Thirty-Fifth
`Annual Meeting of the
`American Society of Clinical Oncology
`May15-18, 1999
`Atlanta, Georgia
`Program/Proceedings
`
`
`
`Copyright 1999 American Society of Clinical Oncology
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`Sy y
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`Hospira v. Genentech
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`IPR2017-00805
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`Genentech Exhibit 2048
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`1
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`Proceedings of ASCO Volume 18 1999
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`CUNICAL PHARMACOLOGY
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`165a
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`*634
`
`*635
`
`Premedication Strategy for Weekly Paclitaxel Based on Experience with 1,608
`
`Infusions of 3- and 4-Week Paclitaxel. J. Quock, G. Dea, N. Lim, M. Tanaka,
`D. Gandara, D. Lau. University of California, Davis Cancer Center, Sacte-
`mento, CA.
`
`Phase | and Pharmacokinetic (PK) Study of irinotecan (CPT-11) in Cancer
`Patients (pts) with Hepatic Dysfunction. E. Raymond, L. Vernillet, V. Boige, A.
`Hua, M. Ducreux, S. Faivre, C. Jacques, M. Gatineau, D. Mignard, J.C.
`Vergniol, O. Rixe, J.P. Armand. Medecine Department, Institut Gustave-
`Roussy, Villejuif, Rhéne-Poulenc Rorer, France.
`Three enzymatic systems have been identified in CPT-11 biotransformation
`pathway: Carboxylesterases which convert CPT-11 into its active metabolite
`SN-38; UDP-GT which transforms SN-38 into glucuronide and CYP3A
`which metabolizes CPT-11 into APC and NPC. As these biotransformations
`are mainly located in liver, hepatic dysfunction could alter CPT-11 PK and
`may increase the risk of toxicity. Study aim was to determine maximal
`tolerated dose and to investigate CPT-11 PK in pts with fiver dysfunction.
`Pts groups(gr) were based oninitial total bilirubin level (Tbili): GrA ($1.0
`UNL) and B (>1.0 to =1.5 UNL) with 350 mg/m?starting dose given every
`3 weeks.
`In grC (>1.5 to $3.0 UNL), 3 dose levels were planned:
`175-240-350 mg/m2. Transaminase level was =20 UNL in all gr. Dose
`adjustments were performed in pts who experienced Tbili modifications or
`dose-limiting toxicity (DLT). Blood was sampled up to 24 h post infusion for
`PK evaluation. Twenty pts were treated (M/F: 14/6, median age: 53, PS
`0-2): 7 pts-26 cycles(cy), 2 pts-7 cy, 6 pts-12 cy and 5 pts-11 cy sofarin
`grA, B, Cat 175 andC at 240 mg/m?, respectively. DLTs observed at 1st cy:
`1/7 pts-grA (grade 4 febrile neutropenia-FNG4), 1/2 pts-grB (FNG4), 1/6
`pts-grC (FNG4) at 175 mg/m? and 3/5 pts-grC (grade 4 diarrhea-
`thrombocytopenia, FNG4) at 240 mg/m2. Preliminary PK parameters
`(mean + SD) obtained by a model-independent analysis from 13 pts-15 cy
`are shown below: (CL: Total body clearance; Vss: volume of distribution at
`steady-state;
`t1/2: Terminal half-life; MR: SN-38 AUC/CPT-11 AUC;
`*CPT-11; §SN-38).
`
`Paclitaxel is a commonly used anticancer drug, which requires premedica-
`tions of dexamethasone, diphenhydramine and cimetidine for prophylaxis
`of hypersensitivity reactions (HSR). With the adventof weeklypaclitaxel for
`radiation sensitization and for treatment of refractory breast and lung
`cancers, frequent premedication with high-dose dexamethaxoneis associ-
`ated with significant side-effects. We analyse our experience of HSR with
`paclitaxel administered every 3 to 4 weeks, and design a premedication
`strategy for weekly paclitaxel in order to minimize toxicity.
`In our institution over a period of 5 years, 358 patients received 1,608
`3-hour infusions of paclitaxel (135-225 mg/m2) given every 3 to 4 weeks.
`HSR were documented in 14 patients only during the first cycle of
`paclitaxel. Of these 14 patients, 11 were retreated with paclitaxel without
`additional HSR, 2 patients had recurrent HSR upon paclitaxel
`re-
`challenge, and 1 patient refused further treatment. These observations
`indicate that: 1. The incidence of HSRto first paclitaxel exposure is 3.9%,
`2. The incidence of recurrence HSR is 0.6% suggesting that 99.4% of
`patients will successfully receive paclitaxel, and 3.
`If no HSR has been
`encountered during first cycle, HSR unlikely will occur with subsequent
`cycles of paclitaxel.
`Based on these observations, premedication strategy has been designed for
`weekly paclitaxel. Prior to the first weekly dose of paclitaxel, all patients
`receive 10 mg dexamethasoneIV, 25 mg diphenhydramine IV and 300 mg
`cimetidine IV. If no HSR occurs, all premedications will be deleted for the
`subsequent weekly paclitaxel doses. For patients who have experienced
`AUC/
`AUC/
`HSR, 20 mg dexamethasone will be given PO 12 hr and 6 hr prior to
`Dose§
`CL*
`Dose*
`Dose
`re-challenge with paclitaxel 24 hr later. This strategy has been applied to
`14 patients who have received 56 one-hrinfusions of weekly pactitaxel at
`(mpi Cy (x1073 (L/h/Vss*=«t1/2*=(x10-3 t1/2§ MR
`
`
`
`
`
`
`
`
`
`
`Gr (h)—(%)=m?) nb-h/L) m2) (Lim?) (h) h/L) 90 mg/m? without premedications and have experienced no HSRto date.
`We concludethat this premedication strategy is feasible and cost-effective
`A
`3580
`7 45.24 12.22 77+ 65+ 075+ 1344182
`for patients receiving weekly paclitaxel.
`5.9
`2.0
`15
`1.1
`#040
`55
`1.2
`B 175-350 4 8194732 76+ 103+ 2.114 234+ 26+
`17.5
`0.2
`13
`2.5
`0.61
`165
`03
`90.14 7.024 71+ 95+ 2.95+ 20.2+3.2+
`35.1
`3.2
`23
`16
`245
`85
`1.6
`
`C 175-240 4
`
`These results show a high increase in systemic exposure to CPT-11
`(=80-100%) and SN-38 (=180-300%) in pts with liver dysfunction, even
`for slight hyperbilirubinemia as observed in gr B. This overexposure to
`CPT-11 and SN-38 may have contributed to the appearanceof DLTsin gr C
`at 240 mg/m?as well as in gr B forpt treated at 350 mg/m. Recommended
`dose of CPT-11 is currently refined for gr B and C. Based on PK andtoxicity
`data, pts with Tbili >3.0 UNL are now investigated at a 100 mg/m? starting
`dose.
`
`*636
`
`Reinduction of Response with Weekly Taxol(T) in Advanced Breast Cancer
`(ABC), Alvarez AM; Mickiewicz E; Brosio C; Giglio R; Cinat G; Rodger J,
`Nicolas C. Instituto de Oncologia Angel H. Roffo, Universidad de Buenos
`Aires, Argentina.
`Objective: There are many examples in which responsesare re-induced in
`metastatic disease, such as: Anthracyclines in breast cancer and piatinum
`based chemotherapy for testicular or ovarian cancer and it was proven
`useful to induce or reinduce responses in different pathology (ASCO 17
`726-1998). T at 80 mg/m2 weekly can be safely administered (ASCO 15
`383-1996) with minimaltoxicity. Therefore, we selected this schedule in
`order to: A) re-induce response in patients (pts) who had relapsed after
`responding to the q/21 days T schedule b) induce response in pts. With
`stable disease c) induce response in pts progressing during treatment.
`Methods: Between July 95 and August 98 35 pts with (ABC), who had
`received 200 mg/m2 of T q/21 days were included. Median age: (range
`32-75). Sixteen T responding pts (CR: 3 and PR 13) Group A, were crossed
`to weekly T at progression. Thirteen pts were stable (Group B). 6 progressed
`during q/21 days T treatment (Group C). All pts were treated with weekly T
`100 mg/m2 for a maximum of 24 weeks (W). This was the secondline of
`treatment for 11 pts, third for 12 pts and fourth for 12 pts. All pts were
`evaluable for toxicity and response. Results: CR 6/35 (17.1%); PR 13/35
`(37.1%); Overall responses: 19/35 (54.2%); NC 10/35 (28.5%); P 6/35
`(17.1%). 13 pts in group A (81.2%) responded: 3 achieved a CR again and
`1/13 PR became a CR. 9 PR had a PR again, 2 NC and 1 P. Patients that
`had more than 6 monthsof time to progression where more likely to respond
`again. 6 pts in group B (46.1%) responded, 2 pts achieved CR; 4 pts PR; 1
`P and 6 NC. !n group C 2 pts (33.3%) responded as PR and 2 NC. Response
`duration for pts with CR: 17, 10, 9+, 7,6+ and 6; with PR between 10 and
`2+ months. Toxicity: Was mild to moderate. Conclusions: 1) WT schedule
`was useful to reinduce response in 13/16 (81.2%) of previous responding
`pts 2) It was possible to induce responsein 6/13 (46.1%) of stable disease
`and in 2/6 (33.3%) pts that had never responded to q21/daysT.
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`2
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