Supplement to
`linical
`Cancer
`Research
`
`An Official Journal
`of the
`American Association
`for
`Cancer Research
`
`-
`v.6 n.ll suppl.
`p.4467s-4598s 2000
`
`~
`
`Health Serials
`
`November 2000 • Volume 6 • Supplement
`PP. 4467s-4597s • ISSN 1078-0432
`
`AVENTIS EXHIBIT 2147
`Mylan v. Aventis, IPR2016-00712
`
`CabRef0002894
`
`

`
`Clinical Cancer Research - Volume 6 - November 2000 (Supplement)
`
`Poster session 24
`
`45795
`
`limiting in animals, but the CNS toxicity could be avoided by slowly infusing the
`compound, thereby avoiding peak plasma levels. The current clinical study
`investigates the feasibility of a weekly 3 hour infusional schedule. The starting
`dose of 110 mg/m2 was determined from an ongoing q 3 week study. Sixteen
`patients with the following characteristics (range) have been treated at dose
`levels of 110, 220, 330, 385 and 440 mg/m2: 10 males, 6 females, median age
`61 (30 - 83), median number of prior chemotherapeutic regimens 2 (2 -12). One
`patient treated with a hepatocellular carcinoma (HCC) at 110 mg/m2 who had
`progressed through prior doxorubicin, gemcitabine + 5FU, and an experimental
`pyrimidine antimetabolite, had a durable (9+ months) PR concomitant with
`symptomatic improvement. At 440 mg/m2, 2 patients had DLTs: a neutrophil
`count that failed to return to 1000/mm 3 on the day of planned dosing resulting
`in a dose omission and CTC grade 3 reversible ataxia. The recommended phase
`II dose is being defined in two groups of patients: HCC and non-HCC. Treat(cid:173)
`ment in HCC patients has been limited by mild reversible thrombocytopenia and
`the current dose is 220 mg/m2. In the non-HCC group, at doses below 440
`mg/m2, no acute CNS toxicity has been seen and the current dose level is 385
`mg/m2. Toxicities include neutropenia, diarrhea, fatigue and peripheral neurop(cid:173)
`athy. Pharmacokinetics are linear up to 330 mg/m2. Data are available for 16
`patients to date (±SD): clearance = 1.11 (0.26) L/h/kg, Vdss = 0.39 (O.17) Ukg,
`apparent terminal half-life = 0.52 (O.24) h. Patients with HCC have a trend
`towards lower clearance, but this is not statistically significant. Conclusion: the
`weekly schedule of T138067 has been well tolerated, with evidence of activity,
`and is therefore recommended for evaluation in phase II.
`
`565 Phase I and pharmacokinetic study of T138067, a synthetic micro(cid:173)
`tubule depolymerizing agent, administered as a 3-hour infusion daily x 5
`every 3 weeks. Schwartz G, Rowinsky EK, O'Dwyer P, Olivo N, Wright M,
`Walling J, Stevenson J. Brooke Army Medical Center, Cancer Therapy and
`Research Center, San Antonio TX, University of Pennsylvania, PA and Tularik
`Inc., South San Francisco, CA.
`T138067 (2-fluoro-1-methoxy-4-[pentafluorophenylsuphonamide]benzene) is
`a novel microtubule inhibitor which covalently binds to 13 tubulin,
`inducing
`depolymerization and apoptosis of cells. Preclinical studies have demonstrated
`that T138067 has activity superior to paclitaxel in MDR overexpressing cell lines
`and xenografts. The compound undergoes rapid elimination via hepatic metab(cid:173)
`olism. In dogs myelosuppression and stomatitis were dose limiting, and in mice
`dose limiting acute CNS toxicity was related to C max. A daily x 5 schedule was
`chosen for clinical evaluation given the short plasma half life and the short half
`life of the T138067 adduct bound to tubulin (10 to 24 hours). To date 8 patients
`(pts): 5 males and 3 females, median age 61 years (range 44 to 77), colorectal
`4 pts, hepatocellular carcinoma 1 pt, renal cell carcinoma 1 pt, gastric stromal
`1pt, have been treated at 3 dose levels (44 mg/m2 5 cycles; 88 mg/m2, 6 cycles;
`175 mg/m2 3 cycles). Treatment has been well tolerated (1 pt with CTC grade
`[G] 1 leukopenia, 1 pt with G2 anemia and 1 pt with G1 thrombocytopenia).
`Pharmacokinetic data are available for 6 patients treated at the 44 and 88
`mg/m2dose levels (SD): clearance = 49.3 (13.5) Uh/m2, Vdss = 15.4 (4.6) Um 2
`,
`apparent terminal half life = 0.3 (O.03) h. No accumulation of T138067 has been
`observed and exposure remains consistent over the 5 days of treatment.
`Accrual of patients in this study continues.
`
`566 Phase I and pharmacokinetic study of BMS-188797, a new taxane
`analog, given every three weeks in patients with advanced malignancies.
`Sullivan DM,' Rago R', Ruckdeschel JC', Dellaportas AM', Mahany JJ', Lush
`RM', Dalton WS', Bulanhagui C,2 Gupta E,2 Tarby C,2 Sonnichsen D,2
`Gustafson N,2 Gallant G.2 'H. Lee Moffitt Cancer Center, Tampa FL, USA.
`2Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton NJ and
`Wallingford CT, USA.
`BMS-188797 is one of several new taxane analogs being evaluated in
`phase I studies with superior activity in a experimental tumor models com(cid:173)
`pared to paclltaxel. The main objective of this study was to establish the
`maximum tolerated dose and the dose-limiting toxicities (DLTs) of BMS(cid:173)
`188797 given every 3 weeks by a 1-hour infusion. Patients (pts) were not
`premedicated. Fifty-one pts (13 renal cell, 11 NSCLC, 4 colon, 4 breast, and
`19 other) - 35 males and 17 females - with a median age of 58 years (range:
`20-77) were treated. Data is available for 41 pts with an ECOG performance
`status of 0 (21 pts), 1 (16 pts) or 2 (4 pts) having received from 0 to 5 prior
`chemotherapy regimens. Eleven pts had received prior taxane and 23 had
`received prior radiotherapy. The following dose levels were explored (# pts):
`3.75 (6), 7.5 (3), 15 (3), 30 (3), 60 (6), 80 (3), 110 (3), 150 (6),175 (5), 200
`mg/m2 (3). At 200 mg/m2, DLT consisting of febrile neutropenia. Drug(cid:173)
`related toxicities included neutropenia, nausea, vomiting, diarrhea, sensory
`neuropathy, arthralgia/myalgia and skin toxicity. No hypersensitivity reac(cid:173)
`tions were reported. Partial responses were cOnl,rmed in 4 pts (2-breast,
`1-renal cell, 1-NSCLC). The terminal half-life was approximately 28.3 hours
`and the average volume of distribution was approximately 164 Um 2
`• The
`CMAX and AUC (24h) values increased in a dose-related manner up to the
`110 mg/m2 dose level, beyond this level
`there were disproportional
`in(cid:173)
`creases in these parameters. BMS-188797 is a new taxane that can be
`safely administered in pts with advanced malignancies. Encouraging antitu(cid:173)
`mor activity has been seen in several pts. The recommended phase II dose
`of BMS-188797 is 175 mg/m2 (1-hour infusion) every 3 weeks.
`
`567 Phase I study of BMS-188797, a new taxane analog, given weekly in
`patients with advanced malignancies. Goldstein L,' Vaders L, Rogatko A,
`Bulanhagui C,2 Gupta E,2 Tarby C,2 Sonnichsen D,2 Gustafson N,2 Gallant G.2
`'Fox Chase Cancer Center, Philadelphia (PA), USA. 2Bristol-Myers Squibb
`Pharmaceutical Research Institute, Princeton (NJ) and Wallingford (CT), USA.
`BMS-188797 is a new taxane analog with superior activity in a number of
`experimental tumor models compared to paclitaxel. The main objective of this
`study was to establish the maximum tolerated dose (MTD) and the dose-limiting
`toxicities (DLTs) of BMS-188797 given weekly on day (d) 1, 8 and 15 every 21
`days (1-hour infusion) in patients (pts) with advanced malignancies. Initially, no
`premedication was given. An accelerated Phase I design using rapid dose
`escalation was used. When pre-defined toxicity was observed, an escalation
`with overdose control (EWOC) scheme was to be used. Eleven pts (3 breast, 2
`renal cell, 1 NSCLC, 1 sarcoma, 1 cervix, 1 endometrial, 1 adrenocortical and 1
`head & neck) - 7 females and 4 males - with a median age of 47 years (range:
`38-67) and an ECOG performance status 0 (9 pts) or 1 (2 pts) were enrolled. All
`pts had received prior chemotherapy (range: 1-5 regimens) and 7 had received
`prior radiotherapy. Data is summarized for 11 pts having received a median of
`2 courses (crs) (range: 1-7):
`
`Dose Level
`5 mg/m2
`20 mg/m2
`40 mg/m2
`80 mg/m2
`120 mg/m2
`123 mg/m2
`
`No. of
`pts
`1
`3
`2
`2
`2
`1
`
`No. of
`crs
`1
`10
`8
`3
`2
`3
`
`DLTs
`
`Delay for neutropenia (Grade 3) - 1 pt
`
`At 120 mg/m2, 1 pt developed a DLT (dose delay for neutropenia). EWOC
`escalation was then initiated. Other drug-related toxicities reported include:
`nausea, vomiting, diarrhea, sensory neuropathy, and myalgia. One grade 2
`hypersensitivity reaction was reported. Patients are now being premedicated.
`One breast cancer patient treated at a weekly dose of 20 mg/m2 reported a
`complete response. Plasma and urine pharmacokinetic data were obtained for
`all patients and will be presented. MTD has not been reached and the study is
`enrolling patients at 141 mg/m2.
`
`568 Phase I and pharmacokinetic study of RPR116258A, a novel taxane
`derivative, administered intravenously over 1 hour every 3 weeks. W
`Denis', EK Rowinsky" L Ochoa', D Hao', K Molpus', E Hooker2, D Semiond2,
`C Garay2, M Besenval2 and AW Tolcher'.
`'Cancer Therapy and Research
`Center, San Antonio, USA and 2Aventis Pharma USA/France.
`RPR116258A, a semisynthetic and potent taxane derivative, is a weak sub(cid:173)
`strate 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 pharmacokinetic (PI<)
`profile of RPR116258A administered as 1-hour infusion every 3 weeks in
`minimally-pretreated patients (pts) with advanced cancer. No prophylactic anti(cid:173)
`emetics or treatment to prevent hypersensitivity reactions were permitted at
`cycle 1. Prior taxanes use was also permitted.
`Eleven pts (7 males/4 females; median age 66 yrs [32-80]; median PS 0 [0-2])
`have been enrolled and 39 treatment courses were evaluable at dose levels of
`10 (3 pts), 15 (6 pts) and 20 mg/m2 (2 pts). The main toxicity was diarrhea Gr 3
`in 2 patients at 15mg/m2 that was controlled by loperamide. Minor Gr 1 or Gr 2
`toxicities included diarrhea (3 pts), fatigue (3 pts), nausea (3 pts), vomiting (2
`pts), neutropenia (3 pts), thrombocytopenia (1 pt), and neurosensory disorders
`Gr 1 (1 pt). Neither hypersensitivity reactions or fluid accumulation has been
`observed.
`Plasma samples were obtained up to 72 hrs post-infusion at cycle 1 and 2
`and showed a three-phasic elimination profile. Preliminary mean (± SD) PK
`parameters indicated a high total body clearance (CL) of 33 (±11) Uh/m2, a
`large volume of distribution 01sJ of 1260 (±720) Um 2 and a long terminal
`half-life of 44 (± 25) hours. Intrapatient variability of CL over 2 cycles was low
`(16%). One minor tumor response has been reported in one prostate cancer
`patient treated at 15 mg/m 2 .
`In conclusion, RPR116258A, a new taxane, is well tolerated at the studied
`dose levels. MTD is not yet reached. Preliminary PK results indicate a long
`terminal half-life justifying the intermittent dosing schedule every 3 weeks.
`
`569 Phase I and pharmacokinetics (PI<) study of RPR 116258A given as
`1-hour infusion in patients (pts) with advanced solid tumors. A Lortholary' ,
`JY Pierga2, R Delva', V Girre2, E Gamelin', A Terpereau2, G Crespel', P
`Pouillart2, H Fontaine3 , D Semiond3 , D Perard3 , M Besenval3 , V Dieras2. 'CPP,
`Angers, 21nstitut Curie, Paris, "Aventis Antony, France.
`RPR 116258A is a new taxoid with a broad spectrum of activity: activity on
`mdr-1 expressing tumor cells in vitro and against B16/TXT resistant melanoma
`and ability to cross blood brain barrier. This new compound was tested in phase
`I study using Simon's design 4B. The drug was administered as 1-hour infusion
`every 3 weeks, with a 5 mg Lv. dexchlorpheniramine premedication. The dose(cid:173)
`limiting toxicities (DLTs) were evaluated after cycle 1. PK samples were col-
`
`Proceedings of the 2000 NCl-EORTC-AACR Symposium
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`CabRef0002895
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`

`
`4580s
`
`Poster session 24
`
`Clinical Cancer Research e Volume 6 e November 2000 (Supplement)
`
`lected during the first 48 or 72 hours at cycle 1 and 2. 16 patients (10 males, 6
`females, median age: 52) were included, 15 treated in the dose escalation
`phase at 10 mg/m 2 (3 pts), 20 mg/m 2 (J pts), 30 mg/m2 (5 pts) and 1 pt at 25
`mg/m 2 to define the recommended dose (RD), with a total of 35 cycles (1-4).
`The maximum tolerated dose was reached at 30 mg/m2 at which 3 DLTs out of
`5 pts were observed: neutropenia Gr 4 > 5 days (2 pts)/ febrile neutropenia
`(1 pt). At the highest dose levels (20/30), the main other toxicities were: diarrhea
`(7 pts) of short duration (4 days) and controlled by loperamide. No cortical
`neurotoxicity was observed except 1 confusion Gr 2 resolved after interruption
`of concomitant treatment (antalgics, anxiolytics and omeprazole). One toxic
`death (septic shock with neutropenia Gr 4 despite prophylactic G-CSF) was
`observed after 3 cycles at 30 mg/m 2 in NSCLC pt. PK analysis showed a
`three-phasic elimination profile. Up to 25 mg/m2 , the drug had a high total body
`clearance (33-56 L/h/m"), a very large volume of distribution (500-2000 Um")
`and a long terminal half life (30-45h). One minor response (NSCLC) and 3 stable
`diseases (colon) were reported. Additional pts will be treated at 25 mg/m2 in
`order to establish the RD.
`
`570 Phase I study of Taxoprexin DHA-paclitaxel (TXP), a novel taxane
`with unique preclinical activity, toxicity profile, and pharmacology. AC
`Wolff', SD Baker', MK Bowling', MA Carducci', MO Bradley2, FH Anthony2, CS
`Swindell2
`, PA Witman 2
`, NL Webb2
`, and RC Donehower'. The Johns Hopkins
`Oncology Center', Baltimore, MD and Protarga, Inc2, Conshohocken, PA.
`TXP is a novel taxane consisting of docosahexaenoic acid (DHA), a natural
`fatty acid, covalently conjugated via an ester linkage to the 2'-OH position of
`paclitaxel (PAC). TXP lacks in vitro microtubule assembly activity, but arrests
`cells at the G2/M phase, presumably by intracellular conversion to PAC. TXP (at
`equimolar dose to the PAC maximum tolerated dose - MTD) showed activity
`equivalent to PAC against Ml09 lung carcinoma in syngeneic mice, but TXP
`MTD was 4.4 times higher than PAC MTD (molar basis) and more active than
`PAC at their MTDs. Increased TXP activity relative to PAC may be due to higher
`sustained PAC concentration following TXP administration. Phase I study ob(cid:173)
`jectives are to determine MTD, toxicity, PK profile of TXP administered as a 2-hr
`infusion every 21 days. To date, 18 pts (median age 62; 8 women) received 54
`cycles of TXP at 200 (4 cycles). 400 (10 cycles). 660 (18 cycles), 880 (11 cycles),
`and 1100 (11 cycles) mg/m 2 . In 6 patients treated at 1100 mg/m 2 (equivalent to
`PAC dose of 803 mg/m2), grade 3 and 4 neutropenia occurred in 2 of 11 (all
`cycle 1) and 6 of 11 (two in cycle 1) cycles, respectively. One grade 1 neuro(cid:173)
`toxicity was seen, but no alopecia. TXP plasma PK analysis during cycle 1
`revealed linear behavior and folloWing mean (SD) parameters: t1l2 = 27 (14) hrs,
`V" = 2.2 (O.98) L, CI = 1.4 (1.2) mUmin. TXP at 880 mg/m2 showed following
`mean (range) PAC exposures, which are less than 1% of TXP exposure: Cmax =
`0.17 (0.040) IJ.M; AUC = 3.2 (2.0) IJ.M'hr; time> 0.05 IJ.M = 21 (6-48) hrs. PAC
`exposure correlated with the degree of neutropenia. TXP may have more
`favorable PK and toxicity profile than PAC. MTD has yet to be determined.
`
`571 Phase I study of cremophor-free, protein-stabilized, nanoparticle
`formulation of paclitaxel (ABI-007) in solid tumors. Nuhad K. Ibrahim', Julie
`A Ellerhorst', Richard L. Theriault', Edgardo Rivera', Bita Esmaeli', Patrick
`Soon-Shiong 2 , Robert S. Benjamin', Gabriel N. Hortobagyi'. 'The University of
`Texas M. D. Anderson Cancer Center, Houston TX USA; 2American Pharma(cid:173)
`ceutical Partners Inc., Los Angeles, CA USA.
`The paclitaxel formulation utilizes a mixture of cremophor EUethanol, due to
`insolubility of paclitaxel. Cremophor has been associated with hypersensitivity
`reactions and may limit the maximum tolerated dose (MTD) of paclitaxel due to
`its own toxicity. The new cremophor-free ABI-007 might be used without
`premedication. To determine its MTD, a phase I study was conducted in
`patients (pts) with advanced solid tumors. Thirteen pts with metastatic breast
`cancer (MBC), and 6 pts with melanoma were treated with ABI-007 without
`premedication in a 30-minute infusion every 21 days. The starting dose was 135
`mg/m2 , and the total number of courses was 93, with the median (M) number
`delivered 5 (range [R], 1-11). M age was 50 years (R, 33-83). M performance
`status was 1 (R, 0-2); M number of prior chemotherapy regimens for the pts
`with MBC was 4 (R, 2-7) and for the pts with melanoma, 2.5 (R, 1-4). The MTD
`was 300 mg/m2 . There was one case of neutropenic fever due to skin infection.
`G3-4 non-hematologic toxicities were rare and included peripheral neuropathy
`5, perioral numbness 5, skin blisters 2, and polyuria/polydypsia 4. Reversible
`ocular toxicities included keratitis G3, 3 pts; blurred vision G 2, 2 pts; eye
`flashes Gl, 1 pt; and dry-eye syndrome Gl-2, 3 pts. No hypersensitivity
`reactions were seen. The dose-limiting toxicity was peripheral neuropathy and
`superficial keratitis. A phase II study of ABI-007 at 300 mg/m2 Q 21 days for
`MBC is in progress.
`
`572 Enhanced bioavailability of oral paclitaxel by valspodar (PSe 833),
`an inhibitor of small bowel P-glycoprotein and cytochrome P450. B. I. Sikic,
`R. Advani, G. A Fisher, J. Halsey, P. Cohen, and B. L. Lum. Division of
`Oncology, Stanford University, Stanford, California 94305; Novartis Pharmaceu(cid:173)
`ticals, Inc., East Hanover, New Jersey 07936.
`Inhibiting small
`intestinal P-glcoprotein (P-gp) by cyclosporine or valspodar
`(PSC) significantly enhances the bioavailability of paclitaxel (Ptx) in mice. Oral
`administration of Ptx would benefit patients by reducing cost, premedications,
`Cremophor exposure, and IV infusions. In this study, PSC and Ptx were co(cid:173)
`administered orally to increase the bioavailability of Ptx. Ten patients in Cohort
`1 received six weeks of treatment with Ptx given IV the first week and PO on
`
`weeks 2-6. PSC was administered on week 3 at 1 mg/kg and sequentially
`increased to 3, 5 and 5 mg/kg x 8 doses. Five patients in cohort 2 received 4
`sequential weeks of treatment with increasing doses of PSC. 15 patients have
`been entered. Toxicities have been mild with Gr. 1 nausea, Gr. 2 ataxia, Gr. 1/2
`arthralgias, and Gr. 1 diarrhea. In cohort 1, PSC increased the oral bioavailability
`of Ptx by 2- to 3-fold as measured by area-under-the-curve and durations of
`exposure to Ptx in plasma above 0.1 IJ.M and 0.05 IJ.M. Evidence of antitumor
`effects was seen in 4 patients. In cohort 2, bioavailability was not affected by
`increased PSC dosing. This may be due to Cremophor in the formulations of Ptx
`and PSC, leading to a rapid GI transit time. Mild diarrhea or loose stools were
`noted in several patients on the day of drug administration. The amount of
`Cremophor in cohort 2 ranged from 20 to 40 g (mL) per weekly dose. Future
`cohorts are assessing the effect of co-administration of loperamide 2 mg with
`Ptx and PSC to decrease bowel motility, as well as adding a second dose of Ptx
`and PSC 6 hours after the initial dose, to achieve similar durations of exposure
`to Ptx in plasma above 0.1 IJ.M and 0.05 IJ.M as for IV Ptx.
`
`573 Preclinical pharmacology of
`the epothilone B analog BMS(cid:173)
`247550 -an epothilone analog possessing potent activity against pacli(cid:173)
`taxel sensitive and resistant human tumors. Lee, Francis Y.F., Vite, Gregory
`D., Borzilleri, Robert M., Arico, Michele A, Clark, John L., Fager, Krista L., Kan,
`David, Kennedy, Kelly A, Kim, Andres S-H., Smykla, Richard A., Wen, Mei-Li,
`Kramer, Robert A. Oncology Drug Discovery, Bristol-Myers Squibb PRI,
`Princeton, NJ 08543.
`BMS-247550, a semi-synthetic analog of epothilone B, demonstrated signif(cid:173)
`icant improvement over paclitaxel
`in several critical aspects. BMS-247550 is
`active against human cancer models that are naturally insensitive to paclitaxel
`or have developed resistance to paclitaxel, both in cell culture systems in vitro
`and in human tumor xenografts grown in nude mice. BMS-247550 has the
`ability to overcome all major forms of paclitaxel resistance mechanisms includ(cid:173)
`ing the 170 kD P-glycoprotein-mediated multidrug resistance and tubulin mu(cid:173)
`tation. BMS-247550 exhibits a very broad spectrum of antitumor activity
`against paclitaxel-sensitive human tumor xenografts: A2780 (ovarian); HCTl16
`and LS174T (colorectal) as well as paclitaxel-resistant human tumors: HCTl16/
`VM46 (MDR resistant, colorectal); A2780Tax (ovarian, tubulin mutation); Pat-7
`(early passage xenograft from a patient who developed resistance to TAXOL~);
`Pat-21 (Breast, early passage xenograft from a patient who was refractory to
`TAXOL" + D-Verapamil combination therapy) and Panc-26 (early passage
`xenograft from a patient with metastatic pancreatic carcinoma). Pharmacoki(cid:173)
`netics-tumor response studies determined that the minimum effective plasma
`concentration in nude mice for antitumor activity was = 30 nM. Surrogate
`biomarker studies in tumor-bearing rats showed a strong correlation between
`BMS-247550 antitumor efficacy and the degree of tubulin polymerization in(cid:173)
`duced in peripheral blood mononuclear cells. These preclinical efficacy data
`suggest that BMS-247550 has the potential to demonstrate improved clinical
`efficacy in TAXOL~-insensitive and sensitive disease types.
`
`574 Phase I and pharmacology study of the epothilone B analog BMS(cid:173)
`247550 in patients with advanced cancer. D Spriggs', M.D., S.Soignet" M.D.,
`B. Bienvenu', M.D., S.. Letrent+, Ph.D and D. Lebwohl+, M.D. H.Burris#, M.D'
`Memorial Sloan Kettering Cancer Center, New York, NY; #Sarah Cannon Cancer
`Center, Nashville, TN; and +Bristol-Myers Squibb, Wallingford, CT.
`The epothilones are a class of agents which induce tubulin polymerization
`and are cytotoxic for taxane refractory tumors in preclinical testing. BMS(cid:173)
`247550 is an epothilone B analog with excellent preclinical activity. Sixteen
`patients with refractory cancers have enrolled in a clinical study which exam(cid:173)
`ined BMS-247550 administered once every three weeks as a 1 hour infusion.
`No premedications were initially administered. Plasma pharmacokinetics(PK}
`and tubulin polymerization in peripheral blood mononuclear cells (PBMCs) were
`assessed during Course 1 and 2. Plasma concentrations of BMS-247550 were
`determined by an LC/MS/MS assay and the degree of tubulin polymerization in
`PBMCs via Western blot. To date, patients have received doses of 7.4,15,30,
`50, and 65 mg/m2 . At doses below 50 mg/m2 , the drug was extremely well
`tolerated and no limiting toxicity was observed. Following a grade 2 immediate
`hypersensitivity reaction, all patients treated at 30 mg/m2 and above received
`diphenhydramine and cimetidine but corticosteroids were not required. At 65
`mg/m2 , two patient experienced grade 4 neutropenia and one patient experi(cid:173)
`enced transient Grade 3 neuropathy. Additional patients will be treated at 50
`mg/m2. The mean CLT , and Vss, and T '/2 values across each dose cohort
`ranged from 230-423 mUmin/m2 , 399-1157 Um 2 , and 23-50 h, respectively.
`PK parameters appeared to be similar across Course 1 and 2. Data from
`patients in the 50 mg/m2 cohort indicate enhanced tubulin polymerization in
`PBMCs at 1 and 6 h post-dose. Antitumor activity has been observed at the 65
`mg/m2 dose level.
`This clinical study has been supported by Bristol-Myers Squibb.
`
`Proceedings of the 2000 NCIe EORTC eAACR Symposium
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`CabRef0002896