Insertion In 5'-nanklng region of apo AI, apo Gill, apo AIV and hence some
`weak changes In appropriate metabolic processes.
`
`NOVEL THERAPEUTICS AND PHARMACOLOGY - -
`
`Clinical and pharmacoklne11c (PK) results of 4 phase I
`studies of the second generation matrix
`metalloprotease (MMP) Inhibitor bay 12-9566, a
`non-pep"dlc blphenyllnhlbltor of MMPs 2, 3 & 9
`L. Sevmour', L. Grochow-2, G. Eckha.n:lt3, C. Erllchman•, H. Hu1e1
`, A. Goei 1 ,
`R. Humphrey6, I. Eiias5 . 1 NCI-Cans.da Clinical Trials Group; 2Johns Hopluns,
`Baltimore; 3CRTC, San Antonio; 4Mayo Clinic, Rochester; 5Bayer
`Corporation, West Haven, CANADA
`
`Introduction: MMPs are Involved In Invasion, metastasis and angu)Qenesls;
`MMPs 2 & 9 are overexpressed In the tumor/stroma of multiple cancers and
`correlate with outcome In many. MMPs are thus attractive targets lor Inhibition.
`BAY 12-9566 has nanomolar Inhibitory activity against MMP 2, 3 & 9 with
`anti-lnvasive, anti-metastatic and anti-angiOgenic effects In predimcal models.
`Methods: 4 dose ranging trials of oral BAY-129566 were conducted In
`North America to define PK/safety. Dose ilmillng toxlclty (DLT) was toxlclty :::
`grade (gr) 3; symptomatic or DL gr 2; MTD was declared If > 2 patients (pts)
`experienced DLT. Eligible pts had PS o-2 and acceptable organ lunctlon.
`Fle8ults: 90 piS (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
`(plts)(nadir d 15-27) reversible with continued therapy; In 4 heavily pretreated
`pts pits fell to gr 213 leading to prophylactic dose reduction; and mild anem1a.
`Mild reversible transaminase 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
`remaln on study (mean 236d [14o-314d]). 1 pt wtth refractory melanoma (3
`prior regimens) had PR < 4 wks duration; 1 pi with refractory ovarian cancer
`(7 prior regimens) has SO alter 9.5 months.
`
`3
`
`4
`
`7
`
`2
`
`Dose Level (DL)
`Number ol pta (N)
`TotaVday (mg)
`Dose (mg)
`Schedul<l
`028 Trough (mean: mg/L)
`AUCo-.:i• 028 (mean, mg/M..) 1161 -
`
`9
`6
`8
`5
`10
`12
`15
`18
`16
`3
`3
`10
`aoo 1200 1600 1600
`400
`100 125 150 200
`400
`400
`400
`100 125 150 200
`600
`400
`BID no OlD BID
`00 00 00 00 OD
`125
`64
`132
`37
`72
`125
`117
`38
`51
`-
`1739 1411 2300 3035 2275 3135
`
`Molecular oncology/ Novel therapeutics and phannacology
`
`Fourty lour pta are evaluable lor response and 3 pts are too early: 9 partial
`responses (7 mesothelioma, 1 pancreatic cancer, 1 renal carcl noma) 18 stable
`disease and 17 progressive disease.
`Conclusion: Th1s combination IS well tolerated and has shown actMty. In
`the light of these good results, we are planning two plhasa II trials at a dose of
`3 mgT and 130 mg of L-OHP: one In mesothelioma and another In advanced
`colorectal cancer.
`
`J6030 J 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. Cakilera 1 , J. De Jong1 , C. Monnerat2, D. Perartfl, L Vemliietl,
`A. Riva3 , M. BesenvaP, J. Bauer2. 10sp. San Giovanni, Belllnzona, 2 CHUV,
`Lausanne, Switzerland; 3 Rh6ne-Poulenc Rorer, Antony. France
`RPR1 09881 A has shown a broad spectrum of activity in In villo and In vitro
`tumor models and Is able to cross the blood bram barrier. Rve phase I
`studies are ongo1ng to define the recommended dose and schedule (1-, 3-, 6-,
`24-hour and 1-hour dl-08 q3w). We report the preilmlnary results of the 3-hour
`schedule with an oral premedication with dexamethasone (-25, -13, 1-hour).
`The starting dose of 75 mgtrn2 was defined according to the safety profile of
`pts treated with other schedules (1-hour/6-lhour). Dose escala!Jon was done
`according to the modified Rbonaccl's schedule. 13 pta (9 maloo/4 females -
`median age: 52) previously treated with ::: 2 prior chemotherapies (CT) were
`included. The dose limiting toxlcttles (DLTs) are as follows:
`
`Dose
`rroo;ym2
`
`75
`90
`
`:: 1 prio< CT
`Nb of
`DLTs at the flrat
`pts
`cycle
`oo
`1
`febrile
`8
`nuetropenla (1)
`
`Nb of
`piB
`
`2
`4
`
`~ 2 prior CT
`DLTil at the first cycla
`
`no
`toxic death. acute resplratOfY distress
`syndrome" (1)
`diarrhea gr.3, fatigue gr3 (1)
`dlarrM8 gr.3, febrile neutropenia (1)
`neutropenia gr.4 > 7d (1)
`
`·In NSCLC pi with pulrnonruy fibrosls secondary to radiotherapy
`
`50% pts presented neutropenia Gr.4. Alopecia Gr.213 was universal; other
`toxlclties were: arlhraigiB, nausea, rash of mild to moderate severity. One pt
`d1ed because of viral Infection while neutropenic alter the 4th cycle. Blood
`samples were collected over a o-48 h period for PK analysis. PK parameters
`were eimllar over the 2 tes1ed doses wtth mean valuea of plasma clearance,
`volume of distribution and terminal half-life of"' 40 1../h/rnl!, 1000 Um2 and 30
`h, respectively (n=11 ). Additional pts wlll be treated at 90 mg/m2 (::; 1 previous
`en or 75 mg/m2 (::; 1 praVlOUS CT + RT) and randomized between 1-h versus
`3-h to establish the best schedule and to confirm its feasibility lor phase II
`study. Two confirmed partial response In 2 NSCLC pts has been observed
`at 90 mg/m2: one untreated pt Pfesented brain metastases and responded In
`both lung and brain leslons.
`
`16040 I 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. Aherne, C. Rees, A.H. Calvert,
`I.A. Judson, S. Dlab, K. Mayne, M. Smith. the ZD9331 Phase 1/nternBtional
`Investigators Group; CRC Centre for Cancer Therapeutics, The Institute of
`Cancer Res9Brch, Sutton, UK
`
`Introduction: lnhlbiuon of TS by rallltrexed (Tomudex~; Zeneca) or the non(cid:173)
`polyglutamatable drug ZD9331 leads to a rise 1n the level of intracellular
`dUMP and hence plasma dUrd In mice and humans. Plasma dUrd levels were
`measured In lour plhase I dose escalating trials of ZD9331, Including two trialS
`where a 30 mm mluslon was g1ven elther 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 -700C). Following de(cid:173)
`protelnlsatlon and solid-phase extraction, samples were analysed for dUrd by
`lsocratic reverse-phase HPLC uslng a spectral scanning UV detector.
`Results: Both trials started at a dose of 4.8mglm2/d. A rise (~2-lold) In dUrd
`was seen at th1s dose that was of -48h duration (-d2-3/d9-1 0). As doses
`Increased, a more prolonged effect and In some patients a greater rise In dUrd
`levels was seen e.g. at 19.2mglm2/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 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 pi"OVlde evidence of TS 1nhlbltlon that Is of longer duration with
`increasing doses of ZD9331. Two patients at 4.8 and 9.6mg/m2/d on the d1
`and 8 schedule showed a partial and minor tumour response respectively. The
`trials are ongo<ng and the MTD has not yet been reached.
`
`Conclusions: Oral BAY 12-9566 (800 mg bld) Is well tolerated With transient
`and usually clinically Insignificant decreases In pit counts and m11d anemia the
`only dose related toxicltles.
`
`j6020 J Updated results of a phase I trial of Tomudex® (T) In
`combination with oxallpiatln (L-OHP) In advanced
`solid tumors: A promising and active combination
`
`M. Ducreyx, K. FIZBZI, C. Daniel, P. Ruffle, A. Kabouche, A. Fandi, M. Sm1th,
`J.P. Armand. lnstltut Gustava Roussy, V/1/ejurf (France), Zeneca
`Pharmscautlcals, Cergy, (France)
`
`Introduction: The aim of the study Is to determine the m8XJmum tolerated
`dose and the recommended dose IOf subsequent phase II trials. The drflerent
`mechanisms of action and toxlclty profiles ofT and L-OHP are the rationale to
`test their combination
`Methods: Twas administered as a 15 minutes Infusion followed by L-OHP
`as a 2 hours Infusion, repeated 3 weekly. Dose escalation Is shown below:
`
`Dose~
`
`T/L-OHP
`(mglrrf)
`Number ol
`(ptslcyclea)
`
`1
`2185
`
`2
`2.5/M
`
`3
`2 51110
`
`4
`3/110
`
`5
`31130
`
`6
`3.51130
`
`7
`3.751130
`
`3110
`
`3121
`
`3112
`
`3110
`
`16/63
`
`14161
`
`516
`
`Patients. so far, 4 7 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 mesothelioma (17), gastrointestinal malignancies (14), renal
`carclnoma (5), lung cancer (4), other (7). Thirty six pts were pre-treated.
`Results: During the first 4 levels, no dose-limiting tOXJclty was observed.
`An asymptomatic Increase in transamlnases was frequent whatever the step.
`During the subsequent steps, grade 3 + 4 toxicities Included: pta (cycles)
`Step 5: vomiting 3 (3), diarrhoea 2 (3), neu1ropenla 1 (2), thrombocytopenia
`1 (1 ), anemia 2 (2), periplheral neutoXIcity 1 (1 ), asthema 1 (1)
`Step 6: vomiting 2 (2), neurotoxicity (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 toxlclty was observed. However,
`gastrointestinal toxicities and asthenia seem dose-limiting.
`
`AnnaiJ of Oncology. Supplement 4 to Volume 9. 1998
`
`0 1998 Kluwer Academic Publishers, Pnnted in The Netherland.<
`
`125
`
`NEPTUNE GENERICS 1021- 00001
`APOTEX 1021 -0001
`
`

`
`Novel therapeutics and phannacology
`
`Conclusions: A rapid, sensJtive and reliable method has been developed for
`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 trlals of ZD9331 and understanding
`the relationship of durabon of target Hlhlbltlon and response/loxJdty.
`
`lsoso I Strategies for Improvement In dose escalation using
`
`the continual reassessment method (CAM) In phase I
`clinical trials
`LL Siu, X. Paoletti, J. O'Qulgley, E.K. Rowlnsky, G.M Clark, D.D Voo Hoff,
`S.G. Eckhardt. Cancer Therapy and Research Canter, 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 alm of
`exposing a greater proporbon of patients (pts) to therepautlc drug doses than
`traditional approaches. The statistical model utilized Is a sequential Bayesian
`estimation scheme In which a prior distribution functloo of the ITlBXlmum
`tolerated dose (MTD) and a dose toxic-response model are selected before
`the trial. The MID Is the dose at which a pre-determined percentage (e.g.
`30%) of the pt )Xlpulatlon 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 which lndude the use of a conventional startlng dose and the
`fixation of dose levels a pnon, customarily by applying the modtfled Fibonacci
`sequence. However, our experience with !Ius dose escalabon method has
`been problematic due to the dependence on non-clinical toxicity Information
`prior to the trial, and the difhcuity of predicting a fixed number of dose levels.
`Therefore, we have deslgned a "dual-stsge" escalation scheme. The 1nitial
`stage Involves utilization of a conventional starting dose wrth doubling of the
`dose In single-pi cohorts until moderate toxicity (e.g. Gr 2 non-hematologiC or
`Gr 3 hematologic) Is encountered, at which point 2 additional pts are secured
`and doae 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
`Bayes1an methodology, a maximum likelihood approach (O'Qulgley and Shen)
`Is applied which offers greater flexibility wttlhout restriction by the paudty of
`prior data. Pracbcal examples and slmula!Jons of models will be provided to
`Illustrate this proposed dose escalation method.
`
`lsoso I Synergistic antitumor effect by novel modified
`
`oligonucleotides targeting PKAI combined with
`cytotoxic drugs or monoclonal antibodies
`G. Tortora, V. Damiano, R. Blanco, S. Pepe, A.A. B1anco, S. Agrawal1 ,
`J. Mendelsohn2, F. Clardiello. Oncologla M9dlca, Unfv F9derlco II, Napo/1,
`Italy; 1 Hybridon, Cambridge, MA, USA; 2 UT-MO Anderson Cancer Center,
`Houston, TX, USA
`
`Introduction: Protein kinase A type I (PKAI) plays a key role In neoplastiC
`transformation and conveys mijogenlc signals of different growth factors and
`oncogenes. Moreover, PKAI Is overexpressed 1n cancer cells with an active
`TGFa-epldenmaJ growth factor receptor (EGFR) autocrlne pathway and shows
`a structural and functional interaction with EGFR. lnhlblbon of PKAI, or its
`regulatory subunij Ria, results In cancer growth mhlbltlon In vftro and In vfYO.
`Methods: A novel class of mixed backbone oligonucleotides (MBOs) tar(cid:173)
`geting PKAI (ASRia), with Improved pharmacoklnetic and b!oavallab1ilty, and a
`humanized monoclonal antibody which blocks activation of EGFR, MAb C225,
`have been tested In vitro and In vfYO on several human cancer cells.
`Results: A dose;:lepandent mhlbltlon 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 with taxanes,
`platinum-derlvatJves and to)Xl 11-selectlve drugs. When the MBOs administered
`elther J.p. or p.o. were added to paclrtaxel, a cooperative effect was also
`obtained In vivo, causing tumor growth Inhibition and Increase of survival In
`nude mJce bearing human cancer xenografts Finally, combmed treatment of
`human breast and renal cancer cells, whiCh overexpress PKAJ and EGFR,
`with the AS Ria MBO and MAb C225, caused a cooperative antitumor 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 with selected
`cytotoxic drugs may represent a feasible novel therapeutic strategy
`
`j6070 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.
`Hospital Rudolfs~ftung Oncol. Dep., Instil phBrma chem Vumna, Austna
`
`Introduction: Combination of DOX with TXT has been shown to be highly
`effective In advanced breast cancer recently Introduced into adJuvant treatment
`Purpose of the present study was to detect a potential PK lntaractlon between
`
`DOX and TXT, as already proven for Paclltaxel + DOX leadlng 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
`50mglm2 30mln Int. followed Immediately (A) of after 1 HR Interval (B) by TXT
`75mg/m2 1 HR Infusion.
`Methods: All pts received TXT alone at cycle 1 for baseline determination
`followed by DOX + TXT (1 8 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, Wln Nonlln noocompartlmentsl analysls
`parlormed.
`Results: of the respective AUG last:
`
`AUG
`ng/mi.H
`
`A
`B
`
`Taxotere
`OOXfTXT
`
`TXT
`
`1484
`t 703
`
`1956
`2450
`
`n
`
`18
`13
`
`p
`
`0.03
`0.05
`
`n
`
`12
`6
`
`Doxorubicin
`OOX
`OOXfTXT
`
`859
`906
`
`848
`833
`
`p
`
`0 9
`0.6
`
`Conclusion: No Influence of TXT oo DOX-AUC documented, DOX-ol cone
`(n=S) Wlth or wfthout TXT n.s. different (p 0 2 - 0.8), thus exptamlng low
`cardlotoxiclty of the cornblnatloo. In contrast, TXT-AUG was SJgnlftcantly In(cid:173)
`creased when combined wrth DOX. suggesbng lnterlerence at the hepatic
`microsomal level, partly expla1ning high clinical efflcacy. A 1 HR delay between
`end of DOX and start of TXT does not change the respective PK behaviour of
`both drugs.
`
`!soaP I Gemcltablne (GEM)- clsplatln (COOP): A schedule
`
`finding phase VII study
`J.R. Kroep 1, G.J. Peters 1, C.J.A. Van Mocrsel 1, J.B. Vermorken3 ,
`P.E Postmus2, A. Cetik 1 , H.M. Plnedo1 , C.J. Van Groeningen 1 • 1 Dept. Oncol.
`and 2Pulm., Univ. Hosp. VU, Amsterdam, NL snd 3Dept. Onco/., Unlv. Hosp.
`Antwerp, B, The Netherlands
`Introduction: Gem and CDDP are active agalnst various solid tumors. Slnce
`precilmcal studies demonstrated the efficacy of various schedules we evaluated
`the tolerabtlrty and clinical efficacy of 4 different Gem/CDDP schedules as part
`of a pharrnacokine!IC and -<lynamlc (PKIPD) study.
`Methods: Gem BOO mg/m2 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 (1 0 pts), or vice versa (14) and Gem 24 hr before COOP (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 perlormance 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 adenocarclnoma, 2 pancreatic, 2 colon
`and 1 small cell lung (SCLC). 26 pts 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, rasp. The most frequent overall grade 314 CTC-toxiclty was throm(cid:173)
`bocytopenia, 6110, 4/14, 219 and 619 (overall 60%), followed by leukopenia,
`8110, 5114, 619 and 619 (43%), in the 4 schedules, rasp. Therefore, Gem was
`not given oo d 15 In 36% of pts in cycle 1. Anemia was observed In 64%
`of pts. No serious bleeding occurred. Myelotoxlclty was cumulabve, but not
`schedule dependent Non-hematological toxlclty consisted mainly of grade 1/2
`nausea/vomiting and langue. One pabent died of toxlcrty following severe neu(cid:173)
`tropenia and sepsis. Creatinine clearance decreased sl1ghtly during therapy.
`Ann-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.
`Coocluslon: (Cumulative) myelosuppression was the major toxicity, al(cid:173)
`though ij was not schedule dependent. Based on toxicity, efllcacy and PKIPD
`data a phase II study, CDDP 24 hr before Gem, has been started in pts with
`upper gastro-mtestlnal tumors
`
`lsogp I MTA (LY231514): Relationship of vitamin metabolite
`profile, drug exposure, and other patient
`characteristics to toxicity
`C. Nlvlklza, s. Baker, R. Johnson, J. Walling, D. Seltz, R. Allen. Ulfy Res6Brch
`Laboratories, lndiBnB, USA; Cancer Treatment and Research Center. Taxss,
`USA; Unlv of Colorado HaBltfl Sciances Canter, Colorado, USA
`
`Introduction: MTA 1s a novel multitargeted antifolate with Inhibitory activity
`against mulbple enzymes. Phase Vll studiEtS have shown activity In a variety
`of tumors Hlstor1cal data on other antifolates have suggested that a patlenfs
`nutntlonal ststus may play a role In the likelihood of experienclng severe tox!dty.
`The purpose of th1s study was to assess the relationship of vitamin metabolrtes,
`drug exJXlSUre, and other prespeclf1ed baseline patient characteristics to toxiclty
`following treatment wrth MTA.
`Methods: Homocysteine (Hcys), cystathionine and methyl maloniC acid were
`measured In 139 phase II patients with tumors of the colon, breast, pancreas,
`and esophagus at baseline and ooce each cycle thereafter. Stepwise regres(cid:173)
`SIOO modeling, multivariate analysis of variance, end discriminant analysis
`were Implemented to determine wh1ch predictors might correlate wlth severe
`toXJclty after one course of MTA. Prognostlc factors considered were age, gen-
`
`126
`
`Annals of Oncology, Supplement 4 to Volume 9. 1998
`
`C 1998 Kluwer Academic Publishers, Pnnted m The Netherlands
`
`NEPTUNE GENERICS 1021- 00002
`APOTEX 1021 - 0002
`
`

`
`der, prior treatment, baseline albumin, liver enzymes, ANC, platelets, vitamin
`metabolites, and AUC.
`Results: Statistically slgruflcant pred1ctors of Grade 4 neutropema (n=21
`pts) were albumin (p = 0.0006) and Hcys (p = 0.0012), wh1la Grade 4
`thrombocytopenia (n=8) was h1ghly predicted by Hcys (p < 0.0001) and
`pre-treatment AST (p = 0.0012). Hcys ;:: 1 Oi<M predicted Grade 4 neutroperua
`In cycle one 75% of the time. Grade 4 neutropenia was predicted by Hcys
`alone In 70% of cases. Hcys and albumin levels cfld not appear to change
`from baseline during treatment wrth MTA While AUC was not found to be a
`predictor of toxicity, little variabtlrty was observed In AUC. Maximum values
`ware still below AUC values related to hematologic toXIcity In phase I studies
`Conclusions: Toxicities resulting from treatment with MTA appear to be
`predictable from pretreatment homocysteine levels. Elevated baseline ho(cid:173)
`mocysteine levels (:: 10JLM) highly correlate with severe hematologic and
`nonhematologic toxicities following treatment with MTA. Homocysteine was
`found to be better than albumm 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 clsplabn.
`
`ls1 OP I Phase I and pharmscoklnetlc (PK) study of Tomudex
`
`(TOM) + 5-Fiuorouracll (5-FU) and levofollnlc acid (LFA)
`In advanced head and neck end colorectal cancer
`F, Gaponlgro, R. Gasarettl, H.L. McLeod', A. Budlllon, G. Certenl, F. De Vita,
`A. Avallone, M. Blglletto, A. Tuccl, 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 Aberd8en, 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 actlvt1y
`of dihydropyrimidlne dehydrogenase (DPD).
`Patients and methods: Patients (pts) with advanced head and neck and
`colo rectal cancer were treated with escalating dosea of TOM on day 1, and
`bolus 5-FU (Immediately after LFA) on day 2, every 2 weeks. In tihe 2"" course
`LFA and 5-FU wBfa administered on day 1 and TOM on day 2 with the alm
`of evaluating DPD arid 5-FU AUC wrth and without pretreatment With TOM.
`Further treatment was giVen according to tihe sequence used In tihe 1"' course.
`Results: Avallable clinical data are summarized below.
`
`Step TOWLFAISFU (rng.im2)
`1.512501600
`2.()'2501600
`2 01250/750
`2 51250/750
`2.51250/g()(J
`3. ()'2S0/9()(I
`3 012501 1050
`3 0/250/ 1200
`
`CIHN" DLT
`Pta
`016
`Or'6
`6
`1/5
`5/1
`1/e(PR)
`016
`6
`1/6 (PR)
`016
`6
`511
`316 (2CR, 1 PR)
`Or'6
`6
`511
`4
`611
`017
`017
`5
`7
`610
`8
`6
`118
`1/8 (CR)
`917
`3115
`6/13 (1CR, 5PR)
`16
`7
`s
`213
`113 (PR)
`2/1
`3
`OR
`Total
`58
`41/17
`-c. coloroctal cancer; HN=h&ad & neck cancer. c. 6139 (15%); HN a 7/16 (44%); • N.
`neutropenia; M • mucoaJtls, R a Renal
`
`Type.
`
`Response
`
`N 4
`N 4, N 4; N 4
`N 4, M 3, R 3
`
`Novel therapeutics and phamwcology
`
`diameter-<:allimated probe, allowed us to locate that lesion for thoracoscopic
`resection. From June 1997 to January 1998 we treated 15 consecutive patients
`(pts) with sutK:entlmeter pulmonary nodules. Nine pts were affected by a
`synchronous and metachronous malignant neoplasm In other sltes. Computed
`thomography of the chest helped In the planmng of the operative procedure, the
`poslbon of pts, and ideal ports. A hot-spot was eas1ly detected, In all patients,
`by the probe Introduced In the pleural space through a 11.5 mm trocar. The total
`exclslon 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 leslons
`(4 metastases and 3 lung cancer) and It confinned the absence of lnflijration
`In the resection margms The surgical procedure was extended for an average
`of 56.6 minutes (range 35-100 min). The average post-<>PSrative 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.
`
`ls12P I Pharrnacoklnetlc (PK) of Tomudex® (raltltrexed) (T)
`and oxallplatln (0) combination: Preliminary results of
`an ongoing phase I study
`K. F1zazl 1, M. Bonnay', D. FourcauH1 , P. Ruffle', 0. Couturas2 , M. Smittr!,
`R Gomenf!, A. Fandi 2 , J.P. Armarid'. 1/nstltut Gustave Roussy, V/1/ejuif,
`2 Zeneca PharmaceuticaJs, Cergy, France
`
`Introduction: The a1m of this study was to evaluate the posslble kinetic
`mteractlons between T and 0 administered to patients with advanced disease.
`Methods: Patients first received T (15 min Infusion), followed 45 minutes
`later by 0 (2-hour Infusion). Three patients recetved T at a dose of 3 mg/m2
`arid 3 at a dose of 3.5 mg/m2. All of them received the same dose of 130
`mgtm2 of 0.
`Results: Plasma concentrations of T declined trf-exponentlally after the
`end of the Infusion. The terminal t1/2 derived from samples up to 28 hours
`post-dose vaned between Individuals from 9 3 to 193.2 h w1th average values
`of 73.4 and 33.7 for the two dose levels. The max1mal concentrations varied
`between 323 and 1185 ng/ml with averages of 681 and 813/n the 3 mgtrn2 and
`3.5 mg/m2 groups respectively. The AUC varied between 720 and 3192 ng.hlml
`with average of 1577 and 1378 In the two groups. The comparisoo between
`the two groups did not revealed any difference, probably due to the very large
`Intra subject vanabllity, however the mean AUC showed an approximately
`proportional Increase with 1ncreaslng dose. The estimated klne~c parameters
`were In agreement with the values previously published. Plasma concentrations
`of 0 declined bi-exponentially aft9f the end of the Infusion. The terminal t1/2
`varied from 18 to 30 h (average of25). Cmax rengadfrom 3.13to 4.53 (average
`of 3.69) llg/ml. The AUC ranged from 74 to 120 (average of 195) 1•g.hlml and
`the Cl vaned between 1.76 arid 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 corldrtlons seems to Indicate that T lrlduced 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 reduction of Cmax measured at the end of the lnfuslon from 5.11 to
`3.69 JLg/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 admlmstered alone. These results Indicate possible PK
`Interaction between the two drugs.
`
`1613P I A phase land pharmacoklnetlc (PK) study of ET-743, a
`novel minor groove binder of marine origin
`administered on a dally x 5 schedule
`M. Hidalgo, M.A. Vllla/ona-Calero, S.G. Eckhard1, G. Weiss, E. Campbell,
`M. Kraynak, J. Beljnen, J. J1meno, D. Von Hoff, E. Rowinsky. Cancer Therapy
`and Research Center, San Antonio, TX, The Netherlands Cancer Institute,
`Amsterdsm, The Netherlands; PharmaMar, S.A., Madnd, Spain
`
`ET-743 Is a novel tetrahydrolsoqulnollne alkaloid Isolated from the marine
`organ1sm EstenBJSCidian furblnata which binds to adenln&-<:ytosine rich regions
`within the minor groove of DNA. This study Is evaluating the feaslblll1y and
`PK behavior of ET-743 administered as a 1-hour lntuslon daily 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 ttg/m2!day. At the 380 JLg/m2day
`dose level, 1 patient with extensive prior treatment with 16 cycles of BCNU
`developed grade 4 thrombocy1openia, grade 4 neutropenia with fever, grade
`3 elevabon In transamlnases. and acute renal fa1lure which resulted In death.
`Four patients (8 cycles), at the 216 (1), 287 (1) and 380 (2) ltgtrrlllday dose
`level developed asymptomatic elevation 1n hepatic transamlnases of grade
`3 severity that typically peaked on day 8 and resolved by day 21. M11d 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
`JLg/m2/day dose level suffered supertlclal venous thrombophlebitis at the drug
`Infusion site. PK parameters obtained In 2 patients at the 216 !1Qim2day dose
`level1ncluded: clearance, 137 and 589 mUmln!m2; t112 , 13.7 and 23.1l.lh; and,
`
`DPD activity has been measured m 14 pts thus far. Pretherapy DPD actlvtty
`was a median 34% higher than aft9f TOM administration (95% C.l. -93 to
`+62%). PK data are available 1n 6 patients thus far, and 5-FU AUC basal
`values do not slgnlflcantly differ from values obtained 24 hours after TOM.
`Conclusions: The combination of TOM+ 5-FUILFA Is well tolerated every
`2 weeks. Clinical actlvl1y looks very encouraging, since the majority of pts had
`already recelved prior chemotherapy. We are now treating some additional
`chemo-nalve patients at step 7, In order to have a more reliable estimate of
`the actMty of the regimen.
`
`ls11 P I Radio-localization of pulmonary nodules using
`gamma-probe and resection by video-assisted
`thoracic surgery
`A. Chell a, G.F. Menconi, F.M.G. Melfi, A. Gonflottl, G. Bonl 1, G Grosso 1 ,
`E. Baldlnf2, C.A. Angeletti . Service of Thoracic Surgery, Department of
`Surgery, 1 Service of Nucl68r Medicine and 2 Service of Medical Oncology.
`Department of Oncology, University of Ptsa, Italy
`
`Vldeo-asslsted thoraciC surgery (VATS) Is emerging as safe procedure for
`diagnosis and treatment of peripheral pulmonary nodules. One limitation of
`thoracoscopic technique Is the lnabilrty 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
`exclelon, Including methylene blue Injection and Introduction of hooked-wire;
`however, all suffer from limitations. Recent advancements In Intraoperative
`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 perileslonal Injection of 0.2 - 0.5 ml of solution ol 99m Tc-labeled
`human serum albumin mlcrospheres (5-1 0 MBq) and 0.2 ml of iod1ne-non-lomc
`contrast medium, two hours before surgery. In VATS a gamma ray detector
`(Sclntl Probe MR 100 - Pol hl.tech., Aquila, Italy), equipped with 11mm
`
`Annal• of Oncology. Supplement 4 to Volume 9, 1998
`
`0 1998 Kluwer Acadenuc Publishers, Printed m 1be Netherlands
`
`127
`
`NEPTUNE GENERICS 1021- 00003
`APOTEX 1021 - 0003
`
`

`
`Novel therapeutics and phannacology
`
`AUCo-.2.<n. 158 and 367 ng-minlml. AUCc-6c~ay~ (790 and 1835) were::: than
`the mouse AUC at the LD10 (854 ng-mlnlml). No drug accumuiabon was noted
`from day 1 to 5. In condusJon, ET-743 produced severe toxiCity with multlorgan
`involvement at the 380 l'glm21day In one exceptionally heavily-pretreated
`patient. Additional subjects are being evaluated at this dose level to define the
`MTD of ET-743 on this schedule of administration.
`
`I614P I A phase I and pharmacologic study of the oral matrix
`metalloprotelnase Inhibitor, BAY 12-9566, In
`combination with paclltaxel and Corboplatln
`S.G. Eckhardt 1 , J. Alzzo1 , C. Britten 1 , L Siu1
`, A. Humphrey2, L. Smetzer1 ,
`M. Sorensen2, P. Sundaresan2, D.O. Von Hoff1 , E.K. Rowinsky 1 • 1 Cancer
`Therapy and Research Center, San Antonio, Texas, USA; 2 Bayer
`Corporahon, West Haven, CT, USA
`
`BAY 12-9566 is a biphenyl nonpeptidic 1nhlbltor of zinc-dependent endopeptl(cid:173)
`dases (matrix metalloprotelnases, MMPs) that degrade the extracellular matrix
`and are associated with the processes of angiogenesis and metastasis 1n
`human malignancies. This phase I and pharmacologic study was perfonned
`to evaluate the feaslblllty and pharmacologic lnterac!Jon of oral BAY 12-9566
`when administered continuously With Intravenous pacUtaxesl and/or carboplatin
`every 3 weeks. The study was dMded Into 3 consecutive co