Univ. of Minn
`Bio-Medical ·
`Library
`
`ARGENTUM
`Exhibit 1011
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`000001
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`

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`Developmental Therapeutics: Molecular Therapeutics
`
`215s
`
`Publ ication Only
`3094
`Phase I pharmacokinetic-pharmacodynamic trial of week ly MS-275, an oral
`histone deacetylase inhibitor. E. A. Donovan, Q. Ryan, M. Acharya, E.
`Chung, J. Trepe/, K. Maynard, E. Sausville, A. Murgo, G. Melillo, B. Conley;
`National Cancer Institute, Bethesda, MD
`is a histone
`Background: MS-275, a synth etic benzamide derivative,
`deacetylase (HDAC) inhib itor with in vitro & in vivo antitumor activity.
`Based on our q2 week dosi ng resu lts, we exp lored maximum to lerabl e dose
`(MTD) & dose limiting tox ic ity (DLT) for a week ly sched ule with 2 oral
`formu lations & 2 ad mi nistration conditions. Methods: MS-275 uncoated
`("A" with meal) or coated ("B" fasting) tablets were given weekly x4 q6
`weeks to pat ients (pts) with adva nced ma lignancy & PS :S 2, LFTss 2.5x
`normal, adequate hematopoetic & renal funct ion , & normal resting MUGA.
`Pharmacokinetics (PK) (va lidated LCMS method) & histone H3 acetylation
`(1-13Ac) in peripheral blood mononuclear cel ls (PBMC) (IHC image ana lysi s
`and novel f low cytometr ic assay for protein acetylat ion) were assessed .
`Results: 13 pts, ECOG PS = 1 (0 - 2 ) rece ived med ian of 1 (1 - 4) course. 4
`"A" (4 - 6 mg/m2) pts & 7 "B" (2- 4 mg/m2) pts were evaluable for cycle 1
`toxic ity (CTC v2.0). "A" grade 3 tox icit ies were hypoa lbum inemia, neutro(cid:173)
`pen ia & 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 fai lure,
`diarrhea & hypoalbum inem ia. Grade 1-2 tox ic ities in > 1 pt for A or B were
`thrombocytopen ia, fatigue , hype rglycem ia, taste disturban ce, hypoalbumin(cid:173)
`leucope nia,
`emia, hypoca lce mia, hypomagnesemia, hypophosphatemia,
`neutropenia, nausea, anorex ia, headache, dyspepsia, flatu lence, myalgias
`& insomnia. Enrollment is ongo ing on " B" 2 mg/m2 fast ing. Median Tmax
`was 0.5h (0.5- 6h). At 4 mg/m2, mea n Cmax was 38.2 ng/ml (14 - 71
`nglml) in "B" vs 4.8 ng/ml (4 - 6 ng/ml) in "A. Mean AUC at 2, 4, & 6
`mg/m 2: 190, 284, & 358 ng* h/ml, respectively. PBMC H3Ac was seen at
`all dose leve ls. 3 pts had stab le disease , 2 at 4 mg/m2 (colon , CTCL) & l at
`2 mg/m2 (CTCL). Conclusions: The MTD for coated MS-2 75 given fasting
`on thi s schedu le was exceeded at 4 mg/m2 p.o. week ly x4 q6 weeks. AUC
`increased with dose. Drug-related hyperacety lat ion was observed.
`
`Publication Only
`3096
`A phase II trial of temsirolimus in metastatic neuroendocrine carcinomas
`(NEC s). /. Duran, L. Le, D. Saltman, J. Kortmansky, W. Kocha, D. Singh,
`G. R. Pond, J. M. Peralba, J. Dancey, L. L. Siu; Princess Margaret Hasp
`Phase II Consortium, Toronto, ON, Canada; Memorial Sloan-Kettering
`Cancer Ctr, New York, NY; Univ of Chicago, Chicago, IL; Johns Hopkins
`Univ Sell of Medicine, Baltimore, MD; National Cancer Institute, Bethesda,
`MD
`Background: NECs are a varied group of endocrin e neoplasms characterized
`by neurosecretory granu les and ce ll surface markers. Except for islet ce ll
`ca rcinomas, NECs are resistant to co nventiona l cytotox ics. Hormona l
`t herapy such as somatostatin ana logs or loca l t herap ies such as hepatic
`resect ion or arteri al embolizat ion are generally del ivered to pal li ate symp(cid:173)
`toms. Tems irol imus is a nove l mTOR inhibitor th at down regu lates cascades
`activated by loss of the tumor suppressor protein PTEN, a defect reported in
`moderately differentiated N ECs. Due to th e lack of effective system ic
`therapy for NECs, loss of PTEN detected in some cases, and a report of a
`part ial response in thi s tumor type from phase I trial s, a multi-centre
`2-stage phase II tr ial in NECs was cond ucted. Methods: Patients were
`eligible if they demonstrated 25% increase in tumor volume, cli nical
`deteri oration or new t umor focus in the last 6 months. Temsirolim us 25 mg
`was administered intravenously over 30 min utes on a week ly basis. Results:
`To date, 23 patients (pts) with progressive NECs have been enrolled with
`the fo llowing demographics from 18 pts with baseli ne data: med ian
`age = 55 , range = 36-68, M:F = 9:9, ECOG 0:1:2 = 8 :9: 1, and 11 pts l1ad
`prior chemotherapy. Toxicity information is avai lable from 15 pts in 50 four
`week ly cyc les. Th e most frequently encountered grade 3-4 toxicities
`expressed as % of treatment cycles are: hypophosphatemia ( 14 %),
`hyperglycem ia (10%), cough (10%), hypoka lem ia (8%), hypercho lesterol (cid:173)
`em ia (8%), and hypertension (8%). The most frequent toxi c ities cons ider(cid:173)
`ing all grades are: fatigue (86%), anemia (7 6%) and lymphopenia (70% ).
`Among 15 pts evaluable for response th us far, 10 have achieved prolonged
`sta ble disease (range: 3-11 cycles), including 1 pt wit h a 24% tumor
`shri nkage by REC IST criter ia after 4 cycles, and 2 pts who have experi(cid:173)
`enced significant clin ica l benefit and are on cycl es 9 and ll, respectively.
`Levels of p70S6kinase in periphera l blood mononuc lear ce lls at 24 hours
`post treatm ent have not shown correlation with clinica l outcome in t l1e
`majority of pts. Markers of ce ll cycle inhibition and apoptosis in paired
`tumor biopsies will be reported Conclusions: Temsirolim us appears to have
`antitumor activ ity in NECs, study accru al is ongo ing.
`
`3093
`Publication Only
`olein (Pgp) inhibitor
`·
`.
`T ·
`p 1
`~ C F.
`anqurdar (XR9576) is a potent and effectrve
`-g ycopr
`that can be administered safely with chemotherapy. M. E. Me;e eeS B :n,
`M. Edgerly, D. Draper, C. Chen, R. Robey, F. Balis, W. D.
`tgg,
`· a es,
`A. T. Fojo; NIHINCI, Bethesda, MD
`.
`)
`(P
`.
`B
`a means to rm prove
`gp as
`ackground: Inh ibition of P-glycoprotern
`en h othesis. Two
`. YP
`chemothe rapeutic effi cacy re ma1ns a va l1d but unprov
`t
`·
`·d
`re
`.
`·
`the Pgp 1nh 1b1tor, ar1qu 1 ar
`W
`ce nt trr als in pat ients with lu ng ca nce r us1ng
`t
`(XR95
`· ·t concerns
`e repor ou r
`. 76), c losed prematu rely due to tox iCI Y M th d~· Patients with
`e 0iv~d tariq ui dar on
`experr ence using tariquida r with chemotherapy.
`~efractory or metastatic adrenocortical ca ncer (ACC~rece vincr istine, and
`ays 1 & 3 with a 96-hou r infusiOn of doxoru
`IC in, with refractor
`etoposide witll mitotane (X-MAVE) every 21 days. Pa~~=~~cetaxel infusio~
`~varran, ce rvi ca l & lung ca nce r rece ived tarl q~~~,ar ~~~stamibi scans. Time(cid:173)
`Tc ~e cu rve ca lculated to
`a very 2 1 days. Study partic ipants had two
`ctlvlty cu rves were generated and areas under tl'
`to that 1 h after
`compare 99"'Tc-sesta mibi acc umu lat1on at base lne
`d b f
`d
`II was measure
`e ore an
`tar'
`·
`6
`f lqUidar. Rhodam ine efflux from CD5 + ce s T d te 15 patients with
`~6er tariquidar to assess Pgp inhibition. Results: 1 ~ :ti~nts with ovari an ,
`~ docetaxel Grade 3
`C have received 71 cycles of X-MAVE, and
`cervica l or lung canc er have received 66 cycle~ 0 'th X-MAVE include:
`n~n-hematologic tox icities (# of cyc les) observe ~~a/vom iting (2), diar(cid:173)
`~h dom 1na1 pa in/con st ipat ion (4), arth ralgia (4), na~·on (l) and hyponatre(cid:173)
`mea ( 1 ), esop hagit is ( l), fati gue (6), ha nd-foot reac d s ne~ (1) fat igue (6),
`h Ia (3 ); those wit h docetaxe l incl ude: dlarrh,;~,V \:St~lnibi accumu lat ion
`i~Ponatrem i a (3), pa in (3 ) and tearrng (2).
`.
`c se of 106% in the liver,
`in creased 39 to 129%, compa red to a mea n 1 ncr~avisua l ized. Quantitat ion
`f 6 of 8 patients with ACC whose les1ons coul~ b 1 ng cance r is ongoing.
`Ro~ the 10 suc h patients with ovarra n, cerv lca ;~ :atients was reduced by
`odam 1ne efflux from CD56+ ce lls assayed In
`· d even after 48 h.
`~hlnean of 85% after tariquidar and was sust~~~ has been performed.
`C armacokinetic sampling before and after tarlq~/ tive Pgp inh ibitor t hat
`c~llclusrons:. Tari quidar is a potent and highly e 0~cdoxorubic i n, etoposide
`an~ be admin istered sa fe ly w1th a comb ination in patients wit h refrac tory
`Vlnc rr stlne or with docetaxel. The eff1cacy
`cancers co ntinu es to be eva luated.
`
`3095
`A Ph
`intravenously
`kl multiple dose
`solid tumors. E. Calvo,
`ad . ase I dose-escalation study of . wee Y
`A tnrnrstered SR271 425 in patients wrth refrac.tork G Shackleton J. -G.
`M C: Lockhart, A. W. Tolcher, E. K. Rowms y, & Research Ctr, San
`A~;2son, R. Rafi, M. L. Rothenberg; Cancer z:,erat~shville, TN; Sanof(cid:173)
`Synt~to, TX; Vanderbilt-Ingram Canc~r S
`tile/abo Research, Malvern,
`PA
`elabo Research, Malvern , PA; Sana t- yn
`
`Publication Only
`
`is a nove l cytotoxic
`R271425
`Back
`DNA ground: Th e thioxanthone ana log, S
`of' ant itu mor activity in
`Prec t-lnteracting agent with a broad spectr~:al tria l aims to determine
`to te lnlca l murine tumor models. Th iS clln -hou r single intravenous dose
`rep rab 1l1ty and tox ic it ies of SR271425 as a {
`ek rest
`to determin e the
`~e hase rl dose (RP II D), and
`rna:ated weekly fo r 2 weeks fol lowed by
`to a~mumtolerated dose (MTD), recommendde . ~modified Fibonacc i dose
`esc
`ess 1ts pharmacokinetic prof1le. Metho s. ous dose of SR271425 is
`ad~atlon design is being used . A s1ngle lntravfe~lowed by 1 week rest, in a
`Va( \ni stered over 1-hour week ly for 2 weeks, 0
`the rabbit model, QTc
`Pralle Y of refractory sol id tumors. Of note, ~n d at doses > 660mg/m,_
`The~ngat1on, related to Cmax, has been repo~ e assessment with serial
`E:cG:fore •. all patients are undergoing cardl~~!~r Results: To date, 17
`64 -675 mg/m 2/week) .
`Pat'
`· Wh 1ch are assessed by a central rev
`Th~ents have been treated at 5 ~ose levels (r~nf~~G performance status is
`o_2 mean age IS 53 (range 24 -74 yea rs) an
`ngation, nausea/vom it ing/
`1
`con s·t'G rade l - 2 tox icities 1nclud 1ng QTc prado The pharmacokinet ics of
`1Pat1on , and fati gue l1ave been observe ·. tent with that observed
`SR 27
`Previol425 fol lowing weekly dosing were coi~~~\R27 1425. Botl1 Cmax
`and All sly 1n a single dose ascend1ng study wd
`t manner. As wou ld be
`Predic Uc (day l) increased in a dose depe~ ~~system ic acc umulation
`wa
`ted from the drugs short l1a lf-l1fe (6.7
`),
`Day 1 versu s Day 8.
`nd c values on
`C
`s Obser d
`Stab I
`. ve as assessed by max a
`t conclusions: Preliminary
`data~ disease has been observed Ill 3 pa~~~;~425 ad min istered at spl it,
`t'
`Weeki n th 1s ongo1ng study suggests that S
`exposure without s1gn1f1-
`1
`ca Y doses will li kely allow greater cumu a IVe
`nt toxicity.
`
`1S
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`6"-
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`000002
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