for the 134 patients will be presented.
`
`Sandoz Inc.
`Exhibit 1016-0002
`
`Teva – Fresenius
`Exhibit 1016-00002