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`
`Molecular oncology /Novel therapeutics and pharmacology
`
`Fourty four pts are evaluable for response and 3 pts are too early: 9 partial
`responses (7 mesothelloma, 1 pancreatic cancer, 1 renal carcinoma) 18 stable
`disease and 17 progressive disease.
`Conclusion: This combination is well tolerated and has shown activity. In
`the light of these good results, we are planning two phase II trials at a dose of
`3 mg T and 130 mg of L-OHP: one In mesothelloma and another In advanced
`cotorectaJ cancer.
`
`603O Phase I study of RPR109881A, a new taxold
`administered as a three hour Intravenous Infusion to
`patients (pts) with advanced solid tumors
`C. Sessa1. S. Caldiera1, J. De Jong', C. Monnerat 2, D. Pdrard3, L Vemlllet3,
`A. Riva3, M. Besenval3, J. Bauer2. 'Osp. San Giovanni, Belllnzona, !CHUV,
`Lausanne, Switzerland; 3Rh6ne-Poulenc Rorer, Antony, France
`
`RPR109881A has shown a broad spectrum of activity in In vivo and In vitro
`tumor models and Is able to cross the Hood brain barrier. Five phase I
`studies are ongoing to define the recommended dose and schedule (1-, 3-, 6-,
`24-hour and 1-hour dl-d8 q3w). We report the preliminary results of the 3-hour
`schedule with an oral premedication with dexamethasone (-25, -13,1-hour).
`The starting dose of 75 mg/m2 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 Fibonacci's schedule. 13 pts (9 males/4 females -
`median age: 52) previously treated with < 2 prior chemotherapies (CT) were
`Included. The dose limiting toxtdties (DLTs) are as follows:
`
`< 2 prior CT
`DLT8 at the first cycle
`
`no
`toxic death, acute respiratory distress
`syndrome' (1)
`darrhea gr.3, fatigue gr3(1)
`diarrhea gr.3, febrile neutropenla (1)
`neutropenla gr.4 > 7d (1)
`
`Nbof
`pts
`
`2 4
`
`<
`
`1 prior CT
`DLTs at the first
`cycle
`no
`febrtle
`nuetropenla(i)
`
`Nbol
`pts
`
`1 8
`
`Dose
`mg/m^
`
`75
`90
`
`'in NSCLC pt wtth pulmonary fiwosls secondary to radiotherapy
`
`50% pts presented neutropenla Gr.4. Alopecia Gr.2/3 was universal; other
`toxicities were: arthralgia, nausea, rash of mild to moderate severity. One pt
`died because of viral Infection while neutropenlc after the 4th cycle. Blood
`samples were collected over a 0—46 h period for PK analysis. PK parameters
`were similar over the 2 tested doses with mean values of plasma clearance,
`volume of distribution and terminal half-life of w 40 L/h/m2, 1000 L/m2 and 30
`h, respectively (n=11). Additional pts will be treated at 90 mg/m2 (< 1 previous
`CT) or 75 mg/m2 (< 1 previous CT + RT) and randomized between 1-h versus
`3-h to establish the best schedule and to confirm its feasibility for phase II
`study. Two confirmed partial response In 2 NSCLC pts has been observed
`at 90 mg/m2: one untreated pt presented brain metastases and responded In
`both lung and brain lesions.
`
`604O Evidence for the duration of the antifolate 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. Aherne, C. Rees, A.H. Cah/ert,
`I.R. Judson, S. Dlab, K. Mayne, M. Smith, the ZD9331 Phase I International
`Investigators Group; CRC Centre for Cancer Therapeutics, The Institute ot
`Cancer Research, Sutton, UK
`
`Introduction: Inhibition of TS by ralttrexed (Tomudex™; Zeneca) or the non-
`polyglutamatable drug ZD9331 leads to a rise in the level of Intracellular
`dUMP and hence plasma dUrd In mice and humans. Plasma dUrd levels were
`measured in four phase I dose escalating trials of ZD9331, Including two trials
`where a 30 mm infusion was given either on day 1 or on days 1 and 8, with
`cycles repeated every 3 weeks.
`Methods: Pre- and post-treatment Wood samples were Immediately cooled
`on Ice and spun to separate the plasma (stored at -70°C). Following de-
`protelnlsatlon and solid-phase extraction, samples were analysed for dUrd by
`Isocratic reverse-phase HPLC using a spectral scanning UV detector.
`Results: Both trials started at a dose of 4.8mg/m2/d. A rise (~2-fold) In dUrd
`was seen at this dose that was of ~48h duration (~d2-3/d9-10). As doses
`increased, a more prolonged effect and In some patients a greater rise In dUrd
`levels was seen e.g. at 19.2mg/m2/d, 3 patients had 3-4-fold 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 with 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-fokJ rises on days 2,8,9 and 15 respectively.
`These data provide evidence of TS inhibition that Is of longer duration with
`Increasing doses of ZD9331. Two patients at 4.8 and g.Bmg/rr^/d on the d1
`and 8 schedule showed a partial and minor tumour response respectively. The
`trials are ongoing and the MTD has not yet been reached.
`
`insertion in 5'-flanking region of apo Al, apo Clll, apo AIV and hence some
`weak changes In appropriate metabolic processes.
`
`NOVEL THERAPEUTICS AND PHARMACOLOGY
`
`6010 Clinical and pharmacoklnetlc (PK) results of 4 phase I
`studies of the second generation matrix
`metalloprotease (MMP) Inhibitor bay 12-9566, a
`non-peptldlc blphenyl Inhibitor of MMPs 2, 3 & 9
`L Seymour1. L. Grochow2, G. Eckhardt3, C. Erllchman4, H. Hirte1, R. Goal1,
`R. Humphrey5,1. Ellas5. 'NCI-Canada Clinical Trials Group;2Johns Hopkins,
`Baltimore; 3CRTC, San Antonio; 'Mayo Clinic, Rochester; 5Bayer
`Corporation, West Haven, CANADA
`
`Introduction: MMPs are involved in invasion, metastasis and angiogenesls;
`MMPs 2 & 9 are overexpressed in the tumor/stroma of multiple cancers and
`correlate with outcome In many. MMPs are thus attractive targets for inhibition.
`BAY 12-9566 has nanomdar Inhibitory activity against MMP 2, 3 & 9 with
`antl-lnvastve, antl-metastatlc and antl-angiogenlc effects in preclinical models.
`Methods: 4 dose ranging trials of oral BAY-129566 were conducted In
`North America to define PK/safety. Dose limiting toxlcity (DLT) was toxiclty >
`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 function.
`Results: 90 pts (median age 67yrs) with colon (31), breast (10), renal(10),
`ovary (8), sarcoma (7), melanoma (6) and other cancers (18) entered 9
`dose levels. Dose related effects were limited to reduction In platelet counts
`(ptts)(nadlr d 15-27) reversible with continued therapy; in 4 heavily pretreated
`pts pits fell to gr 2/3 leading to prophylactic dose reduction; and mild anemia.
`Mild reversible transamlnase elevations and Gl effects (nausea, flatulence)
`were observed In some pts; musculoskeletal effects were not reported MTD
`was not reached although DLT (pits) was seen in 1 pt at DL 6, 8 & 9.6 pts
`remain on study (mean 236d [140-314d]). 1 pt with refractory melanoma (3
`prior regimens) had PR < 4 wks duration; 1 pt with refractory ovarian cancer
`(7 prior regimens) has SD after 9.5 months.
`
`e
`1
`8
`Dose Level (DL)
`18
`12
`15
`10
`18
`3
`3
`3
`10
`Number ol pts (N)
`400 800 1200 1600 1600
`100 125 150 200
`Total/day (mg)
`100 125 150 200 400 400
`400
`400
`800
`Dose(mg)
`OD OD OO OO OD BID T1D QID BID
`Schedule
`38
`37
`51
`64
`72
`125
`125
`117
`132
`D28 Trough (mean; mg/L)
`AUCo_24 D28 (mean, mg/h/L) 1161
`-
`-
`1739 1411 2300 3035 2275 3135
`
`Conclusions: 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.
`
`602O Updated results of a phase I trial of Tomudex® (T) In
`combination with oxallplatin (L-OHP) in advanced
`solid tumors: A promising and active combination
`M. Ducreux. K. Flzaa, C. Daniel, P. Ruffle, A. Kabouche, A. Fandi, M. Smith,
`J.P. Armand. Instltut Gustave Roussy, Vlllejuif (France), Zeneca
`Pharmaceuticals, Cergy, (France)
`
`Introduction: The aim of the study is to determine the maximum tolerated
`dose and the recommended dose for subsequent phase II trials. The different
`mechanisms of action and toxiclty profiles of T and L-OHP are the rationale to
`test their combination
`Methods: T was administered as a 15 minutes infusion followed by L-OHP
`as a 2 hours Infusion, repeated 3 weekly. Dose escalation Is shown below:
`
`Dose level
`T/L-OHP
`(mg/m2)
`Number of
`(pts/cydes)
`
`1
`2/85
`
`3/10
`
`2
`2.5/85
`
`3
`
`2 5/110
`
`4
`3/110
`
`5
`3/130
`
`6
`3.5/130
`
`7
`3.75/130
`
`3/21
`
`3/12
`
`3/10
`
`16/63
`
`14/61
`
`5/6
`
`Patients, so far, 47 patients (pts) have been entered: 30 M/17 F, median
`age 57 years (29 - 72), PS (WHO)- 0 = 15, 1 = 25, 2 = 7. Primary neoplasms
`were malignant mesothelloma (17), gastrointestinal malignancies (14), renal
`carcinoma (5), lung cancer (4), other (7). Thirty six pts were pre-treated.
`Results: During the first 4 levels, no dose-llmlting toxicity was observed.
`An asymptomatic Increase in transamlnases was frequent whatever the step.
`During the subsequent steps, grade 3 + 4 toxtdtles Included: pts (cycles)
`Step 5: vomiting 3 (3), diarrhoea 2 (3), neutropenla 1 (2), thrombocytopenia
`1 (1), anemia 2 (2), peripheral neutoxicity 1 (1), asthenia 1 (1)
`Step 6: vomiting 2 (2), neurotoxlclty (fugax amaurosis) 2 (2), asthenia 3 (4),
`anemia 1 (1), thrombocytopenia 1 (1), diarrhoea 1 (1)
`Step 7: is ongoing and no grade 3-4 toxiclty was observed. However,
`gastrointestinal toxicities and asthenia seem dose-llmlting.
`
`Annals of Oncology, Supplement 4 to Volume 9, 1998 © 1998 Kluwer Academic Publishers, Printed in The Netherlands
`
`125
`
`Teva – Fresenius
`Exhibit 1022-00001
`
`

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`
`DOX and TXT, as already proven for Paclitaxel + DOX leading to Increased
`DOX-AUC and enhanced cardiotoxicity (Gianni et al). Therefore PK behavior
`of both, DOX and TXT, was analyzed using 2 different time schedules: DOX
`SOmg/m2 30min Inf. followed immediately (A) of after 1HR interval (B) by TXT
`75mg/m2 1HR Infusion.
`Methods: All pts received TXT alone at cycle 1 for baseline determination
`followed by DOX + TXT (18 pts schedule A, 13 pts B, sampling for both DOX
`and TXT), followed by DOX baseline analysis (12 pts A, 6 pts B, TXT then
`given delayed after end of DOX sampling). Sampling period 4HR for TXT and
`6HR for DOX, measured by HPLC, Win Nonlin noncompartimental analysis
`performed.
`Results: of the respective AUC last:
`
`DoxomMcIn
`DOX/TXT
`DOX
`859
`906
`
`848
`833
`
`P
`09
`0.6
`
`n 1
`
`2
`6
`
`P
`0.03
`0.05
`
`Taxotere
`DOX/TXT
`1956
`2450
`
`TXT
`1484
`1703
`
`n 1
`
`8
`13
`
`AUC
`ng/mf.H
`
`A B
`
`Conclusion: No Influence of TXT on DOX-AUC documented, DOX-d cone
`(n=8) with or without TXT n.s. different (p 02 - 0.8), thus explaining low
`cardiotoxicity of the combination. In contrast TXT-AUC was significantly in-
`creased when combined with DOX, suggesting Interference at the hepatic
`microsomal level, partly explaining high clinical efficacy. A 1HR delay between
`end of DOX and start of TXT does not change the respective PK behaviour of
`both drugs.
`
`608P| Gemcltablne (GEM) - clsplatin (CDDP): A schedule
`finding phase 1/11 study
`J.R. Kroep'.G.J. Peters', C.J.A. Van Moorsel1, J.B. Vermorken3,
`P.E Postmus2, A. Catik1, H.M. Plnedo', C.J. Van Groeningen'. 'Dept. Oncol.
`and'Pulm., Univ. Hosp. VU, Amsterdam, NL and3Dept. Oncol., Univ. Hosp.
`Antwerp, B, The Netherlands
`
`Introduction: Gem and CDDP are active against various solid tumors. Since
`preclinical studies demonstrated the efficacy of various schedules we evaluated
`the tolerabilrty and clinical efficacy of 4 different Gem/CDDP schedules as part
`of a pharmacoWneuc and -dynamic (PK/PD) study.
`Methods: Gem 800 mg/m2 was administered as a 30 mln infusion 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 pts), or vice versa (14) and Gem 24 hr before CDDP (9), or vice versa
`(9), after one cycle followed by the reversed schedule. Pts (19 male/23 female,
`median age 54 years [31-77], and performance status 1 [0—2]) included, 9
`ovarian, 7 non-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 pts received prior chemotherapy, of which 21
`platinum 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 3/4 CTC-toxicity was throm-
`bocytopenla, 6/10, 4/14, 2/9 and 6/9 (overall 60%), followed by leukopenla,
`8/10, 5/14, 6/9 and 6/9 (43%), in the 4 schedules, resp. Therefore, Gem was
`not given on d 15 in 36% of pts in cycle 1. Anemia was observed in 64%
`of pts. No serious bleeding occurred. Myelotoxlcity was cumulative, but not
`schedule dependent Non-hematological toxicity consisted mainly of grade 1/2
`nausea/vomiting and fatigue. One patient died of toxicity following severe neu-
`tropenia and sepsis. Creatinlne clearance decreased slightly during therapy.
`Anti-tumor effects In 36 evaluable pts: HNSCC, 1 CR; esophageal, 1 CR/2PR;
`ovarian, 2 PR; NSCLC, 1 PR; melanoma, 1 PR and adenocarcinoma, 1 PR.
`Conclusion: (Cumulative) myeJosuppression was the major toxicity, al-
`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 with
`upper gastro-nntestinal tumors
`
`609P MTA (LY231514): Relationship of vitamin metabolite
`profile, drug exposure, and other patient
`characteristics to toxicity
`C. Nivlkiza. S. Baker, R. Johnson, J. Walling, D. Seitz, R. Allen. Ully Research
`Laboratories, Indiana, USA; Cancer Treatment and Research Center, Texas,
`USA; Unlv of Colorado Health Sciences Center, Colorado, USA
`
`Introduction: MTA is a novel multitargeted antifolate with Inhibitory activity
`against multiple enzymes. Phase l/ll studies have shown activity in a variety
`of rumors Historical data on other antlfolates have suggested that a patlenfs
`nutritional status may play a role In the likelihood of experiencing severe toxicity.
`The purpose of this study was to assess the relationship of vitamin metabolites,
`drug exposure, and other prespeclfled baseline patient characteristics to toxicity
`following treatment with MTA.
`Methods: Homocystelne (Hcys), cystathlonine and methylmalonic acid were
`measured In 139 phase II patients with tumors of the colon, breast, pancreas,
`and esophagus at baseline and once each cycle thereafter. Stepwise regres-
`sion modeling, multlvariate analysis of variance, and discriminant analysis
`were implemented to determine which predictors might correlate with severe
`toxicity after one course of MTA. Prognostic factors considered were age, gen-
`
`Novel therapeutics and pharmacology
`
`Conclusions: A rapid, sensitive and reliable method has been developed for
`the measurement of plasma dUrd in patients receiving antjfolate drugs. These
`data suggest that the duration of TS Inhibition is dose-related and will help In the
`choice of dose and schedule for Phase II trials of ZD9331 and understanding
`the relationship of duration of target inhibition and response/toxictty.
`
`605O Strategies for Improvement In dose escalation using
`the continual reassessment method (CRM) In phase I
`clinical trials
`
`LL Siu. X. PaoleW, J. O'Qulgley, E.K. Rowinsky, G.M Clark, D.D Von Hoff,
`S.G. Eckhardt. Cancer Therapy and Research Center, San Antonio, TX, USA
`and U436INSERM, Paris, France
`
`The CRM has been proposed as an alternative dose escalation method in
`the phase I clinical trial design of antineoplastlc agents, with the aim 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 function of the maximum
`tolerated dose (MTD) and a dose toxic-response model are selected before
`the trial. The MTD Is the dose at which a pre-determined percentage (e.g.
`30%) of the pt population would experience dose-limiting toxictty (DLT, e.g. Gr
`3 non-hematologlc or Gr 4 hematologic). In response to the practical and safety
`concerns of cytotoxic chemotherapy, modifications of the CRM (MCRM) were
`Implemented which Include the use of a conventional starting dose and the
`fixation of dose levels a pnon, customarily by applying the modified Fibonacci
`sequence. However, our experience with thjs dose escalation method has
`been problematic due to the dependence on non-clinical 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 with doubling of the
`dose in single-pt cohorts until moderate toxicity (e.g. Gr 2 non-hematologic or
`Gr 3 hematologic) Is encountered, at which point 2 additional pts are accured
`and dose escalation proceeds in a more conservative manner (e.g. at 33%
`to 50% Increments). The second stage begins once DLT is reached, and the
`CRM is used to guide subsequent assignment of dose levels Instead of the
`Bayesian methodology, a maximum likelihood approach (O'Qulgley and Shen)
`Is applied which offers greater flexibility without restriction by the paucity of
`prior data. Practical examples and simulations of models will be provided to
`illustrate this proposed dose escalation method.
`
`606O Synerglstic antltumor effect by novel modified
`oligonucleotides targeting PKAI combined with
`cytotoxic drugs or monoclonal antibodies
`0. Tortora. V. Damiano, R. Bianco, S. Pepe, A.R. Bianco, S. Agrawal',
`J. Mendelsohn2, F. Ciardiello. Oncologia Medics, UnivFederico II, Napoli,
`Italy; 'Hybridon, Cambridge, MA, USA;'UT-MD Anderson Cancer Center,
`Houston, TX, USA
`
`Introduction: Protein klnase A type I (PKAI) plays a key role in neoplasbc
`transformation and conveys mitogenic signals of different growth factors and
`oncogenes. Moreover, PKAI Is overexpressed in cancer cells with an active
`TGFo-epidermal growth factor receptor (EGFR) autocrine pathway and shows
`a structural and functional interaction with EGFR. Inhibition of PKAI, or its
`regulatory subunit Rio, results in cancer growth inhibition In vitro and In vivo.
`Methods: A novel class of mixed backbone oligonucleotides (MBOs) tar-
`geting PKAI (ASRIo), with Improved phannacokinetic and bioavallability, and a
`humanized monoclonal antibody which blocks activation of EGFR, MAb C225,
`have been tested In vitro and In vivo on several human cancer cells.
`Results: A dose-dependent inhibition of soft agar growth was obtained in
`all cancer types tested with the AS Rlor MBOs, as compared to mismatched
`control ollgos. Non-lnhlbltory doses of each MBO resulted In a synergistic
`growth Inhibition and Increased apoptosis, when combined with taxanes,
`platinum-derivatives and topo ll-selectlve drugs. When the MBOs administered
`either I.p. or p.o. were added to paclitaxel, a cooperative effect was also
`obtained in vivo, causing tumor growth Inhibition and increase of survival In
`nude mice bearing human cancer xenografts Finally, combined treatment of
`human breast and renal cancer cells, which overexpress PKAI and EGFR,
`with the ASRIo MBO and MAb C225, caused a cooperative antitumor effect in
`vitro and In vivo.
`Conclusions: Since both the AS Rio MBOs and the MAb C225 are currently
`studied In clinical trials, the combination between them or with selected
`cytotoxic drugs may represent a feasible novel therapeutic strategy
`
`|607O Pharmacoklnetic (PK) Interaction of the combination
`of doxorublcin (DOX) and Taxotere (TXT)
`J. SchOller. M. Czejka, E. Krexner, K. Lehner, H. Bucher, G. Schernthaner.
`Hospital Rudolfsbftung Oncol. Dep., Instil pha/ma chem Vienna, Austria
`Introduction: Combination of DOX with TXT has been shown to be highly
`effective in advanced breast cancer recently Introduced into adiuvant treatment
`Purpose of the present study was to detect a potential PK interaction between
`
`126
`
`Annals of Oncology, Supplement 4 lo Volume 9, 1998 © 1998 Kluwer Academic Publishers, Printed in The Netherlands
`
`Teva – Fresenius
`Exhibit 1022-00002
`
`

`
`Downloaded from
`
`http://annonc.oxfordjournals.org/
`
` by guest on March 5, 2015
`
`Novel therapeutics and pharmacology
`
`diameter-collimated probe, allowed us to locate that lesion for thoracoscopic
`resection. From June 1997 to January 1998 we treated 15 consecutive patients
`(pts) with sub-centimeter pulmonary nodules. Nine pts were affected by a
`synchronous and metachronous malignant neoplasm In other sites. Computed
`thomography of the chest helped In the planning of the operative procedure, the
`position 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
`specimen and Its absence In the resection margins of the lung. Pathological
`examination of specimens showed 8 benign lesions and 7 malignant lesions
`(4 metastases and 3 lung cancer) and It confirmed the absence of Infiltration
`In the resection margins The surgical procedure was extended for an average
`of 56.6 minutes (range 35-100 min). The average post-operative 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 surface projection and fast
`removal of the lesion. This technique offers a simple and reliable method for
`localization of pnmary and metastatic tumors by VATS.
`
`612P Pharmacoklnetlc (PK) of Tomudex8 (raltltrexed) (T)
`and oxaliplatln (0) combination: Preliminary results of
`an ongoing phase I study
`K. Fizazi1, M. Bonnay1, D. Fourcault1, P. Ruffle', O. Couturas2, M. Smith2,
`R Gomenr2, A. Fandi2, J.P. Armand'. 'Instltut Gustave Roussy, Vlllejuif,
`'Zeneca Pharmaceuticals, Cergy, France
`
`Introduction: The aim of this study was to evaluate the possible kinetic
`interactions between T and O administered to patients with advanced disease.
`Methods: Patients first received T (15 mln Infusion), followed 45 minutes
`later by O (2-hour Infusion). Three patients received T at a dose of 3 mg/m2
`and 3 at a dose of 3.5 mg/m2. All of them received the same dose of 130
`mg/m2 of O.
`Results: Plasma concentrations of T declined tri-exponentially after the
`end of the Infusion. The terminal t1/2 derived from samples up to 28 hours
`post-dose varied between Individuals 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 mg/m2 groups respectively. The AUC varied between 720 and 3192 ng.h/ml
`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 vanability, however the mean AUC showed an approximately
`proportional increase with increasing dose. The estimated kinetic parameters
`were In agreement with the values previously published. Plasma concentrations
`of O declined bi-exponentially after the end of the Infusion. The terminal t1/2
`varied from 18 to 30 h (average of 25). Cmax ranged from 3.13 to 4.53 (average
`of 3.69) nQlm\. The AUC ranged from 74 to 120 (average of 195) (<g.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 O to the ones previously published In the same
`experimental conditions seems to indicate that T Induced an increase of O 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 reduction of Cmax measured at the end of the infusion from 5.11 to
`3.69 MQ/ml-
`Conclusions: These preliminary results suggest that the expected concen-
`trations of O obtained after administration of T may be lower that the ones
`observed when O is administered alone. These results Indicate possible PK
`Interaction between the two drugs.
`
`I 613P | A phase I and pharmacoklnetlc (PK) study of ET-743, a
`novel minor groove binder of marine origin
`administered on a daily x 5 schedule
`M. Hidalgo, M.A. Vlllalona-Calero, S.G. Eckhardt, G. Weiss, E. Campbell,
`M. Kraynak, J. Beijnen, J. Jimeno, D. Von Hoff, E. Rowlnsky. Cancer Therapy
`and Research Center, San Antonio, TX, The Netherlands Cancer Institute,
`Amsterdam, The Netherlands; PharmaMar, SA., Madrid, Spain
`
`ET-743 Is a novel tetrahydroisoquinoline alkaloid Isolated from the marine
`organism Estenaiscidian turbinata which binds to adenlne-cytosine rich regions
`within the minor groove of DNA. This study is evaluating the feasibility 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 /ig/nrVday. At the 380 jtg/m^day
`dose level, 1 patient with extensive prior treatment with 16 cycles of BCNU
`developed grade 4 thrombocytopenia, grade 4 neutropenia with fever, grade
`3 elevation in transamlnases, and acute renal failure which resulted in death.
`Four patients (8 cycles), at the 216 (1), 287 (1) and 380 (2) /(g/m^day dose
`level developed asymptomatic elevation in hepatic transamlnases of grade
`3 severity 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
`Mg/m2/day dose level suffered superficial venous thrombophlebitis at the drug
`Infusion site. PK parameters obtained in 2 patients at the 216 /ig/nr'day dose
`level included: clearance, 137 and 589 mL/mln/m2; ti/2,13.7 and 23.1 L/h; and,
`
`der, prior treatment, baseline albumin, liver enzymes, ANC, platelets, vitamin
`metabolites, and AUC.
`Results: Statistically significant predictors of Grade 4 neutropenia (n=21
`pts) were albumin (p = 0.0006) and Hcys (p = 0.0012), while Grade 4
`thrombocytopenia (n=8) was highly predicted by Hcys (p < 0.0001) and
`pre-treatment AST (p = 0.0012). Hcys > 10jtM predicted Grade 4 neutropenia
`In cycle one 75% of the time. Grade 4 neutropenia was predicted by Hcys
`alone In 70% of cases. Hcys and albumin levels did not appear to change
`from baseline during treatment with MTA While AUC was not found to be a
`predictor of toxldty, little variability was observed In AUC. Maximum values
`were still below AUC values related to hematologlc toxidty In phase I studies
`Conclusions: Toxicities resulting from treatment with MTA appear to be
`predictable from pretreatment homocysteine levels. Elevated baseline ho-
`mocystelne levels (> ^0^lM) highly correlate with severe hematologlc and
`nonhematologk: toxicities following treatment with MTA. Homocysteine was
`found to be better than albumin at predicting toxlctty. These results apply to
`the tumor types studied. Further studies are underway in patients with renal
`impairment or patients who received prior clsplatn.
`
`61 OP Phase I and pharmacoklnetlc (PK) study of Tomudex
`(TOM) + 5-Fluorouracll (5-FU) and levofollnlc add (LFA)
`in advanced head and neck and colorectal cancer
`F. Caponlqro. R. CasareW, H.L McLeod1, A. Budillon, G. Carteni, F. De Vita,
`A. Avallone, M. Blglietto, A. Tucci, J. Morsman1, D. Barbarulo, G. Catalano,
`P. Cornelia, G. Cornelia. Southern Italy Cooperative Oncology Group c/o
`National Tumor Institute of Naples, ITALY; 'University of Aberdeen, UK
`
`Background: Synerglsm between TOM and 5-FU + LFA is observed In vitro
`when cella are exposed for 24 hours to TOM, followed by 5-FU + LFA.
`Precllnical studies support the idea that TOM might down-regulate the activity
`of dihydropyrimidlne dehydrogenase (DPD).
`Patients and 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 2nd course
`LFA and 5-FU were administered on day 1 and TOM on day 2 with the aim
`of evaluating DPD and 5-FU AUC with and without pretreatment with TOM.
`Further treatment was given according to the sequence used in the 1" course.
`Results: Available clinical data are summarized below.
`
`Type'
`
`N4
`N 4, N 4; N 4
`N 4, M 3, R 3
`
`Response
`0/6
`1/8 (PR)
`1/6 (PR)
`3/6 (2CR, 1PR)
`0/7
`1/8 (CR)
`6/13(1CR,5PR)
`1/3 (PR)
`OR
`
`DLT
`0/6
`0/6
`0/6
`0/6
`0/7
`1/8
`3/15
`2/3
`
`C/HN"
`1/5
`6/1
`5/1
`5/1
`6/1
`8/0
`9/7
`2/1
`41/17
`
`Pts
`
`66e67e1
`
`6
`3
`58
`
`TOM/LFA/5FU (mg/m2)
`1.5/250/600
`2.O250/800
`2 0/250/750
`2 5/250/750
`2.5/250/900
`3.0/250/900
`3 0/250/1050
`3 0/250/1200
`
`Step
`
`12 34 5e7 8T
`
`otal
`
`"C - colorsctal cancer; HN=hsad & neck cancer. C - 6/39 (15%); HN = 7/16 (44%); N -
`neutropenia; M • mucosttis, R ° Renal
`
`DPD activity has been measured in 14 pts thus far. Pretherapy DPD activity
`was a median 34% higher than after TOM administration (95% C.I. - 93 to
`+62%). PK data are available in 6 patients thus far, and 5-FU AUC basal
`values do not significantly differ from values obtained 24 hours after TOM.
`Conclusions: The combination of T0M+ 5-FU/LFA Is well tolerated every
`2 weeks. Clinical activity looks very encouraging, since the majority of pts had
`already received prior chemotherapy. We are now treating some additional
`chemo-nalve patients at step 7, in order to have a more reliable estimate of
`the activity of the regimen.
`
`| 611P | Radlo-locallzatlon of pulmonary nodules using
`gamma-probe and resection by video-assisted
`thoracic surgery
`A. Chella. G.F. Menconl, F.M.G. Melfl, A. GonflottJ, G. Bonl1, G Grosso',
`E. Baldinl2, C.A. Angelertl. Service of Thoracic Surgery, Department of
`Surgery, ' Service ol Nuclear Medicine and1 Service of Medical Oncology,
`Department of Oncology, University of Pisa, Italy
`
`Video-assisted thoracic surgery (VATS) Is emerging as safe procedure for
`diagnosis and treatment of peripheral pulmonary nodules. One limitation of
`thoracoscopic technique Is the inability to detect those nodules which are very
`deep beneath the pleural surface, and could only be Identified via manual
`palpation. Several methods are used to localize VATS occult lesions prior to
`excision, Including methytene blue Injection and introduction of hooked-wire;
`however, all suffer from limitations. Recent advancements in Intraoperative
`radlo-locallzatlon 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 perileslonal 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
`(Sclnti Probe MR 100 - Pol hl.tech., Aqulla, Italy), equipped with 11mm
`
`Annals of Oncology. Supplement 4 to Volume 9, 1998 © 1998 Kluwer Academic Publishers, Printed in The Netherlands
`
`127
`
`Teva – Fresenius
`Exhibit 1022-00003
`
`

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`
`616P
`
`Phase I trial and pharmaclklnetlcs of
`beta-D-glucosyllsophosphoramlde mustard (D-19575)
`administered as a 6-hour Infusion every three weeks:
`An EORTC-ECSG study
`E. Bnasoulls'. I. Judson2, N. Pavlidls1, P. Beale2, Y. Groot3, G. Veerman3,
`M. Schuessler4, D. Rammou, R. Walker2, A. Hanauske5. 1loanmna University
`Hospital, Greece;2Royal Marsden Hospital, UK;3EORTC-NDDO, *ASTA
`Medlca AG, 5Gasthulsoerg University Hospital, Leuven, Belgium
`
`Introduction: D-19575 Is a beta-D-glucose-linked isophosphoramlde mustard
`aiming to exploit the transmembrane glucose transporters overexpressed In
`tumour cells. This compound was taken into clinical testing because precllnical
`data showed a higher selectivity and less myelosuppression than ifosfamide.
`Methods: The present study employed a two-step 6-hour Intravenous
`infusion (1/4 of the dose in 30-mlnutes, followed by 3/4 over 5j 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 analysis were collected In all patients at the first course of treatment
`Thus far, 17 patients (8F/9M, median age 54, range 33-72) with refractory
`solid malignancies have been treated over the range of 800 to 6000 mg/m2
`and a total of 44 courses of treatment have been given
`Results: Nephrotoxicity was dose-limiting at 6000 mg/m2 which was defined
`as the MTD for this schedule. Additionally, a short lived grade 4 neutropenla or
`leucopenia was seen In 3/6 patients at this dose level. Renal toxicity occurred
`In 2/6 patients as shown by tubular dysfunction and reversible impairment of
`gtomerular fBtration that developed eight days after the second and third course
`of treatment respectively and required hospitalisation. Main findings consisted
`of prolonged metabolic acidosis, polyuria, grade 3 hypokalaemia, prolonged
`hypophosphataemia with phosphaturia, renal glyc