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`Supplement to
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`.Cancer .
`Research
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`•:.):j European Oiganization for Research
`~ and T~eatment of Cancer
`
`November 1999 •Volume 5 • Supplement
`PP. 3729s-3897s • ISSN 1078-0432
`
`Bn;·i·; .:~;~1 '.#(:~;: 1.11. P'/
`DOCU~lEt·iT ~.d?i::L\.r C;;J·JT~iE
`- 8 DEC 1999
`Co' '' E .... r-- 1"E
`1\!r -:Hd"~ ' ...
`INDEXED
`
`West-Ward Exhibit 1007
`Alexandre 1999
`Page 001
`
`

`

`3880s :7/ufhor gndex
`
`Clinical Can cer Research • Volume 5 • November 1999 (Supplement)
`
`Numbers preceded by a "p" denote page numbers ; all others denote abstract numbers.
`
`A
`
`Aapro, M., 215
`Abbensetts, K., 473
`Abbnizzese, /., 224,
`290, 341,414
`Abbnizzese, f. L., 225,
`300, 336, 380,412
`Abdalla, M., 163, 473
`Abdel-Meguid, S. S., 382
`Abel, K. L., 510
`Aboagye, E., 491, p.
`3871s
`Abo deeb, A ., 72, 163
`Aboody, K. S., 460
`Abradelo, C., 620
`Abrahamsen, N., 510
`Abrahamson, /., 209
`Abrams, R., p. 3876s
`Achilles, E. G., 196,
`415
`Achterrath, W. , 346,
`649
`Acinapura, A. /., 72,
`163, 473
`Adams, A., 619
`Adams, /., 6, 184,
`204, 290,414
`Adcock, I., 239
`Adelaide, J., 32
`Adema, G. f., 377
`Adjei, A. A., p . 3873s
`Advani, R., 580
`Afar, D. E. H., 154,
`156
`Agarwal, \!., 340
`Agha-Mohammadi, S.,
`503
`Agrawal, S., 584
`Agus, D. B., 41
`A tleme, G. W. , 572,
`659
`Ahmad, R., 692
`Ahmed, A., 694
`Ailey, B., p. 3869s
`A ingom, E., 49
`Akinaga, S., ll9, 291
`Akiyama, S., 526
`Akiyama, T. , ll9
`Aktas, H., 174, 175
`Akusjarvi, G., 366
`A l-Awar, R., 127
`Albaek, C., 510
`Albers, A ., 150
`Albertion i, F., 431
`A lberts, D., 22
`Alberts, S., 340
`Albertson, H. M., 243
`
`Alexander, W. A., 94
`Alexandre, /., 7
`Alford, T.L., 664
`Algazy, K., 338, 345,
`579
`Algenstaedt, P., 196
`Alghazi, Y., 694
`Ali, S., 239
`Ali-Osman, F., 555
`Alisauskas, R., 454
`Allen, D., 64
`Allen, M., 694
`Alli, E., 685
`Allis, D. C., 238
`Allred, E. N., 415
`Allsbrook, W. C., 19
`Almiroudis, D., 428
`Alnemri, E., 260
`A lonso, G., 165
`Alonso, S., 313
`Alrawi, S. f., 72, 163,
`473
`Altomonte, \!., 24
`Alvarez, E., 657
`Alvarez-Salas, L. M.,
`587
`Amado, R., 13
`An, G. W., 291
`Anasagasti, M. f., 65
`Anderson, M., 191
`Andion, C., 165
`Andreassi, f. L., 178
`Angers, E., 530
`Angevin, E., 7
`Anthoney, A ., 307,
`313
`Anthony, L., 212, 213
`Anthony, N. [. ,
`p. 3869s
`Antolin, S., 165
`Anton, L., 165
`Antonian, L. 1 410
`Aoki, K., 592
`Appia, F., 10
`Aracil, C., 474
`Arafat, W. 0., 419
`Arakawa, F., 506
`Arany, I., 386
`A rasteh, K., 12
`Ardila-Osorio, H., 276
`Arencibia, I., 442
`Argnani, A., 678
`Ariel, I., 407
`Armand, f. P., 7
`Armand, f-P., 348
`Arnould, S., 599
`Arrastia, C. D., 386
`Arris, C. E., 124
`Artemov, D., 397
`
`Asao, T., 262, 563
`Ashktorab, H., 694
`Asim, M. , 692
`Asimakis, M., llS
`Atkas, H., 173
`Aubert, C., 578
`Augenlicht, L., 2ll
`Aulitzky, W. E., 378
`Avallone, A., 218, 226,
`447
`Averbuch, S., 29, 99,
`554
`Avila, /., 314
`Awada, A., 20, 513
`Ayers, D., 325
`Aylesworth, C., 332
`Ayres, M., 538
`Azimahtol Hawariah,
`L. P., 679
`Azuma, I., 158
`Azure, M. T., 199, 200
`Azzabi, A. S. T., 333
`
`B
`
`Baba, M., 494
`Baccini, C., 384
`Back, T. C., 379, 381
`Baddeley, H., 14
`Badea, I., 272
`Baggs, R., 199, 200
`Baguley, B. C., 396,
`675
`Bai, R., 630, 643
`Baichwal, V., 635,
`637, 651
`Bailey, H. H., 39
`Baker, C., 351
`Baker, S., 1, 332
`Baker, S. 0., :tl9
`Bakke, S., 553
`Balana, C., 330
`Balcerzak, S. P., 223,
`553
`Balestrazzi, E., 402
`Banerjee, D., 534
`Baohua, H., 464
`Baranov, E., 59
`Barazzuol, f., 122
`Barbarino, M., ll8
`Bardelli, A., 36
`Barer, F., 357
`Barkhimer, D., 12
`Barlow, H. C., 564
`Bamadas, A., 214
`Barnard, D., 362
`Barret, f-M. , 322, 674
`
`Bartsevich, V. V., 251
`Bar-Yehuda, S., 357
`Basanez, G., 429
`Basart, D., 539, 552
`Basas, f., 478
`Baselga, f., 29
`Bash-Babula, [. , 685
`Basilica, C., 36
`Bassano, L., 312
`Basser, R., 10
`Bassetto, M. A ., 222
`Bastow, K. F., 671
`Bates, S., 641
`Bates, S. E., 553
`Batey, M. A., 543
`Batist, 9., 221, 530,
`554
`Baumgart, f., 551
`Baumgarten, f., 666
`Bavetsias, \!., 565, 566
`Baynes, R. D., 349
`Bealieu, B. B., 343
`Beauchamp, R. D., 21
`Bechtel, P. E., 687
`Beck, f., 378
`Beckebaum, S., 149
`Becker, K-F., 87
`Becker, M., 69
`Beckmann, H., 635,
`637, 651
`Bedi, A., 397
`Beer, T., 531
`Beerheide, W. , 294
`Begleiter, A., 259
`Begley, M., ll4
`Beijnen, f. H., 307,
`308
`Bekesi, f. G., 281, 627,
`628
`Belanger, K., 1
`Belcourt, M. F., 458,
`459
`J)elf, r ., z:n
`Bellizzi, A ., 356
`Bellomy, K., 544
`Bender, /., 553
`Bennett, R. f., 607
`Ben-Porath, I., 371
`Bentzen, C., 22
`Bentzeq,__ C. L., 62,
`186
`Benvenisty, N., 371
`Ben-Yosef, T., 371
`Benyumov, A., 270
`Benz, C. C., 26, 92
`Bera, T., p. 3869s
`Berg, W., 465
`Bergeron, R. /., 467
`Berlin, f. , 614
`
`Bermudes, 0., 459,
`501
`Bernard, H-U., 294
`Bernardi, R. /., 37
`Bernareggi, A., 329,
`333, 613
`Bernhard, E. f., 193
`Berry, S., 194
`Bertino, f. R., 305,
`534, 654
`Bessette, P., 530
`Bevan, P., 512
`Bevers, S., 618
`Bewley, f. R., 657
`Bhalla, K., 76
`Bharaj, B., 481
`Bhaskaran, V., 480
`Bhat, A. S., 321, 632
`Bhujwalla, Z. M. , 397
`Biachwal, \!., 652
`Bianco, A . R., 28, 584
`Bianco, R., 28, 584
`Bibby, M. C., 470
`Biedrzycki, B.,
`p. 3876s
`Bigg, D. C. H., 665
`Biglietto, M. , 218
`Bindenip, L., 267
`Bingcang, A. L., 560
`Birnbaum, D., 32
`Biroccio, A., 280
`Bishop, C., 39
`Bishop, W., 77
`Bittencourt, M., SO
`Black, M. H., 482,
`484
`Black, P. M., 460
`Blackledge, G., 554
`Bladou, F., 45
`Blagosklonny, M., 134
`Blagosklonny, M. V.,
`359, 641
`B lair, I. A ., 345
`Blake, R., 410, 4ll
`Blanke, C. D., 21
`Blasi, M.A. , 402
`Blask, D. E., 146
`Bleiberg, H., 20, 513
`Blumenthal, R. D.,
`147, 390, 408, 432,
`454, 456
`Boadu, E., 475
`Bodey, B., 74
`Bodey, B. fr., 74
`Boeing, A., 21, 614
`Boem er, S., 615
`Boise, L., 647
`Bo/, K., 513
`Bold, G., 256
`
`Proceedings of the 1999 Ai\CR • NCI• EORTC fntern ati o na l Conference
`
`West-Ward Exhibit 1007
`Alexandre 1999
`Page 002
`
`

`

`3730s Abstracts: Poster Session 1 continued
`
`Clinical Cancer Research • Volume 5 • November 1999 (Supplement)
`
`#5 Phase I clinical and pharmacokinetic (PK) trial of E7070, a novel
`sulphonamide, administered daily x 5 every 3 weeks in patients with
`solid tumors. Fumoleau, P .• Punt, C.J.A., Priou, F .. de Mulder, P.H.M ..
`Bourcier, C .. Van de Walle, B .. Wanders. J .• Faber, M.N .. Hanauske. A.R ..
`Ravic. M., Finnegan, V .. from EORTCIECSG, NDDO Oncology and EISAI
`Ltd-London, UK.
`Introduction: E7070 is a new chloroindolyl sulfonamide inhibiting the
`activation of cdk2 and cyclin E in cancer cells at concentrations ranging
`from 1.4-131.4 µ.g/ml in vitro and inducing cell cycle arrest in G1 and
`apoptosis. E7070 showed an original cytotoxicity profile suggesting a
`unique mechanism of action using the NCI-COMPARE program. Study
`design: E7070 was given as a 1 h. i.v. infusion (IV) on 5 consecutive days
`(d), repeated every 3 weeks. The total E7070 dose was escalated from 50
`to 1000 mg/m2/course through 7 dose levels using a standard Phase I
`design (3-6 pts cohort). PK study was performed during the 1st course (er).
`Patient characteristics: to date, 25 patients with miscellaneous solid tu(cid:173)
`mors: 17 females/8 males. median age (yrs): 53 (27-69), median PS: 1
`(0-2). Study results: data is summarized for 25 pts and 69 crs (1-6).
`
`Dose-Level
`10 mg/m2 x 5
`
`13 mg/m2 x 5
`26 mg/ m2 x 5
`52 mg/ m2 x 5
`104 mg/m2 x 5
`200 mg/ m2 x 5 (MTD)
`
`160 mg/m2 x 5
`(currently explored)
`
`No. of
`pts
`6
`
`No. of
`crs
`17
`
`3
`3
`3
`3
`3
`
`4
`
`6
`6
`14
`7
`9
`
`10
`
`DLT's
`1 /6 -atrial fibrillation at
`2nd course
`
`0/3
`0/3
`013
`013
`2/3 -febrile neutropenia,
`-gd 4 neutropenia &
`thrombocytopenia
`1 /4 -gd 4 neutropenia &
`thrombocytopenia
`& gd 4 mucositis
`
`Preliminary PK results indicate that E7070 displays a long half-life T'h and
`a large volume of distribution. At dose-levels above 52 x 5 mg/m 2 Cmax
`increases proportionally while AUG increases more than dose-proportional
`and the clearance & Vdss tend to decrease suggesting a non linearity in the
`PK's. So far, no response is reported.
`
`#6 Phase I study of PS-341, a novel proteasome inhibitor, in pa(cid:173)
`tients with advanced malignancies. Papandreou Christos N, Pagliaro
`Lance. Millikan Randall, Daliani Danai, Herrmann John, Hong Yang, Smith
`Mathew, Adams Julian, Elliott Peter, Lightcap Eric, McCormack Teresa,
`Pien Chris, Newman Robert, Logothetis Christopher J. Department of
`Genitourinary Medical Oncology, The University of Texas M.D. Anderson
`Cancer Center, Houston, TX, 77030 and Leukosite, Inc., Boston, MA 02139
`The ubiquitin-proteasome pathway plays an important role in neoplastic
`growth and metastasis through regulation of cell-cycle regulatory proteins
`(p53, p21 ;wa11. and p27K;p1). In addition, it regulates the activation of the
`nuclear factor NF-kB, a key transcriptional regulator of cell adhesion
`molecules {E-Selectin, intercellular adhesion molecule-1 (ICAM-1) and
`vascular cell adhesion molecule-1 (VCAM-1)), which are involved in tumor
`metastasis and angiogenesis in vivo. We are currently conducting a Phase
`I trial with PS-341, a proteasome inhibitor, in patients with advanced
`malignancies. Objectives: 1) Define maximum tolerated dose and dose
`limiting toxicity of PS-341 as an intravenous (i.v.) push administration over
`a ra nge o f doses (0.13- 0 .7 5 mg/m 2 ) in p a ti e nts with a dva nce d m a ligna n (cid:173)
`cie5. 2) Correlate toxicity with protea5ome inhibition in peripheral 01000 .
`Methods: To date, 12 patients (9: androgen-independent prostate cancer,
`2: metastatic renal cell carcinoma, 1: metastatic colon cancer) have been
`treated (4 at: 0.13 mg/m2 and 2 each at: 0.25, 0.4, 0.6, 0.75 mg/m 2) with i.v.
`PS-341 weekly for 4 weeks in a 6-week cycle. Dose escalation is defined
`by the continuous reassessment method. Proteasome activity in patients'
`peripheral blood is measured ex-vivo using fluorogenic peptide substrates.
`Results: All patients completed at least one cycle of treatment. Four of 12
`patients received 2 or more cycles of PS-341 . No toxicity has been ob(cid:173)
`served so far. One patient achieved partial response {major radiographic
`response of retroperitoneal lymph nodes (RPLN) without PSA change] and
`a second patient had radiographic stabilization of RPLN with unchanged
`PSA. A 55-60 % proteasome inhibition in peripheral blood has been
`achieved at the current dose level (0.75 mg/m2). Conclusion: 1) Up to the
`current dose of PS-341, no toxicity was observed. 2) At 24 hrs after drug
`infusion, proteasome inhibition was achieved as predicted. 3) Responses
`were seen even at low levels of proteasome inhibition. Further dose esca(cid:173)
`lation (with pharmacokinetics and proteasome inhibition studies) is in
`progress. This early evidence of clinical activity without toxicity justifies
`further development of this agent with a novel mechanism of action. This
`work was supported by awards from the Association for the Cure of
`Cancer of the Prostate (CaPCURE) to C.N.P. and C.J.L.
`
`,
`
`#7 CCl-779, A new Rapamycin analog, Has Antitumor Activity at
`Doses Inducing Only Mild Cutaneous Effects and Mucositis: Early
`Results of an Ongoing Phase I Study. J. Alexandre'. E. Raymond'. H.
`Depenbrock 0
`, S. Mekhaldi•, E. Angevin•, C. Paillet', A. Hanauske0
`, J.
`Frisch, A. Feussner, J.P. Armand• . Department of Medecine, lnstitut
`Gustave-Roussy, 94805 Villejuif cedex, France, Onkologische Tagesklinik 0
`Munich, Germany, Genetics Institute, Munich, Germany.
`Like rapamycin, CCl-779 interacts with the protein kinase mTOR thus
`preventing the phosphorylation of elF4E-BP1 and p70S6K thereby inhib(cid:173)
`iting the initiation of the translation of messenger RNAs. We report the early
`results of a phase I study of CCl-779 given as a weekly 30 min. i.v. infusion
`in patients (pts) with advanced solid tumors. So far, 12 patients (pts) have
`been treated at the doses of 7.5, 15.0. 22.5. 34.0, 45.0, and 60.0 mg/m2/w
`using a modify continuous reassessment method for dose escalation.
`CCl-779 does not appear so far to have any significant immunosuppres(cid:173)
`sive effect. No opportunistic infection was observed. The immunopheno(cid:173)
`type of peripheral lymphocytes (CD3, CD4, CD8, CD45, CD14, and CD56)
`and the mitogen proliferation assays (phytohemaglutinin, concanavaline A,
`PWM) did not reveal any significant modifications. However, a reactivation
`of peri-oral herpes lesions was observed in 5 pts within the first month of
`treatment and rapidly resolved under oral acyclovir. Interestingly, signifi(cid:173)
`cant tumor regressions were rapidly observed in 2 pts with lung metastasis
`of renal cell carcinomas both treated with 15 mg/m2/w and in one patient
`with a neuroendocrine tumor of the lung treated with 22.5 mg/m 2/w.
`Responses occurred after 8 weekly, doses. Additionally, 2 patients expe(cid:173)
`rienced tumor stabilization. Neither grade Ill-IV nor dose-limiting toxicity
`have been reported so far. Only mild grade 1-11 skin reactions and mucositis
`were observed at each dose level but did not increase in intensity while the
`dose-escalation was performed. Dryness of the skin with mild itching, fine
`scaling, and mild facial erythema occurred in 6 pts after the 1st infusion and
`lasted during the overall period of treatment. Mild hypersensitivity reac(cid:173)
`tions w·ere observed in all the pts including: (1) sub-acute urticaria in 1 pt
`immediately after the 1st infusion which did not reoccurred during subse(cid:173)
`quent cycles, (2) << Eczema-like>> lesions on the anterior side of arms in
`2 pts, and (3) aseptic follicles were associated with self-limited erythema(cid:173)
`tous papules with central vesiculations occurring in bold areas in 7 pts. In
`the latest 7 pts. concomitantly to the skin reactions. grades I or II mucositis
`were observed associated with genital mucous membrane erosion in 1 pt.
`Skin biopsies were performed in all the pts experiencing skin reactions and
`consistently showed an aspect of folliculitis with infiltrate of neutrophils
`associated with non-specific superficial peri-capillar dermatitis. With re(cid:173)
`peated dosing transient regressions were usual, accelerated in some pa(cid:173)
`tients by topical steroid therapy and antiseptics. No alopecia was reported.
`Nails changes consisting of thickness and dystrophia progressively in(cid:173)
`creased in pts receiving more than 8 doses. The study is ongoing to
`determine the dose limiting toxicity and the dose to be recommended for
`phase II studies.
`
`#8 Phase I clinical and pharmacokinetic (PK) study of the Crypto(cid:173)
`phycin analog LY 355703 administered on an every 3 weeks (wks)
`schedule. Pagani, 0., Greim, G .. Weigang, K .. Westphal, K .. Van den
`Bosch, S., DePas. T .. Burgess, M., Weimer, I. and Sessa, C. /OSI, Be/1-
`inzona, CH; Klinikum Nurnberg, Nurnberg, D; EIO, Milano, I; Lilly Research
`Centre, Windlesham, UK.
`Cryptophycins are antimitotic antitumor agents from blue-green algae
`which inhibit microtubule dynamics with characteristics partially like vin(cid:173)
`blastine and partially like paclitaxel. The synthetic Cryptophycin L Y355703
`is highly potent (in vitro activity at picomolar concentrations) has antitumor
`activity in murine and human tumour xenografts, and high activity in
`tumours expressing the MOR phenotype, including models resistant to
`po.elit::'l)(GL Jn to)( iC(')logy studi es d ose- limiting t o)(ieitie s (DL T) w e re n e utro-
`penia in rats and diarrhea in dogs, the latter being the most sensitive
`species. The starting dose for this study on a single q 3wks schedule was
`0.1 mg/ m2. corresponding to 1/ 10 of the Maximum Tolerated Dose in
`dogs; doses were escalated according to a modified Continual Reassess(cid:173)
`ment Method. LY355703 was administered as 2 h i.v. infusion. Premedi(cid:173)
`cation with i.v. Dexamethasone, H1 and H2 antagonists 30 min before LY
`dose was given starting from the 0.88 mg/m2 dose because of moderate
`hypersensitivity reactions to Cremophor EL observed at the previous dose
`(0.68 mg/m2). The plasma concentration of L Y355703 was investigated by
`LC-MS-MS method "<l.!_h a detection limit of 0.25 ng/ml. Twenty-nine
`patients (pts) with a variety of solid tumours (soft tissue sarcoma 8, renal 5,
`colon 4) and 10 dose levels have been evaluated so far. At the highest dose
`level of 1.92 mg/m2. 2 of 5 pts presented self-limiting DLTs (G3 neuro(cid:173)
`pathic pain in 1 pt, G3 myalgia and constipation in the other) which
`appeared within 3 days of the infusion and required opioids. The dose of
`1. 7 mg/m2 was then tested in 2 pts with occurrence of self-limiting G3
`myalgia within 48 hours in both. in spite of prophylactic analgesia. Overall.
`peripheral neuropathy was mainly sensory and of moderate degree and not
`necessarily dose related nor cumulative; neutropenia was sporadic and
`only moderate; total alopecia was observed only in pts who presented
`DLTs. PK was linear from 0.1 mg/m2 to 1.92 mg/m2 with mean (± SD) t 1/ 2
`of 2.6 hr( ± 1.02). Gip of 90.4 Uhr (± 50.3) and no apparent correlation to
`
`Proceedings of the 1999 AACR•NCJ•EORTC Interna tional Conferen ce
`
`West-Ward Exhibit 1007
`Alexandre 1999
`Page 003
`
`