— SUPPLEMENT TO —
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`JO
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`8 6
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`2005 ASCO Annual Meeting Proceedings
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`Univ. of Minn.
`Bio-Medical
`Library
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`O UFZ UD
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`West-Ward Pharm.
`Exhibit 1011
`Page 001
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`West-Ward Pharm.
`Exhibit 1011
`Page 001
`
`

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`Developmental Therapeutics: Molecular Therapeutics
`
`915.
`
`Publication Only
`3094
`Phase | pharmacokinetic-pharmacodynamic trial of weekly MS-275, an oral
`histone deacetylase inhibitor. £. A. Donovan, @. Ryan, M. Acharya, E.
`Chung, J. Trepelt, K. Maynard, E. Sausville, A, Murgo, G. Melillo, B. Conley;
`National Cancer Institute, Bethesda, MD
`is a histone
`Background: MS-275, a synthetic benzamide derivative,
`deacetylase (HDAC)
`inhibitor with in vitro & in vivo antitumor activity.
`Based on our q2 week dosing results, we explored maximum tolerable dose
`(MTD) & dose limiting toxicity (DLT) for a weekly schedule with 2 oral
`formulations & 2 administration conditions. Methods: MS-275 uncoated
`(“A" with meal) or coated (“B"fasting) tablets were given weekly x4 q6
`weeks to patients (pts) with advanced malignancy & PS=2, LFTs=2.5x
`normal, adequate hematopoetic & renal function, & normal resting MUGA.
`Pharmacokinetics (PK) (validated LCMS method) & histone H3 acetylation
`(H3Ac) in peripheral blood mononuclear cells (PBMC) (IHC image analysis
`and novel flow cytometric assay for protein acetylation) were assessed.
`Results: 13 pts, ECOG PS =1 (0-2) received median of 1 (1-4) course. 4
`“A" (4—6 me/m2) pts & 7 “B" (2-4 mg/m2) pts were evaluable for cycle 1
`toxicity (CTC v2.0), "A" grade 3 toxicities were hypoalbuminemia, neutro-
`penia & vomiting. On “B", 2 pts had DLT at 4 mg/m2, one with grade 4
`dyspnea/grade 3 pleuritic pain & dyspepsia & one with right heart failure,
`diarrhea & hypoalbuminemia. Grade 1-2 toxicities in >1 pt for A or B were
`thrombocytopenia, fatigue, hyperglycemia, taste disturbance, hypoalbumin-
`emia, hypocalcemia, hypomagnesemia, hypophosphatemia,
`leucopenia,
`neutropenia, nausea, anorexia, headache, dyspepsia, flatulence, myalgias
`& insomnia. Enrollment is ongoing on “B" 2 mg/m2 fasting. Median Tmax
`was 0.5h (0.5-6h). At 4 mg/m2, mean Cmax was 38.2 ng/mL (14-71
`ng/mL) in “B" vs 4.8 ng/mL (4-6 ng/mL) in “A. Mean AUC at 2, 4, & 6
`me/m2: 190, 284, & 358 ne*h/mL, respectively. PBMC H3Ac was seen at
`all dose levels. 3 pts had stable disease, 2 at 4 mg/m2 (colon, CTCL) & 1 at
`2 me/m2 (CTCL). Conclusions: The MTD for coated MS-275 given fasting
`on this schedule was exceeded at 4 mg/m2 p.o. weekly x4 q6 weeks. AUC
`increased with dose. Drug-related hyperacetylation was observed.
`
`Publication Only
`3096
`A phase Il trial of temsirolimus in metastatic neuroendocrine carcinomas
`(NECs).
`/. Duran, L. Le, D. Saltman, J. Kortmansky, W. Kocha, D. Singh,
`G. R. Pond, J. M. Peralba, J. Dancey, L. L. Siu; Princess Margaret Hosp
`Phase |! Consortium, Toronto, ON, Canada; Memorial Sloan-Kettering
`Cancer Ctr, New York, NY; Univ of Chicago, Chicago, IL; Johns Hopkins
`Univ Sch of Medicine, Baltimore, MD; National Cancer Institute, Bethesda,
`MD
`
`Background: NECsare a varied group of endocrine neoplasms characterized
`by neurosecretory granules and cell surface markers. Except forislet cell
`carcinomas, NECs are resistant
`to conventional cytotoxics. Hormonal
`therapy such as somatostatin analogs or local therapies such as hepatic
`resection or arterial embolization are generally delivered to palliate symp-
`toms. Temsirolimus is a novel mTOR inhibitor that downregulates cascades
`activated by loss of the tumor suppressorprotein PTEN, a defect reported in
`moderately differentiated NECs. Due to the lack of effective systemic
`therapy for NECs, loss of PTEN detected in some cases, and a report of a
`partial response in this tumor type from phase |
`trials, a multi-centre
`2-stage phase Ii
`trial
`in NECs was conducted. Methods: Patients were
`eligible if they demonstrated 25% increase in tumor volume, clinical
`deterioration or new tumorfocus in the last 6 months. Temsirolimus 25 mg
`was administered intravenously over 30 minutes on a weekly basis. Results:
`To date, 23 patients (pts) with progressive NECs have been enrolled with
`the following demographics from 18 pts with baseline data: median
`age=55, range=36-68, M:F=9:9, ECOG 0:1:2= 8:9:1, and 11 pts had
`prior chemotherapy, Toxicity information is available from 15 pts in 50 four
`weekly cycles, The most frequently encountered grade 3-4 toxicities
`expressed as % of
`treatment cycles are: hypophosphatemia (14%),
`hyperglycemia (10%), cough (10%), hypokalemia (8%), hypercholesterol-
`emia (8%), and hypertension (8%). The most frequent toxicities consider-
`ing all gradesare: fatigue (86%), anemia (76%) and lymphopenia (70%).
`Among 15 pts evaluable for response thus far, 10 have achieved prolonged
`stable disease (range: 3-11 cycles),
`including 1 pt with a 24% tumor
`shrinkage by RECIST criteria after 4 cycles, and 2 pts who have experi-
`enced significant clinical benefit and are on cycles 9 and 11, respectively.
`Levels of p7OS6kinase in peripheral blood mononuclear cells at 24 hours
`post
`treatment have not shown correlation with clinical outcome in the
`majority of pts. Markers of cell cycle inhibition and apoptosis in paired
`tumor biopsies will be reported. Conclusions: Temsirolimus appears to have
`antitumor activity in NECs, study accrual is ongoing.
`
`West-Ward Pharm.
`Exhibit 1011
`Page 002
`
`3093
`Publication Only
`Tatiquidar (XR9576)is a potent and effective P-glycoprotein (Pep) —
`t can be administered safely with chemotherapy. M.£. Meng. fee
`. Edgerly, D. Draper, C. Chen, R. Robey, F. Balis, W. D. Figg,
`9-
`ALT. Fojo; NIH/NCI, Bethesda, MD
`.
`Background:
`Inhibition of P-glycoprotein (Pgp) as 4 means liasTe
`Shemotherapeutic efficacy remains a valid but unproven ee (ariguidae
`"centtrials in patients with lung cancerusing the Pgp inhibitor,
`2 our
`(XR9576), closed prematurely due to toxicity eaves. Wee ith
`Xperience using tariquidar with chemotherapy. Methods:
`tari
`idar on
`refractory or metastatic adrenocortical cancer(ACC)received ista and
`ays 1 & 3 with a 96-hour infusion of doxorubicin, ee a =
`Stoposide with mitotane (X-MAVE) every 21 days. Pane ” infusion
`Ovarian, cervical & lung cancer received tariquidar with a anes ype Seas
`every 21 days. Study participants had two °°"Tc-sestamin! Sie
`activity curves were generated and areas under = Oethee 1 h after
`Compare °""Tc-sestamibi accumulation at baseline to thal)2
`‘ariquidar. Rhodamineefflux from CD56+ cells was eedl5 atients with
`alter tariquidar to assess Pgp inhibition. Results: To date,
`t oa ovarian
`Chave received 71 cycles of X-MAVE, and 16 patien soual Grade 3
`cal or lung cancer have received 66 cycles of SSMAVE include:
`Ron-hematologic toxicities (# of cycles) observed with Ken Te
`abdominal pain/constipation (4), arthralgia (4), Eean natre-
`rhea (1), esophagitis (1), fatigue (6), hand-foot reaction (1), th!Was
`Mla (3); those with docetaxelinclude:diarrhea (1), aes “aletion
`hYPonatremia (3), pain (3) and tearing (2). “"Te-sestam= aS
`'Ncreased 39 to 129% compared to a mean increase of ba ae ee
`"6 of8 patients with ACC whose lesions could be ile sensing
`10 such patients with ovarian, cervical or lung cat
`i
`:
`r
`ients was reduced by
`Odamine efflux from CD56+ cells assayed in oe even after 48 h.
`Mean of 85% after
`tariquidar and was SUSY
`Pharmacokinetic sametine before and after tariquidar has pagent
`Snclusions: Tariquidar is a potent and highly effective Pep CO as
`CaN be administered safely with a combination of doxoru fel one
`Nd Vincristine or with docetaxel. The efficacy in patients with
`relractory
`a
`"cers continues to be evaluated.
`
`Publication Only
`3095,
`A phase | dose-escalation study of weekly multiple dose iano
`atministered $R271425 in patients with refractory solid ee _oe
`4 C. Lockhart, A. W. Tolcher, E. K. Rowinsky, & Shae A ee
`Morrison, R. Rafi, M. L. Rothenberg: Cancer Therapy & Rusealty© ~To
`nio,
`TX; Vanderbilt-Ingram Cancer or ay (heeanlista,
`pathelabo Research, Malvem, PA; Sanofi-Synthe
`
`on abilityand toxicities of SR27 1425 asa I-hour oecesar
`menated weekly for 2 weeks followed by 1 week bas dose (RPID), and
`to2'™UM tolerated dose (MTD), recommended qeacktnd Fibonacci dose
`“Sess its pharmacokinetic profile. Methods: A MOTTcpo71425 is
`lation designis being used. A single intravenous
`Er yt in a
`varlnistered over 1-hour weekly for 2 weeks, tollont
`spbit model, QTc
`se Of refractory solid tumors. Of note,
`In the aoe ~660me/m’,
`T Slongation, related to Cmax, has been reported at
`ssment with serial
`Eeaefore, all patients are undergoing cardiology aeposultt To date, 17
`patie’ which are assessed by a central
`revieWOt_|”7,meim2/week).
`Tha tts have been treated at 5 dose levels (ranges,
`ie
`:
`G
`performance status is
`0.5 \nean age is 53 (range 24 -74 years) and ECOG Pornomnitings
`‘
`‘ Grade 1-2 toxicities including QTc prolongati harmacokinetics of
`S|
`ation, and fatigue have been observed. ‘The z ‘eh that observed
`bray 425 following weekly dosing were consis271425 Both Cmax
`. “Viously in g single dose ascending study with SR nner. As would be
`bteq,
`2c (day 1)
`increased in a dose dependent mé mic accumulation
`Weulitted from the drugs short half-life (6.7 h), no let 1 versus Day 8.
`St S Observed ag assessed by Cmax and Con, va jusions: Preliminary
`dae © disease has been observed in 3 patients. one inistered at split
`a On this ongoing study suggests that SR27 1425 adm without signifi
`Pekly doses will likely allow greater cumulative exposure
`ant toxicity
`
`c “
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`West-Ward Pharm.
`Exhibit 1011
`Page 002
`
`