Downloaded from
`
`http://annonc.oxfordjournals.org/
`
` by guest on March 5, 2015
`
`Insertion In 5'-flanklng region of apo Al, apo Gill, apo AIV and hence some
`weak changes In appropriate metabolic processes.
`
`NOVEL THERAPEUTICS AND PHARMACOLOGY - -
`
`Cllnlcal and pharmacoklnetlc (PK) results of 4 phase I
`studies of the second generation matrix
`metalloprotease (MMP) Inhibitor bay 12-9566, a
`non-pep«dlc blphenyl Inhibitor of MMPs 2, 3 & 9
`, H. H1rte1
`L. Seymqur1 , L. Grochow2, G. Eckhardt3, C. Erllchman4
`, A. Goei 1 ,
`R. Humphrey6, I. Elias~. 1 NCI-Canada Cllnlcaf Trials Group; 2 Johns Hopluns,
`Baltimore; 3CRTC, San Antonio; 4Mayo Clinic, Rochester; 58ayer
`Corporation, West Haven, CANADA
`
`Introduction: MMPs ara Involved In Invasion, metastasis and ang1ogenesls;
`MMPs 2 & 9 are overexpressed In the tumor/stroma of multiple cancers end
`correlate with outcome In many. MMPs ara thus attractive targets for Inhibition.
`BAY 12-9566 has nanomolar Inhibitory actlv1ty against MMP 2, 3 & 9 with
`anti-lnvaslve, anti-metastatic and anti-angiogenlc effects In preclinical models.
`Methods: 4 dose ranging trials of oral BAY-129566 wera conducted In
`North America to define PK/safety. Dose limiting toxicity (DLT) was toxlcity 2::
`grade (gr) 3; symptomatic or DL gr 2; MTD was declared If > 2 patients (pts)
`experienced DLT. Eligible pts had PS 0-2 and acceptable organ functlon.
`Results: 90 pis (median age 67yrs) with colon (31), breast (10), ranal(10),
`ovary (8), sarcoma (7), melanoma (6) and other cancers (18) entered 9
`dose levels. Dose related affects ware limited to reduction In platelet counts
`(plts)(nadir d 15-27) raverslble with continued therapy; In 4 heavily pretreated
`pts pits fell to gr 213 leading to prophylactic dose reduction; and mild anemia.
`Mild reversible transaminase elevations and GI effects (nausea, flatulence)
`were observed In some pts; musculoskeletal effects wera not reported MTD
`was not reached although DLT (pits) was seen in 1 pt at DL 6, 8 & 9.6 pts
`remaln on study (mean 236d [14o-314d]). 1 pt wl1h refractory melanoma (3
`prior regimens) had PR < 4 wks duration; 1 pt with refractory ovarian cancer
`(7 prior regimens) has SD alter 9.5 months.
`
`Dose Level (DL)
`Number ol pta (N)
`TotaVday (mg)
`Dose (mg)
`Schedul<I
`028 Trough (mean; mg/L)
`
`4
`7
`6
`6
`2
`1
`5
`3
`9
`12
`10
`18
`15
`16
`3
`3
`3
`10
`600 1200 1600 1600
`100 125 150 200
`400
`400
`100 125 150 200
`400
`400
`400
`800
`BID no CID BID
`OD OD 00 00 OD
`125
`117
`132
`37
`125
`51
`64
`72
`3B
`AUCo-.24 028 (mean, mg/M.) 1161 -
`-
`1739 1411 2300 3035 2275 3135
`
`Concluelon11: Oral BAY 12-9566 (800 mg bid) Is well tolerated With transient
`and usually clinically Insignificant decreases In pit counts and mild anemia the
`only dose related toxicities.
`
`16020 I Updated results of a phase I trlal of Tomudex® (T) In
`combination with oxaliplatln (L-OHP) In advanced
`solid tumors: A promising and active combination
`
`M. Ducreyx, K. Flzazi, C. Daniel, P. Ruffle, A. Kabouche, A. Fandi, M. Smith,
`J.P. Annand. /nstltut Gustave Roussy, Vl/18jurf (France), Zeneca
`Pharmsceutlcals, Cargy, (France)
`
`Introduction: The aim of the study Is to determine the mBXJmum tolerated
`dose and the recommended dose for subsequent phase II trials. The different
`mechanisms of action and toxicity profiles of T and L-OHP are the rationale to
`test their combination
`Methods: Twas administered as e 15 minutes Infusion followed by L-OHP
`as a 2 hours Infusion, repeated 3 weekly. Dose escalation Is shown below:
`
`Dose~
`T/L-OHP
`(mglm2)
`Number of
`(ptslcyclea)
`
`1
`2185
`
`3110
`
`2
`2.5185
`
`3
`2 51110
`
`4
`31110
`
`5
`31130
`
`6
`3.51130
`
`7
`3.751130
`
`3121
`
`3112
`
`3110
`
`16163
`
`14/61
`
`516
`
`Patients: so far, 47 patients (pts) have been entered: 30 M/17 F, median
`age 57 years (29 - 72), PS (WHO)· O = 15, 1 = 25, 2 = 7. Primary neoplasms
`wera malignant mesothellorna (17), gastrolntestinal malignancies (14), renal
`carcinoma (5), lung cancer (4), other (7). Thirty six pts were pre-treated.
`Results: Durlng the first 4 levels, no dose-limiting toX1city was observed.
`An asymptomatic Increase in transamlnases was frequent whatever the step.
`During the subsequent steps, grade 3 + 4 toxlciUes included: pts (cycles)
`Step 5: vomiting 3 (3), diarrhoea 2 (3), neutropenla 1 (2), thrombocytopenla
`1 (1 ), anemia 2 (2), peripheral neutoX1city 1 (1 ), astherna 1 (1)
`Step 6: vomiting 2 (2), neurotoxlcity (fugax amaurosis) 2 (2), asthenle 3 (4),
`anemia 1 (1), thrombocytopenla 1 (1), diarrhoea 1 (1)
`Step 7: Is ongoing and no grade 3-4 toxicity was observed. However,
`gastrolntestinal toxicities and asthenia seem dose-limiting.
`
`Molecular oncology/ Novel therapeutics and phannacology
`
`Fourty four pts are evaluable for response and 3 pts ara too early: 9 partlai
`responses \T mesothel loma, 1 pancreatic cancer, 1 renal carcinoma) 18 stable
`disease and 17 progressive disease.
`Conclusion: This combination 1s well tolerated and has shown actMty. In
`the light of these good results, we era planning two phase II trials at a dose of
`3 mg T and 130 mg of L-OHP: one In mesothelioma and another In advanced
`colorectal cancer.
`
`l 6030 I Phase I study of RPR109881A, a new taxold
`
`administered as a three hour Intravenous Infusion to
`patients (pts) with advanced solid tumors
`C. Sessa 1 , S. Calchera 1 , J. De Jong 1 , C. Monnerat2, D. Perard3, L Vemlllet3,
`A. Riva3 , M. Besenva13, J. Bauer2. 10sp. San Giovanni, Belllnzona, 2 CHUV,
`Lausanne, Switzerland; 3 Rh6ne-Poul6nc Rorer, Antony. France
`RPR109881A has shown a broad spectrum of activity in In vl\lo and In vitro
`tumor models and Is able to cross the blood brain barrier. Five phase I
`studies are ongoing to deflne the recommended dose and schedule (1-, 3-, 6-,
`24-hour and 1-hour dl-d8 q3w). We report the prallmlnary results of the 3-hour
`schedule with an oral pramedicatlon with dexamethasone (-25, -13, 1-hour).
`The starting dose of 75 rnglrn2 was defined according to the safety profile of
`pts treated with other schedules (1-hour/6-hour). Dose escalation was done
`according to the modified Flbonacci's schedule. 13 pts (9 males/4 females -
`median age: 52) previously treated with ::: 2 prior chemotherapies (CT) were
`included. The dose limiting toxicities (DLTs) ara as follows:
`
`Dose
`rr¢n2
`
`75
`90
`
`:: 1 prio< CT
`Nbof
`Dl Ts et th& flrst
`pts
`cycle
`no
`1
`lebr'ile
`6
`nuetropenle (1)
`
`Nb ol
`pta
`2
`4
`
`:: 2 prior CT
`DL Tu et the llrat cycia
`
`no
`toxic death. ecuie resplratOIY distress
`syndrome· (1)
`dierrtiee gr.3, fatigue gr3 (1)
`diarrhea gr.3, febrile neutropenle (1)
`neutropenla gr.4 > 7d (1)
`
`• 1n NSCLC pl with pulmonruy fibrosls llBCOlldery to radiotherapy
`
`50% pts presented neutropenla Gr.4. Alopecla Gr.213 was universal; other
`toxicities were: arthralgia, nausea, rash of mild to moderate severity. One pt
`died because of viral Infection while neutropenic alter the 4th cycle. Blood
`samples wera collected over a o-48 h period for PK analysis. PK parameters
`were elmller over the 2 tested doses with mean values of plasma clearance,
`volume of distribution and terminal half-Ille of "' 40 L/h/m2, 1000 Um2 and 30
`h, respectively (n=11 ). Additional pts will be treated at 90 mg/~ (::; 1 previous
`CD or 75 rnglm2 (:;: 1 previous CT + RT) and randomized between 1-h versus
`3-h to establish the best schedule and to conflrm its leas1bility for phase II
`study. Two confirmed partial response In 2 NSCLC pts has been observed
`at 90 rnglrn2: one untreated pt p<esented brain metastases and responded In
`both lung and brain leslons.
`
`Evidence for the duration of the antlfolate action of the
`thymldylate synthase (TS) Inhibitor ZD9331 using
`plasma dUrd as a surrogate marker of enzyme
`Inhibition
`A. L Jackman, F. Mitchell, S. Lynn, G W. Aheme, C. Rees, A.H. Calvert,
`I.A. Judson, S. Diab, K. Mayne, M. Smith. the ZD9331 Phase I International
`Investigators Group; CRC Centre for Cancer Therapeutics, The Institute of
`Cancer Res9Brch, Sutton, UK
`
`Introduction: lnhlbiuon of TS by raltitrexed (Tomudex~; Zeneca) or the non(cid:173)
`polyglutamatable drug ZD9331 leads to a rise in the level of intracellular
`dUMP and hence plasma dUrd In mice and humans. Plasma dUrd levels wera
`measured In lour phase I dose escalating trials of ZD9331, Including two trials
`where a 30 mm mfuslon was given either on day 1 or on days 1 and 8, with
`cycles repeated every 3 weeks.
`Methods: Pre- and post-treatment blood samples were Immediately cooled
`on Ice and spun to separate the plasma (stored at -7Cl°C). Following de(cid:173)
`proteinlsatlon and solid-phase ex1ractlon, samples were analysed for dUrd by
`lsocratic reverse-phase HPLC uslng a spectral scanning UV detector.
`Results: Both trials started at a dose ol 4.8mglrn2/d. A rise (-2-lold) In dUrd
`was seen at this dose that was of -48h duration (-d.2-3/d9-10). As doses
`Increased, a mora prolonged effect and In some patients a greater rise In dUrd
`levels was seen e.g. at 19.2rnglrn2/d, 3 patients had 3-4-lold rises on d2 that
`had not returned to pre-treatment levels by d5. In those patients who had a
`second dose on d8, a further rise In dUrd of the same magnitude occurred on
`d9 wrth return to pre-treatment levels by d15-22. At 32mg/m2/d, some patients
`had plasma dUrd that had not completely returned to pre-treatment levels by
`d8. One patient had 5, 2, 8 and 3-lold rises on days 2, 8, 9 and 15 respectively.
`These data provide evidence of TS 1nhlbltion that Is of longer duration with
`increasing doses of ZD9331. Two patients at 4.8 and 9.6mg/rn2/d on the d1
`and 8 schedule showed a partial and minor tumour response respectively. The
`trials are 0!1g04ng and the MTD has not yet been reached.
`
`Annals of Oncology, Supplement 4 to Volume 9, 1998
`
`0 l 998 Kluwer Academic Publishers, Pnnted in The Netherlands
`
`125
`
`Teva – Fresenius
`Exhibit 1008-00001
`
`

`
`Downloaded from
`
`http://annonc.oxfordjournals.org/
`
` by guest on March 5, 2015
`
`Novel therapeutics and phannacology
`
`Conclusions: A rapid, sensJtive and reliable method has been developed tor
`the measurement of plasma dUrd in patients receMng anbfolate drugs. These
`data suggest that the duration of TS Inhibition Is dose-related and will help In the
`cholce of dose and schedule for Phase II tr1als of ZD9331 and understanding
`the relationship of durabon of target inh1bltlon and response/toxicity.
`
`I soso I Strategies for Improvement In dose escalation using
`
`the continua! reassessment method (CRM) In phase I
`cllnlcal trials
`
`LL Siu, X. Paoletti, J. O'Qulgley, E.K. Rowlnsky, G.M Clark, D.D Voo Hoff,
`S.G. Eckhardt. Canc8r Therapy and Resoorch Center, San Antonio, TX, USA
`and U436 INSERM, Paris, France
`
`The CAM has been proposed as an alternative dose escalation method in
`the phase I clinical trial deslgn of antineoplastic agents, with the elm of
`exposing a greater proportion of patients (pts) to therapeutic drug doses than
`traditional approaches. The statistical model utilized Is a sequential Bayesian
`estimation scheme In which a prior distribution tunctloo of the rnBXlmum
`tolerated dose (MTD) and a dose toxic-response model are selected before
`the trial. The MTD Is the dose at which a pre-<letermined percentage (e.g.
`30%) of the pt population would experience dose-limiting toxicity (DLT, e.g. Gr
`3 non-hematologic or Gr 4 hematologic). In response to the pracbcal and safety
`concerns of cytotoxic chemotherapy, mod1flcatlons of the CAM (MCRM) were
`Implemented whlch lndude the use of a conventional startlng dose and the
`fixation of dose levels a pnon, customarily by applying the modified Fibonacci
`sequence. However, our experience with ttus dose escalabon method has
`been problematic due to the dependence on non-d1nlcal toxicity information
`prior to the trial, and the difficulty of predicting a fixed number of dose levels.
`Therefore, we have designed a "dual-stage" escalation scheme. The initial
`stage involves utilization of a conventional starting dose wrth doubling of the
`dose In slngle-pt cohorts until moderate toxicity (e.g. Gr 2 non-hematologic or
`Gr 3 hematologic) Is encountered, at which polnt 2 additional pis are accured
`and dose escalation proceeds In a more conservative manner (e.g. at 33%
`to 50% Increments). The second stage begins ooce DL T Is reached, and the
`CAM Is used to guide subsequent assignment of dose levels Instead of the
`Bayesian methodology, a maximum likelihood approach (O'Quigley and Shen)
`Is applied which offers greater flexlblllty wtthout restrlctlon by the paucity of
`prior data. Pracbcal examples and slmula!Jons of models will be provided to
`Illustrate this proposed dose escalation method.
`
`1 soso I Synergistic antltumor effect by novel modified
`ollgonucleotldes targeting PKAI combined with
`cytotoxic drugs or monoclonal antibodies
`G. Tortora, V. Damiano, R. Blanco, S. Pepe, A.A. Bianco, S. Agrawai1 ,
`J. Mendelsohn2, F. Ciardiello. Oncologla Med/ca, Univ F9derlco II, Napo/1,
`Italy; 1 Hybridon, Cambridge, MA, USA; 2 UT-MD Anderson Cancer Center,
`Houston, TX, USA
`
`Introduction: Protein kinase A type I (PKAI) plays a key role In neoplasbc
`transformatloo and conveys mltogenic signals of different growth factors and
`oncogenes. Moreover, PKAI Is overexpressed 1n cancer cells wtth an active
`TGFa-epldermaJ growth factor receptor (EGFR) eutocrine pathway and shows
`a structural and functional interactlon with EGFR. Inhibition of PKAI, or its
`regulatory subunit Ria, results In cancer growth inhibition In vitro and In VIVo.
`Methods: A novel class of mixed backbone oligonucieotides (MBOs) tar(cid:173)
`geting PKAI (ASRla), with Improved pharmscoklnetic and b!oavallab1hty, and a
`humanized monoclonal antibody which blocks activation of EGFR, MAb C225,
`have been tested In vitro and In vlYo on several human cancer cells.
`Results: A dose;:lependent inhibition of soft agar growth was obtained In
`all cancer types tested with the AS Ria MBOs, as compared to mismatched
`control ollgos. Non-lnhlbltOf)' doses of each MBO resulted In a synergistic
`growth Inhibition and Increased apoptosls, when combined wtth taxanes,
`platinum-dBrlvatJves and topo II-selective drugs. When the MBOs administered
`elther l.p. or p.o. were added to pacirtaxel, a cooperative effect was also
`obtained In VIVo, causing tumor growth Inhibition and Increase of survival In
`nude mJce bearing human cancer xenografts Finally, cornbmed treatment of
`human breast and renal cancer cells, which overexpress PKAJ and EGFR,
`wtth the ASRla MBO and MAb C225, caused a cooperative antltumor effect In
`vitro and In VIVo.
`Conclusions: Since both the AS Ria MBOs and the MAb C225 are currently
`studied In clinical trials, the combination between them or wtth selected
`cytotoxic drugs may represent a feasible novel therapeutic strategy
`
`j 6070 I Pharmacoklnetlc (PK) Interaction of the combination
`
`of doxorublcln (DOX) and Taxotere (TXT)
`J. Schuller, M. Czajka, E. Krexner, K. Lehner, H. Bucher, G. Schemthaner.
`Hosp/ta/ Rudo/fsbftung Oncol. Dep., lnstft phsrma chem Vienna, Austna
`
`Introduction: Combination of DOX with TXT has been shown to be highly
`effective In advanced breast cancer recently Introduced into adluvant treatment
`Purpose of the present study was to detect a potential PK interactlon between
`
`DOX and TXT, as already proven for Paclltaxel + DOX leadlng to Increased
`DOX-AUC and enhanced cardiotoxiclty (Gianni et al). Therefore PK behavior
`of both, DOX and TXT, was analyzed using 2 different time schedules: DOX
`50mgim2 30mln Inf. followed Immediately (A) of after 1 HR interval (B) by TXT
`75mgim2 1 HR lnfusloo.
`Methods: All pis received TXT alone at cycle 1 for baseline determination
`followed by DOX + TXT (18 pts schedule A, 13 pis B, sampling for both DOX
`and TXT), followed by DOX baseline anafysls (12 pis A, 6 pis B, TXT then
`given delayed after end of DOX sampling). Sampling period 4HR for TXT and
`6HR for DOX, measured by HPLC, Wln Nonlln noocompartlmental analysls
`performed.
`Results: of the respective AUG last:
`
`AUG
`ng/ml.H
`
`A
`B
`
`Taxotere
`OOXfTXT
`1956
`2450
`
`TXT
`1484
`1703
`
`n
`18
`13
`
`p
`0.03
`0.05
`
`n
`12
`6
`
`Doxorublcln
`OOX
`DOXfTXT
`859
`848
`906
`833
`
`p
`0 9
`0.6
`
`Conclusion: No Influence of TXT oo DOX-AUC documented, DOX-ol cone
`(n=S) with or wfthout TXT n.s. different (p O 2 - 0.8), thus explaining low
`cardlotoxlc!ty of the combination. In contrast, TXT-AUC was SJgnlftcantly In(cid:173)
`creased when combined wrth DOX, suggesbng Interference at the hepatic
`microsomal level, partly explaining high clinical efficacy. A 1 HR delay between
`end of DOX and start of TXT does not change the respective PK behaviour of
`both drugs.
`
`I soap I Gemcltablne (GEM) - clspletln (COOP): A schedule
`
`finding phase VII study
`J.R. Kroep 1 , G.J. Peters 1 , C.J.A. Van Moorsel 1 , J.B. Vermorken3 ,
`P.E Postmus2, A. Catik 1 , H.M. Pinedo1 , C.J. Van Groeningen 1 • 1 Dept. Oncol.
`and 2 Pulm., Univ. Hosp. VU, Amsterdam, NL and 3 Dept. Onco/., Univ. Hosp.
`Antwerp, B, The Netherlands
`
`Introduction: Gem and CDDP are active agalnst various solid tumors. Slnce
`preclinical studies demonstrated the efficacy of various schedules we evaluated
`the tolerabtlrty and clinical efficacy of 4 different Gem/CDDP schedules as part
`of a pharmacoklnebc and -<fynamlc (PK/PD) study.
`Methods: Gem BOO mglm2 was administered as a 30 min lnfuslon on d 1, 8,
`15, and CDDP 50 mg/m2 over 1 hr on d 1, 8 every 28 days; Gem 4 hr before
`CDDP (10 pis), or vice versa (14) and Gem 24 hr before CDDP (9), or vice versa
`(9), after one cycle followed by the reversed schedule. Pis (19 male/23 ferMie,
`median age 54 years (31-77], and perfonnance status 1 [0-2]) lnduded, 9
`ovarian, 7 noo-small cell lung (NSCLC), 5 head/neck squamous cell (HNSCC),
`5 esophageal, 4 melanoma, 4 cervix, 3 adenocarcinoma, 2 pancreatic, 2 colon
`and 1 small cell lung (SCLC). 26 pis received prior chemotherapy, of which 21
`platlnum based.
`Results: A mean of 4.2, 2.6, 3.8 and 3.5 cycles was given In the four
`schedules, resp. The most frequent overall grade 314 CTC-toxicity was throrn(cid:173)
`bocytopenla, 6110, 4114, 2/9 and 619 (overall 60%), followed by leukopenla,
`8110, 5114, 619 and 619 (43%), in the 4 schedules, resp. Therefore, Gem was
`not given oo d 15 In 36% of pis in cycle 1. Anemia was observed In 64%
`of pis. No serious bleeding occurred. Myelotoxlclty was cumulabve, but not
`schedule dependent Non-hematological toxicity consisted mainly of grade 1/2
`nausea/vomiting and fatrgue. One pabent died of toxlcrty following severe neu(cid:173)
`trope111a and sepsis. Creatlnine clearance decreased slightly during therapy.
`Ann-tumor effects In 36 evaluable pis: HNSCC, 1 CR; esophageal, 1 CR/2PR;
`ovarian, 2 PR; NSCLC, 1 PR; melanoma, 1 PR and adenocarcinoma, 1 PR.
`Conclusion: (Cumulative) myelosuppress1on was the major toxicity, al(cid:173)
`though It was not schedule dependent. Based on toxicity, efficacy and PK/PD
`data a phase II study, CDDP 24 hr before Gem, has been started in pts wtth
`upper gastro-mtestinal tumors
`
`I sogp I MTA (LY231514): Relatlonshlp of vitamin metabolite
`proflle, drug exposure, and other patient
`characteristics to toxicity
`
`C. Nlvlklza, S. Baker, R. Johnson, J. Walling, D. Seltz, R. Allen. Ully Research
`Laboratories, Indiana, USA; Cancer Treatment and Research Center, Texas,
`USA; Univ of Colorado Healtf1 SciBflCBS Center, Colorado, USA
`
`Introduction: MTA 1s a novel multitargeted antifolate wtth Inhibitory activity
`agalnst mulbple enzymes. Phase l/ll studies have shown activity In a variety
`of tumors Historical data on other antifolates have suggested that a petienfs
`nutntlonal status may play a role In the likelihood of experiencing severe toxicity.
`The purpose of this study was to assess the relationship of vitamin metabolrtes,
`drug exposure, and other prespedfled baseline patient characteristics to toxicity
`following treatment wrth MTA.
`Methods: Homocystelne (Heys), cystathionlne and methy1malonic acid were
`measured In 139 phase II patients wtth tumors of the colon, breast, pancreas,
`and esophagus at baseline and once each cycle thereafter. Stepwise regres(cid:173)
`SIOll modeling, multivariate analysis of variance, and dlscrlmlnant analysis
`were Implemented to determine which predictors might correlate with severe
`toX1city after ooe course of MTA. Prognostic factors considered were age, gen-
`
`126
`
`Annals of Oncology. Supplement 4 to Volume 9. 1998
`
`Cl 1998 Kluwer Acooem1c Publishers, Pnnted in The Netherlands
`
`Teva – Fresenius
`Exhibit 1008-00002
`
`

`
`Downloaded from
`
`http://annonc.oxfordjournals.org/
`
` by guest on March 5, 2015
`
`Novel therapeutics and phamiacology
`
`diameter-rollimated probe, allowed us to locate that leslon for thoracoscoplc
`resection. From June 1997 to January 1998 we treated 15 consecutive patients
`(pts) with sub-centimeter pulmonary nodules. Nine pis were affected by a
`synchronous and metachronous malignant neoplasm In other sltes. Computed
`thomography of the chest helped In the planning of the operative procedure, the
`poslbon of pts, and ideal ports. A hot-spot was easily detected, In all patients,
`by the probe Introduced In the pleural space through a 11.5 mm trocar. The total
`excision of the lesion was confirmed by detection of radioactivity In the removed
`speamen and Its absence In the resection margins of the lung. Pathological
`examination of specimens showed 8 benign lesions and 7 malignant leslons
`(4 metastases and 3 lung cancer) and It confirmed the absence of Infiltration
`In the resectlon margins The surgical procedure was ex1ended for an average
`of 56.6 minutes (range 35-100 min). The average post-<iperatlve hospital stay
`was 3.6 days (range 3-6 days) In our experience this technique proved safe
`and accurate, allowing easy detection of the pleural surtace projection and fast
`removal of the leslon. This technique offers a simple and reliable method for
`local1zatlon of pnrnary and metastatic tumors by VATS.
`
`i s12P I Phannacoklnetlc (PK) of Tomudex® (raltltrexed) (T)
`and oxallplatln (0) combination: Preliminary results of
`an ongoing phase I study
`K. F1zazl1, M. Bonnay1, D. Fourcautt1 , P. Ruffle1, o. Couturas2 , M. Smith2,
`R Gomenl2, A. Fandi2 , J.P. Armand 1• 1 tnstltut Gustave Roussy, Vlllejuif,
`2 Zen6C8 PharmaceuticaJs, Cergy, France
`
`Introduction: The aim of this study was to evaluate the posslble kinetic
`interactions between T and 0 administered to patients with advanced disease.
`Methods: Patients first recelved T (15 min Infusion), followed 45 minutes
`later by 0 (2-hour Infusion). Three patients received T at a dose of 3 mglm2
`and 3 at a dose of 3.5 mglm2. All of them received the same dose of 130
`mglm2 of 0.
`Results: Plasma concentrations of T declined tri-exponentlally after the
`end of the Infusion. The terminal t1/2 derived from samples up to 28 hours
`post-dose vaned between lnclMduals from 9 3 to 193.2 h with average values
`of 73.4 and 33.7 for the two dose levels. The maximal concentrations varied
`between 323 and 1185 ng/ml with averages of 681 and 813 In the 3 mg!m2 and
`3.5 mglm2 groups respectively. The AUG vaned between 720 and 3192 ng.tVml
`with average of 1577 and 1378 In the two groups. The comparison between
`the two groups did not revealed any difference, probably due to the very large
`Intra subject vanabllity, however the mean AUG showed an approximately
`proportional Increase with 1ncreaslng dose. The estimated kinetic parameters
`were In agreement with the values prevlously published. Plasma concentrations
`of 0 declined bi-exponentially after the end of the Infusion. The tenninal t1/2
`varied from 18 to 30 h (average of 25). Cmax ranged from 3.13 to 4.53 (average
`of 3.69) µg/ml. The AUC ranged from 74 to 120 (average of 195) 119.h/ml and
`the Cl vaned between 1.76 and 3.43 (average of 2.47) 1/h. The comparison
`of the kinetic parameters of 0 to the ones previously published In the same
`experimental condrtlons seems to lndlcate that T Induced an Increase of 0 Cl
`(from 1.32 to 2.47 1/h) with a reduction of the terminal t1/2 from 38.7 to 24.8
`h and a reducllon of Cmax measured at the end of the lnfuslon from 5.11 to
`3.69 µg/mL
`Conclusions: These preliminary results suggest that the expected concen(cid:173)
`trations of 0 obtained after administration of T may be lower that the ones
`observed when 0 Is administered alone. These results Indicate possible PK
`lnteractJon between the two drugs.
`
`I 613P I A phase I and phannacoklnetlc (PK) study of ET-743, a
`novel minor groove binder of marine origin
`administered on a dally x 5 schedule
`M. Hidalgo, M.A. Vlllalona-Calero, S.G. Eckhardt, G. Weiss, E. Campbell,
`M. Kraynak, J. Beljnen, J. Jimeno, D. Von Hoff, E. Rowlnsky. Cancer Therapy
`and Research Center, San Antonio, TX, The Netherlands Cancer Institute,
`Amsterdam, The Netherlands; PhannaMar, S.A., Madnd, Spain
`
`ET-7 43 Is a novel tetrahydrolsoqulnollne alkaloid Isolated from the marine
`organism EstenBJSCidian turblnata which binds to adenln!TCylosine rich regions
`within the minor groove of DNA. This study is evaluating the feaslblllty and
`PK behavior of ET-743 administered as a 1-hour Infusion dally x 5 every 3
`weeks In patients with advanced solid malignancies. Twenty-seven patients
`(median age 58, range 35-79; median ECOG PS-1) have received 67 courses
`of ET-743 at doses ranging from 6 to 380 1<g/m2-/day. At the 380 1tg/m2day
`dose level, 1 patient with ex1enslve prior treatment with 16 cycles of BCNU
`developed grade 4 thrombocytopenia, grade 4 neutropenla with fever, grade
`3 elevabon In transamlnases, and acute renal failure which resulted In death.
`Four patients (8 cycles), at the 216 (1), 287 (1) and 380 (2) 1<g/m2-lday dose
`level developed asymptomatic elevation in hepatic transamlnases of grade
`3 severtty that typically peaked on day 8 and resolved by day 21. Mild to
`moderate, dosedependent nausea and vomiting, which appeared on day 4
`and resolved on day 8, was observed In 14 patients. Two patients at the 380
`µglm2/day dose level suffered supertlcial venous thrombophleb!tls at the drug
`Infusion site. PK parameters obtained In 2 patients at the 216 µglm2-day dose
`level included: clearance, 137 and 589 mUmlnirrf.; t112 , 13.7 and 23.1 Uh; and,
`
`DPD activity has been measured in 14 pis thus far. Pretherapy DPD activity
`was a median 34% higher than after TOM administration (95% C.L -93 to
`+62%). PK data are available in 6 patients thus far, and 5-FU AUG basal
`values do not slgnlflcantly differ from values obtained 24 hours after TOM.
`Conclusions: The combination of TOM+ 5-FU/LFA Is well tolerated every
`2 weeks. Cllnlcal activity looks very encouraging, since the majortty of pis had
`already received prior chemotherapy. We are now treating some addlbonal
`chemo-nalve patients at step 7, In order to have a more reliable estimate of
`the actMty of the regimen.
`
`i s 11 P I Radlo-locallzatlon of pulmonary nodules using
`
`gamma-probe and resection by video-assisted
`thoracic surgery
`A. Challa, G.F. Menconl, F.M.G. Melfi, A. Gonflottl, G. Bonl 1 , G Grosso 1 ,
`E. Baldlni2, C .A. Angelettl. ServlC8 of Thoracic Surgery, Department of
`Surgery, 1 Service of NuclBBr Medicine and 2 Service of Med/cal Oncology.
`Department of Oncology, University of Pisa, Italy
`
`Vldeo-asslsted thoracic surgery (VATS) Is emerging as safe procedure for
`diagnosis and treatment of peripheral pulmonary nodules. One llm1tatlon of
`thoracoscoplc technique Is the Inability to detect those nodules which are very
`deep beneath the pleural suliace, and could only be ldenbfied via manual
`palpation. Several methods are used to localize VATS occult lesions prior to
`excision, Including methylene blue Injection and Introduction of hooked-wire;
`however, all suffer from limitations. Recent advancements In lntraoperatlve
`radio-localization of non-palpable breast lesions prompt us to develop a new
`technique for detection of pulmonary nodules by VATS. CT-scan are used
`to guide pelileslonal Injection of 0.2 - 0.5 ml of solution of 99m Tc-labeled
`human serum albumin mlcrospheres (5-10 MBq) and 0.2 ml of iodine-non-Ionic
`contrast medium, two hours before surgery. In VATS a gamma ray detector
`(Sclntl Probe MR 100 - Pol hi.tech., Aquila, Italy), equipped with 11mm
`
`Annal• of Oncology, Supplement 4 to Volume 9, 1998
`
`0 1998 Kluwer Acadenuc Publishers, Printed in 1be Netherlands
`
`127
`
`der, prior treatment, baseline albumin, liver enzymes, ANG, platelets, vitamin
`metabolites, and AUG.
`Results: Statistically slgruflcant predictors of Grade 4 neutropenia (n=21
`pis) were albumin (p = 0.0006) and Heys (p = 0.0012), while Grade 4
`thrombocytopenla (n=8) was highly predicted by Heys (p < 0.0001) and
`pre-treatment AST (p = 0.0012). Heys:::: 10µM predicted Grade 4 neutropenia
`In cycle one 75% of the time. Grade 4 neutropenla was predicted by Heys
`alone In 70% of cases. Heys and albumin levels cfld not appear to change
`from baseline during treatment wrth MTA While AUG was not found to be a
`predictor of toxicity, little vartabtlrty was observed In AUG. Maximum values
`were still below AUG values related to hematologic toXJcity In phase I studies
`Conclusions: Toxicities resulting from treatment with MTA appear to be
`predictable from pretreatment homocysteine levels. Elevated baseline ho(cid:173)
`mocystelne levels (:::: 1 OµM) highly correlate with severe hematologic and
`nonhematologlc toxicities following treatment with MTA. Homocyste!ne was
`found to be better than albumin at predicting toxicity. These results apply to
`the tumor types studied. Further studies are underway In patients with renal
`Impairment or patients who received prior cisplabn.
`
`i s1 OP I Phase I and pharmacoklnetlc (PK) study of Tomudex
`
`(TOM) + 5-Fluorouracll (5-FU) and levofollnlc acid (LFA)
`In advanced head and neck and colorectal cancer
`F, Gaponlgro, R. Casarettl, H.L. McLeod 1 , A. Budllion, G. Carten!, F. De Vita,
`A. Avallone, M. Blglletto, A. Tucci, J. Morsman1 , D. Barbarulo, G. Catalano,
`P. Comella, G. Comella. Southam Italy Cooperative Oncology Group c/o
`Nations/ Tumor Institute of Naples, fTALY; 1 University of Aberdeen, UK
`Background: Synergism between TOM and 5-FU + LFA Is observed In vitro
`when cells are exposed for 24 hours to TOM, followed by 5-FU + LFA.
`Preclinical studies support the idea that TOM might down-regulate the activity
`of dihydropylimidlne dehydrogenase (DPD).
`Patients end methods: Patients (pts) with advanced head and neck and
`colorectal cancer were treated with escalating doses of TOM on day 1, and
`bolus 5-FU (Immediately after LFA) on day 2, every 2 weeks. In the z-od course
`LFA and 5-FU wern administered on day 1 and TOM on day 2 with the aim
`of evaluating DPD and 5-FU AUG wrth and without pretreatment with TOM.
`Further treatment was given according to the sequence used In the 111 course.
`Results: Avallable clinical data are summarized below.
`
`Step TOM/LFA/5FU (rr.gtm2)
`1.51250/600
`2.()'250/600
`2 0/250/750
`2 51250/750
`2.5/250/fJOO
`3. ()'25()/9()()
`3 0/250/ t 050
`3 0/250/ t 200
`
`CIHN"
`Pis
`Response
`Or'6
`6
`1/5
`511
`1/6(PR)
`6
`2
`511
`1/6 (PR)
`6
`3
`316 (2CR, 1 PR)
`6
`511
`4
`611
`0/7
`7
`5
`6
`6/0
`1/8 (CR)
`8
`917
`7
`6/13 (1CR, SPA)
`18
`1/3 (PR)
`2/1
`3
`8
`OR
`Total
`41/17
`58
`-c • colorectal cancer; HN=haad & neck cancer. C • 6139 (15%); HN a 7/16 (44%); • N •
`neutropenla; M • mucoaJtls, R a Renal
`
`DLT
`0/6
`0/6
`0/6
`Or'6
`0/7
`1/8
`3115
`213
`
`N4
`N 4, N 4; N 4
`N 4, M 3, R 3
`
`Teva – Fresenius
`Exhibit 1008-00003
`
`

`
`Downloaded from
`
`http://annonc.oxfordjournals.org/
`
` by guest on March 5, 2015
`
`Phase I trial and pharmaclklnetics of
`beta-D-glucosyllsophosphoramlde mustard (D-19575)
`administered as a 6-hour Infusion every three weeks:
`An EORTC-ECSG study
`E. Bnasoulls 1 , I. Jucison2, N. Pavhdls 1, P. Beale2, Y. Groot3, G. Veerman 3 ,
`M. Schuessler", D. Rammou, A. Walker2, A. Hanauske5. 1 loannma University
`Hospital, Greece; 2 Royal Marsdan Hospital, UK; 3 EORTC-NDDO, 4 ASTA
`Med/ca AG, 5Gasthulsberg University Hospital, Leuven, Belgium
`
`Introduction: D-19575 ls a beta-D-glucose-llnked isophosphoramlde mustard
`aiming to explolt the transmembrane glucose transporters overexpressed In
`tumour cells. This compound was taken Into dlnical tesbng because preclinical
`data showed a higher selectivity and less myelosuppresslon than ilosfamlda.
`Methods: The present study employed a two-step 6-hour Intravenous
`infusion (1/4 of the dose In 30-minutes, followed by 314 over Si hours) In
`order to increase the exposure and cellular uptake of the drug that has a short
`half-life. Treatment was given once every 3 weeks. Blood and urine samples
`for PK analysls were collected In all patJen