1060
`
`Clinical Pharmacology
`
`Proceedings of ASCO Volume 20 2001
`
`GEIIEIIAI. POSTER, SAT. 8:00 AM - 12:00 PM
`419
`Photo I and Pinnnacolrinetic Study of ilPlt116258A, a Novel Texans Deriva-
`tive, Administered intravenously over l Hour Every 3 weeks. A. D. Goetz, L. J.
`Denis, E. K. Rowinsliy, L. Ochoa, K. Molpus, B. Deblonde, D. Semrand, M.
`Besenval, A. W. Talcher; Institute forDrugDevelopmenf, San Antonio, TX,-
`Avenris Pharma, Washington DC
`is a weak
`RPR116258A, a semisynthetic and potent taxane derivative,
`substrate for P-glycoprotein and able to cross the blood brain barrier. These
`features confer broad antitumor activity in tumor models, including mdr-1
`cell lines. This clinical phase I study evaluates the safety and pharmacoki-
`netic (PK) profile of RPR1 16258A administered as 1-hour infusion every 3
`weeks in minimally-pretreated patients (pts) with advanced cancer. No
`prophylactic antiemetics or treatmentto prevent hypersensitivity reactions
`were permitted at cycle 1. Fourteen pts (9 maiesls females; median age 64
`yrs [32—80]; median PS 0 [0-2]) have been enrolled and 49 treatment
`courses were evaluable at dose levels of 10 (3 pts), 15 (6 pts). 20 (3 pts)
`and 25 mg/m"’ (2 pts). The main toxicity was short-lasting neutropenia Gr 4
`in one patient at 25mg/m’ and Gr 3 diarrhea in patients at 15 (1 pt) and 25
`mg/m’ (1 pt) that was well controlled by loperamide. Minor Gr 1 or Gr 2
`toxicities included diarrhea (3 pts). fatigue (3 pts), nausea (3 pts). vomiting
`(2 pts). neutropenia (5 pts), thrombocytopenia (1 pt), and neurosensory
`disorders Gr 1 (1 pt). Neither hypersensitivity reactions or fluid accumula-
`tion has been observed. Plasma samples were obtained up to 72 his
`post~infusion of cycles 1 and 2 and showed a -three-phasic elimination
`profile. Preliminary mean (2 SD) PK parametersindicated a high total body
`clearance (CL) of 30.5 (: 1 1 .7) Llh/m’, a large volume of distribution (V,,_)
`of 1438 (£701) Urn? and a long wrminal half-life of 55 (t 29) hours.
`lntrapatient variability of CL over 2 cycles was low (25%). One unconfirmed
`partial tumor response has been reported in a TCC bladder cancer patient
`and minor responses have been reported in patients with prostate cancer
`( 1) and osteosarcoma (1). In conclusion, the novel taxane RPRl16258A is
`well tolerated at the studied dose levels up to 25 mg/m‘. Preliminary PK
`results indicate a long terminal half-life justifying the intermittent dosing
`schedule every 3 weeks.
`
`‘
`
`differences
`
`BENEIAL POSTER,SAT.8:wAM -12:00PM
`‘
`421* ’
`Afhlooland PharIacoiririn!c(|?K)3IIliyof’ihelloveiTaxanu BIS 104476
`Allrlnietororlaca I-llourinlravonoostllolullsion Weekly. M. Beeram, M.
`Hidolgo, G. Rodriguez, K. Molpus, R. Df,9"8i'W. A. Tortora, L Smrfh, C.
`Tarby, L. Ochoa, S. Choc, A. Tolcller, G. Gallant, E. Rowinsky; institute for
`Drw Development, Cancer Therapy and %erarch« Center; The University
`of Texas Health science Center at Saniflnionia. San Antonio, TX; Bristol-
`Myers-Squibb, Wallingford, CT
`BMS 184476 is :—a‘ novel tonne with greater potency and a broader
`speotrurn antiturnor activity than paclitaxei in preclinical. modes. Further-
`more, 'BMSLl84476 is more soluble in aqueorfifsoiutions than pacllltaxel,
`‘ requiring 6B%‘less Cremophor ELO, which zrnayrender shorter iv adminis-
`tration schedules more feasible and and/or decrease the requirement for
`prernedication to prevent hypersensitivity rea¢tio’ns.- The maximum toler-
`ated dose. (MTD) of BMS-184476 administered. asa 1-hour IV infusion
`awry 3
`'60 mg/m2. with an unacceptably high incidence of
`rnucositis, and diarrma at higher doses. Based’ on distinct
`torricologic profiles of the laxanaon weekly schedules,
`flltritehavlor of Bills 184476 administered as a 1-hour
`W infusionion arruninterruptod weekly schedule is beingrevaluated. To
`date, 24 patients (median -age, 56, median ECOG PS - 1) have received 63
`three-week courses of BMSr18i)4'l6 at doses of 20, 25, 30, 35, and 40
`mg/m2.wee’kiy. Doseeiimitingtoxicity (DL‘l'),consisting.of grade 4 noutrope-
`nia with-feveril pt)
`bmlonoad neutropenia requiring a treotmentdelay
`exceeding 2 mltsil
`occurred in 1 heavily-pretreated (HP) and »1
`rnioimally—pretreated(MP):pt—at the 40 mg/m2 doseierrel. in addition. 1 of
`8 pts treated at thI.35.mym2 dose level developedigrade 3 diarrhea
`associated with dehydration and syncope. MP and HP pts are currently
`being treated at the 40 and 35, mg/m2. dose levels respectively. Prelimi-
`nary PK parameters determined in _Iitlpatienistrea_ted at dose levels of 20-
`35 mg/m2-revealed a .
`ionai. increment in Crnair and AUCO-24 that
`ranged from 3429 .-1054 l'l‘b1[flfld from 867 nM.h to 1458 nM.h. Meant
`1/2. Cl, and Vssrarrged
`31.3to~51.5 hours; 167 to 349 mil minl m2;
`and 514 to 744 l.‘fm2 respectively. These results indicate that EMS-
`184476 administered on weekly. IV schedule is well tolerated. At the 35 &
`40 mgIrn2 dose levels, which are projected to be the MTDs for HP and MP
`pts. respectively, the dose intensity is 1.75 and 2-fold higher than the MTD
`on the every 3-week schedule, but further studies are required to determine
`the clinical significance of this observation.
`
`GENERAL POSTER, SAT, 8:00 AM - 12:00
`420
`Phase I clinical and Plrarrnacokinotio (PK) Trial of the iiovol Tug
`IMS-184473 Administered as a I-Hour lV Infusion in combination mg
`clspiatin Every 21 Days. M. L. Gallagher. J. P. Stevenson, W. Sun,
`Vaughn, S. M. Hahn, D. G. Heller, R. Flrller, C. Tarby, D. Sannichsen
`Nason, G. Gallant, P. J, 0'Dwyer; University of Pennsylvania, Philadel
`PA; Bristol-Myers Squibb, Princeton, NJ; University of Pennsylamv&
`Philadelphia, PA
`BMS-184476 is a 7-methylthiomethyl ether derivative of paclitaxel th
`?
`displays in vitro potency at nM concentrations against paclitaxel-resi
`human tumor cell lines with MDR mediated by P-glycoprotein and alteggg”
`tubulin, and exhibits efficacy superior to paclitaxel against human to ’ *
`xenografts, producing significantly greater cures. Given the known syn
`1
`between taxanes and cisplatin in vitro and their clinical activity,
`performed a phase I trial of BMS-184476 as a 1-hour IV infusion foliovq
`by cisplatin every 21 days. 24 patients with a range of solid tumors and
`good performance status have received 84 cycles of therapy. EMS dose hag,
`ranged from, 40 - 60 mym2 with cisplatin fixed at 75 mg/m2. At mg
`planned final dose level of BMS—184476 60 mg/m2 and cisplatin IQ
`mglmz we observed DLT in the form of Gr 3/4 diarrhea (2 pts), Gr 3 NN~(s
`pts) and Gr 4 neutropenia 5 days (1 pt). We subsequently instituted:
`prophylactic regimen of ondansetron, dexamethasone, metoclopraml
`‘
`and pm loperamide and observed no further DLT in 6 additional pts. Mild:
`moderate peripheral neuropathy (Gr 1/2, 4 pts) has been infrequent as
`alopecia. Clinical responses include 3 PRs imesothelioma, esophageal
`H+N ca). 2 MR (cholangioca. mesothelioma) and 4 SD. Preliminary cycle
`PK analyses reveal dose-proportional increases in plasma BMS-18447 ,
`Cmax and AUC valuesrdetailed below (SD). BMS-184476 60 mymz and
`cisplatln 75 mglmz are recommended for further evaluation on this
`schedule, using antiemetic prophylaxis. The lack of significant peripherii
`neuropathy allowed prolonged dosing in responding pts. Antitumor activity“
`was observed in range of tumor types, and BMS-184476 PK parameters
`were not significantly different from single-agent studies at similar doses
`Don
`AUC(24l'l)
`CH
`MM m
`,
`1732 (425)
`218(84)
`2375 (491)
`253 (69)
`2509 (52Z(
`275 (88)
`
`nw_r(n) vssiuma
`43(17)
`545(129)
`24 (3)
`327 (81)
`27 (10)
`409 (151)
`
`n
`5
`3
`
`CMAX(ngli‘nL)
`9l3($5)
`14% (217)
`1541 (474)
`
`cannon rosrni. SAT. 8:00AM —12=ooro
`422
`Phase I Study of BIS-188797. a flow Tulane Analog Administered Weekly I
`Patients with Advanced llalignancics. R. Advani, G. A. Fisher, ‘C. Jamba
`A. Yuen. C. Cho, 3. L. Lurrr, C. Tarby, 5. Cline, C. A. Bulanhagui, 6. Gallon
`B. I. Sikic; Stanford University Medical Center, Stanford, CA; Bristol-M ‘
`Squibb, Princeton. NJ
`BMS-188797 is-a noveltexane with superior activity in experimental to
`models compared tripaclitaxel. The main objective of this study was
`establish the maximum tolerated dose (MTD) and dose limiting toxiciti
`(DLT) of this agent given weekly on d. 1, 8, 15 every 21 d. as a 1 int
`infusion. Eighteen patients with advanced malignancies (median print
`regimens 2.5) were enrolled between 4/00 and 11/00. Tumor ty
`included: 4 ovarian. 3: lung, 2 colon, 2 GI stromal, 2 sarcoma and 5 othe
`Three dose levels were evaluated: 35 mg/m'*’ (n=3), 50 mglmz (n=9) a
`65 mg/m= (n=6). in 65 mglmz, are patients had DLTs (1 gr.4 neutropenw’
`7d and 2 gr. 3 diarrhea); hence the dose level of 50 mglmz was expanded
`a cohort of 9 pls. This dose of 50 mg/m2 is the MTD and was well tolerated
`with only 1/9 pts. experiencing a DLT (gr. 4 neutropenia with fever). Othfi
`transient gr. 2 side effects included nail changes (n=4). fatigue (n= ‘
`edema (n=3), nausea (n=3). diarrhea (n=2) and neuropathy (n=1).
`V
`patients are evaluable for response: 2 PR (ovarian 6+ mo, lung 4 + mo). :
`MR (lung 4+ mo, esophageal 3 + mo) and 2 SD (ovarian 6 mo. rectal.§
`mo). Allthe responders had previously received a paclitaxel containi
`V
`regimen. Plasma and urine pharrnacokinetic (PK) data are available for lg
`pts at 35 mg/ma (n-=3). 50 mg/m’ (n=5) and 65 mg/m2 (n=3). Meaiii
`values of CMAX and AUC (48 h) increased in a dose-related man
`individual T‘l2 values ranged from 11.9 to 25.9 h and individual
`values ranged from 84 to 192 um’. Complete PK data will be presented.
`conclusion, the MTD and the recommended phase ii dose of single age
`BMS-188797 is 50 mglmz. The drug demonstrates very encouragi
`antitumor activity. and is now being evaluated in combination ll.
`carbopiatin.
`~
`.
`“i
`
`AVENTIS EXHIBIT 2040
`Mylan v. Aventis
`
`AVENTIS EXHIBIT 2040
`Mylan v. Aventis
`IPR2016-00627
`
`1