Program/proceedings / AmE:rican
`Society of Cli
`v 19 (May 20-23 2000)
`General Collection
`W1 AM785MG
`Received: 11-18-2000
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`
`NOVARTIS EXHIBIT 2058
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 3
`
`

`

`Editor: Michael C. Perry, MD
`Associate Editor: Clay M. Anderson, MD
`
`ASCO Education and Training Department:
`Director: Michele K. Dinkel
`Assistant Director: Laura K. Ulepic
`ASCO Publications:
`Managing Editor and Senior Director: Deborah Whippen
`Special Projects Coordinator: Nicole Johnson
`Editorial Assistant: Nathan Grace
`
`The American Society of Clinical Oncology Program/Proceedings (ISBN 0-9664495-4-1) is
`published by the American Society of Clinical Oncology, Alexandria, VA 22314. The 2000
`issue is produced and printed by Lippincott Williams & Wilkins, 351 West Camden Street,
`Baltimore, MD 21201-2436.
`
`Editorial correspondence and production questions should be addressed to American
`Society of Clinical Oncology Program/ Proceedings, American Society of Clinical Oncology
`Publications Department, 850 Boylston Street, Chestnut Hill, MA 02467. Telephone:
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`
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`Copyright© 2000, 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
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`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 of 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 Medical Support Systems, Cambridge,
`MA. Composition services and print production provided by Lippincott Williams & Wilkins,
`Baltimore, MD, and Cadmus Professional Services, Linthicum, MD.
`
`Copyright 2000 American Society of\GhimcalvOoottrogy.
`at the N LM and may ti<=
`S.Ubject US Copyright L,nvs
`
`
`
`NOVARTIS EXHIBIT 2058
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 3
`
`

`

`Proceedings of ASCO Volume 19 2000
`
`Clinical Pharmacology
`
`187a
`
`*725
`Carboplatin Dosing in Obese Patients. P. R. Hutson, K. D. Tutsch, M.
`Pomplun, H. I. Robins, C. L. Tiggelaar, D. 8. Albert,, C. A. Feierabend, N.
`Rieck, R. Arzoomanian, G. Wilding; UW Sch of Pharmacy, Madison, WI;
`UWCCC, Madison, WI
`The Calvert or Chatelut equations are commonly used to estimate carbopla(cid:173)
`tin clearance and thus the dose needed to establish a target AUC. The
`accuracy of sequentially using the Cockroft-Gault (CG) and Calvert equa(cid:173)
`tions to respectively estimate creatinine (Cler) and carboplatin clearance in
`obese patients was retrospectively examined in two Phase I trials of
`carboplatin combined with thymidine (THY) and with hyperthermia (WBH).
`Neither THY or WBH affected carboplatin pharmacokinetics. Unbound
`carboplatin AUC was measured by atomic absorption spectrometry in 59
`subjects receiving an average of 390 mg/m 2 carboplatin (range 100-576
`mg/m 2 ) with an average body mass index of 26.6 kg/m 2 (range 17.9-40.4;
`values > 25 are considered obese). Ideal body weight was estimated as
`(50kg male : 45kg female) + 2.3kg * (Height (inches)-60). The effects of
`various weight adjustments for CG/Calvert or Chatelut equations are shown
`in the following table. Prediction bias was measured as mean prediction
`error (MPE) = (calculated AUC_- l!)easured AUC). Accuracy was measured
`using root mean squared predIctIon error (RMSE). Minimization of both
`parameters to zero is optimal:
`
`Weight used In Equation
`
`CG/Calvert
`
`Chatelut
`
`Actual Wt (ABW)
`
`Ideal Wt (IBW)
`
`Ideal + 40% Fat
`
`Mean (ABW & IBW)
`
`Measured Cler
`
`MPE
`
`0.36
`
`1.18
`
`0.79
`
`0.70
`
`0.12
`
`RSME
`
`1.44
`
`1.98
`
`1.61
`
`1.55
`
`1.41
`
`MPE
`
`-2.85
`
`-0.82
`
`-1.18
`
`-1.25
`
`n/a
`
`RSME
`
`3.62
`
`2.42
`
`2.50
`
`2.53
`
`n/a
`
`Conclusion: Carboplatin AUC-targeted dosing using the Calvert equation in
`obese patients can use actual weight, even for very obese patients; no
`substantive improvement is obtained by using lean weight or intermediate
`values. Use of ideal or lean weight appears to optimize the Chatelut
`equation. Supported by NIH U01-CA62491 and GCRC grant M01-
`RR03186.
`
`*727
`Identification of Biochemical Parameters That Predict the Onset of Severe
`Toxicities in Patients Treated with ET-743. J. G6mez, L. L6pez Lazaro, C.
`Guzman, A. Gonzalez, J. L. Misset, C. Twelves, A. Bowman, K. Hoekman,
`M. Villalona, D. Ryan, L. Paz-Ares, J. Jimeno; Pharma Mar S A, Madrid,
`Spain; ET 743 Phase I group
`ET-743 is a novel marine compound that is under active phase II
`development.The potential limiting toxicities, pancytopenia-fatigue, at the
`proposed recommended dose (RD) have been consistently characterized.
`However 6/331 patients (l.81 %; 95%CI: 0.67%-3.90%) treated with
`ET-743 have developed severe or multiorgan toxicities (MOT) including
`long lasting pancytopenia, renal and hepatic failure and rhabdomyolysis;
`three out of those six cases died. Therefore full clinical and pharmacoki(cid:173)
`netic (PK) data from 93 phase I patients treated at the RD or at the maximal
`tolerable dose among five phase I trials have been included in a multivari(cid:173)
`ate analysis to identify factors that can anticipate the onset of MOT in order
`to improve patients safety. Results: Patients with intercycle peaks (IPK) of
`alkaline phosphatase (ALP) above normal values (NV), median apex
`intercycle day=15, in a given cycle had a high risk of severe or MOT in the
`following cycle than those without ALP-I PK: 24% vs. 4. 7% (p<0.001). In
`addition data from 108 cycles were included in a stepwise logistic
`regression model. The following variables remained as the main predictors
`of severe or MOT: ALP-I PK> 1.1 NV p=0.0134, cycle baseline bilirubin >
`0.6 NV p=0.0042 and AST-IPK > 5 NV p=0.0193.0ther clinical,
`demographic and laboratory variables were not statistically significant.
`Moreover, an AUC > 70 h.mcg/I correlates to both severe or MOT and
`ALP-I PK, raising the possibility that intercycle peaks of ALP are a marker of
`subclinical cholangitis yielding to decreased elimination of ET-743.
`Conclusions: these findings indicate the need to monitor the biliary
`biochemistry (bib) at entry and during the intercycle period, performing one
`bib test within intercycle days 14-17. Patients with normal bib at baseline
`can be safely treated with the proposed RD of 1500 mcg/m2. A dose
`reduction to 1200 mcg/m2 is mandatory in case of ALP-I PK. A prospective
`identification of the RD in patients with impaired bib is warranted.
`
`*726
`CCl-779, a Rapamycin Analog and Multifaceted Inhibitor of Signal Transduc(cid:173)
`tion: a Phase I Study. M. Hidalgo, E. Rowinsky, C. Erlichman, R. Drengler,
`8. Marshall, A. Adjei, L. Hammond, L. Speicher, E. Galanis, T. Edwards,
`J. Boni, G. Dukart, J. Buckner, A. Tolcher; Institute for Drug Development,
`San Antonio, TX; Mayo Clin, Rochester, MN; Wyeth-Ayerst, Radnor, PA
`CCl-779, an ester analog of rapamycin which is being developed for cancer
`therapy, inhibits the transduction of several critical proliferative signals.
`CCl-779 binds to FKBP-12 intracellularly, forming a complex that inhibits
`the kinase activity of mammalian target of rapamycin (mTOR). This action
`interferes with key signal transduction pathways, including those regulated
`by the p70s6 kinase and PHAS-I protein resulting in the inefficient
`translation of proteins involved in cell cycle progression and produces cell
`cycle arrest at the G 1-S boundary. CCl-779 demonstrated growth inhibitory
`properties in preclinical models. This study is evaluating the feasibility,
`pharmacokinetics (PK) and biological effects of escalating doses of
`CCl-779 administered as a 30-minute IV infusion daily x 5 every 2 weeks as
`a single agent in patients (pts) with solid neoplasms. To date, 35 pis have
`received 167 courses (median 4, range 1-12) at doses ranging from
`0. 75-11.3 mg/m2/d. Isolated, asymptomatic, grade 3 hypocalcemia at the
`2.16 mg/m2/d dose level has been the only dose-limiting toxicity noted to
`date. Other generally mild-moderate toxicities noted, some over a broad
`dose range, are neutropenia, thrombocytopenia, rash, mucositis, hypertri(cid:173)
`glyceridemia, and allergic phenomena. In 17 pis receiving doses of 0.75 to
`3.12 mglm2/d, CCl-779 exhibited increasing peak concentrations with
`increasing dose, preferential red blood cell partitioning, and a median
`terminal half-life of 15.2 h. Lymphocyte subset and mitogen proliferation
`assays have not shown any consistent pattern, and it is projected that they
`will not be useful as pharmacodynamic surrogates. Minor antitumor
`responses and/or prolonged (> 4 months) stable disease have been noted
`in several drug-refractory cancers including: soft-tissue sarcoma (2), and
`cervical (1), uterine (1), non-small cell lung (1), and renal cell (4)
`carcinomas. CCl-779 dose escalation is ongoing. However, the tolerance
`and antitumor activity observed to date, associated with plasma concentra(cid:173)
`tions that portend biological activity in vitro, are encouraging.
`
`*728
`CCl-779, a Rapamycin Analog with Antitumor Activity: A Phase I Study Utilizing
`a Weekly Schedule. E. Raymond, J. Alexandre, H. Depenbrock, S. Mekhaldi
`E. Angevin, A. Hanauske, £. Baudin, 8. Escudier, J. Frisch, J. Boni, J'.
`Armand; Gustave-Roussy, Villejuif, France; Onkologische Tagesklinik,
`Munich, Germany; Wyeth Ayerst/Genetics Institute, Munich, Germany
`Background: CCl-779, an ester analog of rapamycin, inhibits the protein
`kinase mTOR and has antitumor activity in animal models. Patients (pts)
`and Methods. CCl-779 was given as a weekly 30 min infusion in pts with
`advanced solid tumors. Dose escalations were made using the modified
`CRM as a guide. Results. 16 pts (M/F: 11/5) were treated at the doses of
`7.5 (1 pt), 15 (2 pts), 22.5 (1 pt), 34 (3 pts), 45 (4 pts), 60 (1 pt), 80 (1
`pt), 110 (1 pt), 165 (1 pt), and 220 mg/m 2/w (1 pt). So far, no dose
`limiting toxicity was observed. Grade (Gr) 1-2 skin toxicity was observed
`without any evidence of relationship to dose: dryness with mild itching (7
`pts), eczema-like lesions (3 pts), sub-acute urticaria (1 pt), and aseptic
`folliculitis (10 pts). Skin biopsies from some patients with folliculitis
`showed superficial peri-capillar dermatitis. Five pts experienced reactiva(cid:173)
`tion of peri-oral herpes lesions. Grl-2 mucositis was observed in 9 pts. All
`pts receiving 2: 8 doses experienced Grl nails changes. Thrombocytopenia
`was observed in 3 pts treated at 34 (Gr3), 45 (Gr2) and 80 mg/m2/w (Grl),
`requiring treatment delay in 2 pts. Asymptomatic increases of triglyceride
`and cholesterol levels were observed in 8 and 4 pts, respectively. A
`reversible decrease in testosterone associated with increased levels of LH
`and FSH were observed in 5/6 men receiving more than 4 doses at
`Immunological analysis of blood showed no
`dosages 2: 15mg/m2/w.
`immunosuppression. Pharmacokinetic analysis in blood from 12 pts
`and AUC
`receiving up to the 60 mg/m 2/dose indicates an increasing of C
`of CCl-779 with increasing dose, a median half-life of 17 .3 h.'~•~d a mean
`clearance of 22Uh. 15 pis were evaluable for efficacy: 1 partial response in
`a pt with a IL2-IFNa resistant metastatic renal cell carcinoma treated with
`15 mg/m2/w and 6 pts with disease stabilization ranging from 12%
`increase to 39% decrease of the tumor size in pts with bulky disease (2
`renal carcinoma, 1 neuroendocrine tumor of the lung, 2 soft tissue
`sarcomas, 1 rectal, 1 adrenal cortical carcinoma, 1 melanoma). Conclu(cid:173)
`sion. Current data show that CCl-779, a drug with a unique mechanism of
`action, has antitumor activity and mild toxicity at doses above 15 mg/m 2/w.
`
`Th is mate,ria I was rn,pcied
`at tlhe N UM a,nd may b>e
`s,uibject US Co,pyright Laws
`
`NOVARTIS EXHIBIT 2058
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 3
`
`