Lilly Ex. 2051
`Sandoz v. Lilly IPR2016-00318
`
`

`
`Thirty-Fifth
`
`Annual Meeting of the
`
`American Society of Clinical Oncology
`
`May 15-18, 1999
`
`Atlanta, Georgia
`Program/Proceedings
`
`Copyright 1999 American Society of Clinical Oncology
`
`Lilly Ex. 2051
`Sandoz v. Lilly IPR2016-00318
`
`

`
`Editor: Michael C. Perry, MD
`Associate Editor: Clay Anderson, MD
`
`ASCO Science and Education Program:
`Director: Michele K. Dinkel
`
`Assistant Director: Laura K. Ulepic
`Coordinator: Nicole Johnson
`ASCO Publications:
`
`Managing Editor and Director: Deborah Vlfhippen
`Editorial Assistant: Nathan Grace
`
`The American Society of Clinical Oncology Program/Proceedings (ISBN 0-9664495-4-1) is
`published by the American Society of Clinical Oncology, Alexandria, VA 22314. The 1999 issue
`is produced and printed by Lippincott Williams & Wilkins, 351 West Camden Street,
`Baltimore, MD 21201-2436.
`
`Editorial correspondence and production questions should be addressed to American
`Society of Clinical Oncology Program /Proceedings, American Society of Clinical Oncology
`Publications Department, 850 Boylston Street, Chestnut Hill, MA02467. ‘Telephone:
`(617)739-8909. Fax: (617)739-8541. Email: ascopubs@asco.org.
`
`Single issue rate, $50.00. For all areas outside the United States and possessions, there is
`an additional charge for surface delivery of $10.00. For airmail delivery, add $15.00.
`
`Prices are subject to change. Back volumes exist and are available at previous published
`prices. For further information, call (617)739-8909.
`
`Copyright © 1999, American Society of Clinical Oncology. All rights reserved. N0 part of this
`publication may be reproduced or transmitted in any form or by any means, electronic or
`mechanical, including photocopy, recording, or any information storage and retrieval system,
`without Written permission by the Society.
`
`The American Society of Clinical Oncology assumes no responsibility for errors or omissions
`in this document. The reader is advised to check the appropriate medical literature and the
`product information currently provided by the manufacturer of each drug to be administered
`to verify the dosage, the method and duration of administration, or contraindications. It is
`the responsibility ofthe treating physician or other health care professional, relying on
`independent experience and knowledge of the patient, to determine drug, disease, and the
`best treatment for the patent.
`
`Abstract management and indexing provided by Marathon Multimedia Inc, Northfield,
`MN. Electronic page composition and print production provided by Lippincott Williams &
`Wilkins, Baltimore, MD, and the Mack Printing Group, Easton, MD.
`
`Copyright 1999 American Society of Clinical Oncology.
`
`Lilly Ex. 2051
`Sandoz v. Lilly IPR2016-00318
`
`

`
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`Program and Proceedings Information
`ASCO 0n.Line (www.asco.org) Information .
`ASCO Ofiicers and Directors .
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`Adult Leukemia and Lymphoma .
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`Lilly Ex. 2051
`Sandoz v. Lilly IPR2016-00318
`
`

`
`ASCO OnLine
`
`The Official Website of the American Society of Clinical Oncology
`
`www.asco.org
`
`.
`
`The 1999 Annual Meeting Abstracts Are Available April 15 to Members on
`ASCO OnLine in the Members-Only Area.* Fully Searchable!
`
`New for ’99
`1999 VIRTUAL MEETING
`“The Next Best Thing To Being There”
`
`ASCO is pleased to present its first ever Virtual Meeting in conjunction with the 1999
`Annual Meeting. The oflicial ASCO Virtual Meeting will be located on the Internet at
`www.asco.org and will give online visitors access to essential components of the Annual
`Meeting such as
`- Select Audioclips and Digitized Slides from Key Presentations
`- Official Online Poster Presentations
`- Onsite Annual Meeting News Written by ASCO Members and Staff
`- Select Presentation of Official ASCO Materials, including the Educational Book and
`Program / Proceedings
`- A Virtual Tour of the ASCO Exhibit Floor
`The Virtual Meeting will be available before the 1999 Annual Meeting and for several
`months after the Meeting. So log on to www.asco.org and visit the only oflicial ASCO
`Internet resource of the Thirty-Fifth Annual Meeting. The Virtual Meeting is truly “The
`Next Best Thing To Being There.”
`ASCO gratefully acknowledges the following companies for their sponsorship of the ASCO
`Virtual MeetingT:
`Zeneca Pharmaceuticals
`Gold:
`Eli Lilly
`Bronze: Rhéne-Poulenc Rorer
`
`Bristol-Myers Squibb
`
`*Upon the conclusion of the Annual Meeting, the abstracts will also be available on the public area
`of ASCO OnLine.
`
`TAS of 3/9/99.
`
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`

`
`Program/Proceedings
`of the
`
`American Society of Clinical Oncology
`
`Michael C. Perry, MD
`
`Program / Proceedings Editor
`
`American Society of Clinical Oncology
`
`Oflicers
`
`1998-99
`
`Allen S. Lichter, MD
`
`President
`
`Joseph S. Bailes, MD
`President—Elect
`
`Robert J. Mayer, MD
`
`Immediate Past President
`
`William P. Vaughan, MD
`
`Secretary-Treasurer
`
`Board of Directors
`
`Douglas W. Blayney, MD
`George J. Bosl, MD
`Nancy E. Davidson, MD
`Jay R. Harris, MD
`Harry E. Hynes, MD
`Patricia Legant, MD
`Patrick J. Loehrer, Sr., MD
`Monica Morrow, MD
`Larry Norton, MD
`Philip A. Pizzo, MD
`Margaret A. Tempero, MD
`Barbara L. Weber, MD
`
`John R. Durant, MD
`Executive Vice President
`
`Lilly Ex. 2051
`Sandoz v. Lilly IPR2016-00318
`
`

`
`21 2o
`
`B13
`
`CLINICAL PHARMACOLOGY
`
`514
`
`Proceedings of ASCO Voiume i 8 1999
`
`nose-schedule Dptimization the Heitacyclic ttamptothecin (EFT) Analog Dit-
`B951t: A Phase I and Pharniacolrinetic Study with Escalation at Bath Treatrnent
`Duration and Dose. C Geger, l. Hammond. TJohnson, l. Snretzer. J Coyle, R
`Drengier. D tron Hoff. R De Jager, and E Row.-‘nslry. Cancer Therapy and
`ltesearcli Center and Brooke Army Medical Center, San Antonio, TX; Joe
`rtrrrnglon Cancer Center, Lubbock. TX. Daiicni Pharmaceuticals. Fon‘ Lee NJ.
`The water-soluble heiiacyclic CPT analog Dll-8951i is undergoing develop-
`ment based on its greater potency at inhibiting topoisonlerase (topol 1 than
`topotecan and SN—38. broad antitumor activity. no crossresistance against
`rndrl-overerrpressing tumors. and intrinsic activity that may lead to less
`intersubiect variability in Pit and toxicity than prodrugs requiring activa-
`tion. Neutroperiia wasthe principal toxicity on all schedules in initial phase
`lsludies (single dose q 3 wits. daily X 5 q 3 wks, and witty )4 3 :1 ti wt-is.
`with a 30-min or 24-h infusion for each schedule}. [in a 30-min daily x
`5-day schedule, recommended phase It doses are 0.5 and 0.3 mgrm?-ld in
`minimally- and heavily-pretreated patients (MP 8; HP}. respectively. Since
`the activity of topo l
`inhibitors depends on DNA replication, and more
`trequentlcontinuous schedules result
`in greater cytotoiricity and dose
`intensity in preclinical models. prolonged D):-8951f administration by
`continuous W infusion (Civil for 5-21 days is being studied. This study is
`designed in 2 stages using the modified Continual Reassessment Method to
`both increase the Clill duration and escalate dose, with a minimum of 1
`patientldose-schedule level.
`In stage i.
`the Clill duration has been
`successively increased from 5 days to 10, 15. and 21 days: the starting
`dose level was 0.15 mglmild :4 5 d t1l3'° x toxic dose low in dogs). In
`stage ll. doses are doubled until modest toxicity. and phase I objectives are
`being sought separately in HP and MP patients. To date. 7 patients have
`been treated with 0.15 l‘I1g1'lTl?'ld at
`the following levels: 5-day CIVI (4
`patientsllfi courses). 10-day CIVI lll3l. 15-day Clill (U2). and 21-day
`C1\llt1l1).Exceptl‘orthe1‘-i patientat the 0.15mg/m?ld x 5-day level who
`had grade at neutropenia lasting :- 5 days and grade 4 thrombocytopenia.
`resultingin the accrual of 3 other patients at this level. ‘2 grade 1 hematologic
`toxicity has not occurred in either HP or MP patients. DX-8951i clearance in
`the toxic patient (0.26 llhlmzt who had been ingesting Essiac tea was
`4-5-fold lower than the other patients t0.99—1.42 llhl'm'=). and the C55 ol
`the toxic patient (24.18 ng{mL) was 4-5-told greater. A patient with taxane-
`& platinum-refractory NSC lung cancer had a partial response. Although
`the antitumor activity of DX-89511 ls schedule-dependent. Pis tolerate
`Dl<8951lat least at an equivalentdose intensity (20.15 X 21 days 2 3.15
`mglm3 over 21 days) than with shorter schedules (0.5 X 5 = 2.5 mglntii
`over 2'1 days on 30 min X 5 schedule),
`indicating that prolonged Clvl
`schedules may result in a greater therapeutic index.
`815
`
`Phase I and Pharmacnlrinetic Studies nl 10-Propargyl-lCl-Deazaaniinopterin
`(Pull) in Patients with Advanced Solid Tumors. Stefan C. Grant. Lee M. ltrug,
`Kenneth K. Ng, Vincent ll. Miller. Wi'llr‘arrr Tong. Robert T. Heelan, Francis
`M. Sirolnalr. Carey White. Mark G. Kris. Memorial Sloan-Kettering Cancer
`Center. New York, Mr’.
`PD): isa new antilolate with a propargyl group substitution at carbon-10. In
`tumor cell lines, PDX has superior altinity for the one carbon. reduced folate
`transporter. and the enzyme iolylpolyglutamate synthetase. In human lung
`and mammary carcinoma xenograits, PBX demonstrated a 3-4 iold im-
`proved tumor response with less toxicity compared to rnethotreriate. we
`have undertaken a phase l
`trial of PD)( in patients with advanced solid
`tumors. Eligibility criteria: itarnofsliy per1ormancestatus(KPS) a ?0%; no
`significant pleural allusion or edema; no radiationlchemotherapy ior 3
`weeks; normal WBC, platelets. bilirubin; ASTlAl.T s 3)! upper limits of
`normal. Using a modified Fibonacci scheme, one patient is enrolled per
`dose level. expanding to 3 for toiricity. Weekly treatment lor 3 weeks of a
`4-week cycle resulted in dose-limiting Inucositis at 30 mg/m’rweelt.
`Subsequently. the schedule was changed to treatment q 2 weeks on a
`4-week cycle. Sixteen patients have been treated with the o 2 week
`regimen. Patient characteristics: 100% non-small cell lung cancer. median
`age 60 (range 35-?1l;male4'l%:KPS 2 80% in 31%; median number of
`prior chemotherapy regimens:
`1 (range 1-3}. Two patients are too early tor
`evaluation lat 130 rng!m7~'i. Median number oi cycles: 3 (range 1-14). Five
`of fourteen patients had stable disease for 3. 4, 6, 8, and 10 months,
`Overall. toxicities have been mild and reversible with dose delay. The most
`severe toxicities observed have been 2+ mucositis (4 patients} and 2+
`transarninase elevation (2 patients}. One patient with 2+ lteratitis had
`therapy discnntiniied.
`‘Pharmacoliinetic studies at 30. 120. and 130
`mgrmz indicate that plasma AUC has a linear relation to dose and does not
`change with repeated treatment. PD)( is well tolerated and the number of
`patients with stable disease is encouraging. Maximum tolerated close has
`not been reached and accrual continues.
`
`in Patients with Sufi“
`A Phase I study or Genicitatiine and Paclitattel
`Malignancles. Shawn D. Gllsson. Donald Fleming. G. Michelson, EJ-
`Hendler. T. Hadley. L. Bliupalam. Jellrey B. Hargis, Renato it La Rocca‘
`Department of Medicine University of Louisville, Louisville. KY.
`'
`A phase I study was designed consisting ol escalating doses of gemcitabine
`along with tiite-d~dose paclilaitei (150 mglrnzl. The maturity of patients
`enrolled were heavily pretreated with chemotherapy. radiotherapy or both.
`All patients were naive oi the study drugs and possessed both adequate
`performance and end organ function. Eighteen patients were entered on
`the study. Characteristics included a median age of 66 (range 41 to 7'?) and
`advanced stage disease. The tumor types included colon cancer (5)
`bladder cancer (2). non-small cell lung cancer (3). esophageal cancer [2}'
`pancreatic cancer (3). and cancer of unknown primary (2). Paclitaitei (156
`mg/m2 over three hours] was given on day one and gemcitab1ne(800. 900
`and 1000 mglm2 over 30 min.) wasgiven in three separate dose-escalating’
`cohortstl~3l on day one (following paclitaitel administrationiand clay eight
`The treatment cycled every 21 days. The dose limiting toxicity (DLTl proved
`to be neutropenia. which limited the day eight administration of gemcitab.
`me.
`
`Dose Level Gemcitabine dose mg/m2 (total doses) Total Patients DLT
`1
`800 (22)
`3
`0/3
`2
`900 (54)
`6
`1/5
`3
`1000 (60)
`9
`4/9
`
`'
`
`All non-hematologic toxicities were mild and included Gl disturbances
`(nausea, vomiting, and diarrhea). dermatologic (rash) and neurologic
`(paresthesias) along with transient elevations of liver function tests. Four
`patients manifested an objective response (lCR, 3PR). in conclusion, the
`combination of gemcitabine and paclitaxel seems to be well tolerated and
`the recommended starting dose for a phase ii study. in pretreated patients
`using a day one—day eight treatment schedule, should be 900 mg/m2 for
`gemcitabine (day one, day eight) along with 150 mg/m2 for‘ paclitaxel (day
`one).
`
`316
`
`Phase 1 Study cl sequential use at Tnpotecan and 5 Flunrouracll in Patients
`with Advanced Cancer. Hageboutros A.
`lthatri J. Muslim M. Hanna 6,
`li'odrriari WD. Gr-yn J, Woodland C, Trltsclilerl, Astley K. Devereuir L, Berger
`A. Grana G. Goldberg J. Cooper Hospitalruniverslty Medical Center.
`Camden. NJ.
`
`inhibitor. which stabilizes a covalent
`Topotecan is a topoisorncrase l
`complex oi enzymes and causes strand cleavage of DNA. 5FU is an
`antimetabolite that interfereswith DNA synthesis. Preclinical stud ies using
`human cancer cell line models have shown a therapeutic synergy between
`the two drugs. These studies have shown that the maximum cytolytic eilecl
`was achieved using sequential 5FU followed by Topotecan. tn the current
`clinical study. EFU was used at a fixed dose of 3?5mglm’ given intraver
`nously for iive consecutive days.
`Topotecan dose was escalated in cohorts of patients from 0.5 to 1.0 mglnle
`given intravenously following the 5FtJ on each of the five days. The regirneli
`was repeated every twenty-eight days.
`Eleven patients were entered at the difterent dose levels. Both hematoloslc
`and gastrointestinal
`toiticity were close limiting. Diarrhea was the d059-
`limiting gastrointestinal toxicity at the dose of 0.?5mgIm? of Topotecafh
`Two cases of grade 4 neutropenia were also observed at this dose level. One
`patient with small cell lung cancer had a complete response. one P51l°"L
`with metastatic colorectal cancer had a partial remission. Three other
`patients had stabie disease. Overall the regimen was well tolerated and 3
`phase ii dose of Topotecan 0.?'5mg‘m3 following SW 375 mgJm2i|'|1F8"3'
`nously over five days every twenty-eight days is recommended.
`
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`
`

`
`Proceeclings ofASCO Volume 18 1999 CLINICAL PHARMACOLOGY — GASTROINTESTINAL CANCER
`
`2330
`
`897
`
`897a
`
`Phase I and Pharmacokinetic (PK) Trial of the Antifolate y-Methylene-10-
`Deazaaminopterin (MDAM)
`in Patients with Advanced Solid Tumors. L
`Zukowski, 8. Carter, R Hoff, M. Royce, D. Medgyesy, R. Brlto, l-'. Ravandi, l’.
`Lassere, R. Newman, F Hausheer, R. Pazdur. The University of Texas M. D.
`Anderson Cancer Center, Houston, TX, and E‘ioNurrierik Pharmaceuticals,
`lnc., San Antonio, TX.
`MDAM, a non—po|yg|utamylatable antifolate structurally similar to metho-
`trexate (MTX), was shown in preclinical studies to have a broad spectrum of
`activity against human solid malignancies. Relative to MTX, MDAM has
`more rapid tumor selective cellular uptake, and less susceptibility to
`certain drug resistance mechanisms. MDAM is potentially less toxic to
`nor mal host tissues with more rapid cellular efflux and less susceptibility to
`aldehyde—mediated hydroxylation. The purpose of this trial is to determine
`the maximum tolerated dose (l\/ITD) and clinical PK of MDAM in patients
`with advanced solid tumors. MDAM is administered as a 1-hour infusion for
`5 days (cl) repeated every 3 weeks. Ten patients (pts), median age 61 yrs,
`PS 0 or 1, and advanced colorectal carcinoma, have been entered at the
`following dose levels: 80 mglmzld (3 pts), 160 mglm2/d (3 pts), and 240
`mg/m7ld (4 pts). No toxicities were observed at 80 mglm’. Grade (gr) 2
`nausea and vomiting (1 pt), gr 1 diarrhea (1 pt), and gr 1 anorexia and
`fatigue (1 pt) were noted at 160 mg/m2/d. At 240 mg/m2/d, the following
`toxicities were observed: Gr 2 stomatitis (1 pt), gr 2 granulocytopenia (1
`pt), gr 1 muscle weakness (3 pts), and gr 1 fatigue (3 pts). No objective
`responses have been noted although 1 pt demonstrated stable disease for
`five cycles. Plasma and urine levels of MDAM and its metabolite, MDAM-
`OH, were assessed on days 1, 5 during cycle 1 (HPLC assays). Data at 240
`mg/m2 revealed an average 59% decrease in MDAM AUC from d 1 to d 5.
`During this time, MDAM—OH levels increased by 28%. MDAM Cm, on d 1
`was 53 uM; on d 5, it was 22 uM. MDAM—OH levels were 7.6 uM on d1 but
`remained low through the 5 d period. Accrual continues at 300 mg/m2/d.
`
`A Phase I Trial of Vinorelbine and Gemcitahine in Relatively Elderly Patients
`with Refractory Solid Tumors. M. Greenhawt, M. Jahanzeb, A. Koletsky, C.
`Frankel, R Pearce, and C. Byrne. /ntercenter Cancer Research Group and
`Salick Healthcare Inc., Palm Beach, FL,
`Vinorelbine and gemcltabine have exhibited excellent tolerability, a broad
`and overlapping spectrum of activity (e.g. cancers of lung, breast, and
`genitourinary tract) and nonoverlapping toxicity except for myelosuppres—
`sion. We decided to explore the maximum tolerated dose and dose—|imiting
`toxicity (DLT) of these agents when given concurrently in a weekly X 3
`schedule followed by a one week break in a 28 day cycle. Planned half
`doses of both drugs were given on day 8 to avoid day 15 dose omissions.
`Patients with solid tumors refractory to standard therapy and no more than
`2 prior chemotherapeutic regimens were eligible. Five cohorts involving a
`total of 17 patients have been enrolled, but the last cohort (level 5; 3
`patients) is too early to evaluate. Eleven patients have metastatic non—small
`cell lung cancer, 2 patients have advanced head and neck cancer and one
`patient each has ovarian, endometrial, pancreatic, uterine and hepatocellu—
`lar cancers. There are 8 males and 9 females. Median age is 67 years
`(range 47-80). Median number of prior regimens is 1 (range 0-2). Starting
`doses (level 1) of gemcltabine and vinorelbine were 600mg/m2 and 20
`mg/m3 respectively. Vinorelbine was escalated to 25 mg/m2 in level 2 and
`30 mglm2 in level 3, while the dose of gemcitabine remained unchanged.
`In levels 4 and 5, gemcltabine dose was escalated to 700 mg/m2 and 800
`mglmz respectively. As of 11/98, 79 cycles have been delivered (median 2;
`range 1-17). One episode of grade 4 neutropenia, 4 episodes of grade 3
`neutropenia and 2 episodes of grade 3 thrombocytopenia have been
`observed. Besides 2 episodes of grade 3 nausea, we have seen no Grade Ill
`toxicity including vomiting, neurotoxicity, or alopecia. Five patients have
`progressed and one patient went off study for depression while all others
`remain on study. In 13 patients evaluable for response, 1 PR was observed
`and 5 patients achieved stable disease lasting 6 months. We plan to add
`G—CSF if myelosuppression turns out to bethe DLT. Accrual to this trial will
`continue and updated data will be presented.
`‘
`
`*a9s
`
`GASTROINTESTINAL CANCER
`
`*s99
`
`Weekly lrinotecan (CPT-11), Leucovorin (LV), and Fluorouracil (FU) is superior
`to Daily ><5 LV/FU in Patients (PTS) with Previously Untreated Metastatic
`Colorectal Cancer (CR6). LB Saltz, PK Locker, N Pirotta, GL Elfring, LL
`Miller. Memorial Sloan—Kettering Cancer Center NY, NY, and Pharmacia &
`UpJohn, inc, Kalamazoo, MI, for the CPT—ll CRC Study Group.
`CPT—11
`is active against FU—refractory CRC. We hypothesized that a
`combination of CPT—11/LVlFU would have greater first—line antitu mor
`activity than LV/FU alone. We have demonstrated that a regimen of CPT—11
`125mg/m2 over 90 minutes followed by a LV 20 mg/m3 bolus and a FU 500
`mg/m9 bolus, with all drugs given IV weekly X 4, repeated every 6 weeks, is
`safe and tolerable (JCO 1996; 14:2959—67). We now report a phase III,
`randomized, multicenter trial of this regimen versus a standard regimen of
`W 20 nig/mi plus FU 425 rnglmz given daily X 5 every 28 days, and versus
`CPT-ll 125 mglrn‘-' alone given weekly X 4, repeated every 6 weeks. Pts
`had measurable metastatic CRC with either no prior chemotherapy or a
`disease-free interval of 2-1 year after adiuvant therapy, performance status
`{P5} 0-2. and normal marrow. hepatic, and renal function. Preliminary
`afely and efficacy data are available for all 666 treated pts.
`CPT—11/LV/FU
`LV/FU
`(n = 222)
`(n = 221)
`
`CPT—11
`(N = 223)
`
`Response Rate (overall)
`Response Rate (confirmed)
`TTF lniedian)
`TTF >_~. 5 Mo
`Grti Neutropenia
`N‘3UU'0Denic Fever tNFl
`Gr3l4 Diarrhea
`Gr3l_-1 Mucositis
`Gr3i4 Vorriiting
`
`49%
`33%
`5.0 mo
`42%
`%3°/0
`6%
`22%
`<1%
`10%
`
`27%
`18%
`3.8 mo
`25%
`37%
`13%
`13%
`10%
`4%
`
`29%
`17%
`3.1 mo
`24%
`11%
`4%
`30%
`<1%
`12%
`
`Ohieiztive response ram (p -«: 0,001). median time-to-treatment failure iTTF;
`E? 0.05) and % ol pts with TTF 2 6 mo lp < 0.01) are superior in the
`l’T—11ii_.viru arm compared to the LWFU arm. with a median followup of 7.1
`$0-I5“WlV§l diifererices are not apparent at this early time tcensoring in >50‘1t=
`b it) 5). Toirrcrtics indicate more Gr3l-fl diarrhea and vomiting with CF'T—1 1lLWl‘-‘U
`d: more Grti neutropenia, NF. and Gr3M mucositis with LWFU. Drug-related
`héaths occtirrerl ll’I 1% of pts in each group. Tl1isCPT—1 ti'L\llFU combination can
`1 coifsideretl a new standard regimen for fir'st~linc treatment of metastatic CRC.
`"dies of ll‘liS-3 regimen in the adjuvant setting are in progress.
`
`i 5FU/Folinic Acid
`A Randomized Phase III Trial comparing lrinotecan (IRI)
`(FA)
`to the Same Schedule of 5FU/FA in Patients (pts) with Metastatic
`Golorectal Cancer (MGRC) as Front Line Chemotherapy (CT). JY Douillard, D
`Cunningham, AD Roth, JR Germa, RD James, P Karasek, R Jandik, T
`lveson, J Carmichael, G Gruia, M Dembak, D Sibaud, P. Rougier. Centre R
`Gauducheau, St-Herblaln, France; Royal Marsden Hosp., London, UK,-
`Hosp. Cantonal, Geneve, Switzerland; Hosp. Durant y Reynals, Barcelona,
`Spain; Christie Hosp., Manchester, UK; Inst. Of Oncol., Brno; Univ. Hosp.
`H. Kralove, Czech Rep; Royal 8. Hants Hosp., Southampton; City Hosp.,
`Nottingham, UK; Rhone Poulenc Rorer, France; Hosp. A. Paré, Boulogne,
`France.
`IRI has been shown to be active in MCRC with significant
`Single agent
`survival advantage over best supportive care or best 5FU schedule in pts
`with prior 5FU failure (Lancet 31 Oct 1998). This phase III multicentric
`trial compared group A: Combination of IRI at 180 mg/m2 day (d) 1 and
`5FU 400 mg/m2 as IV bolus followed by 600 mg/m2/d as a 22 hours (h)
`continuous infusion (c.i.) + FA on d1—d2 repeated every 2 weeks (wks) or
`lRl at 80 mg/m2 and 5FU 2.3 g/m2 as a 24-h c.i. —l FA weekly X 6 every 7
`wks, versusgroup B: The same regimen of 5FU/FA alone.
`As of Feb. 1998, 387 pts (199 in A and 188 in B) were randomized. Tumor
`assessments were to be done every 6 wks and treatment was to be
`continued until progression. The main pts characteristics are comparable
`between groups A and B: Median age 62 vs 59, primary colon/rectum
`55/45 vs 65/35, performance status 0 49% vs 51%, prior adjuvant CT,
`26% vs 24%, numberof organs 2 2 41% vs36%, respectively. Preliminary
`results based on the investigator judgment are in group A vs B: progression
`free survival 35.1 (PFS) wks vs 18.6 wks; response rate 39% (74/190
`evaluated pts) vs 22% (41/183 evaluated pts) respectively. Final results
`based on ongoing independent experts review including subgroup analysis,
`will be presented at the meeting. The main NCI grade 3/4 adverse events by
`pts in group A vs B are; neutropenia 40% vs 13%, diarrhea 20% vs 10%:
`other toxicities were <5% and comparable in both groups. No cumulative
`adverse events are observed (except alopecia).
`Conclusion:
`lRl combined with 5FU/FA is showing a higher antitumor
`activity than 5FU/FA alone with increased PFS. The safety profile of the
`combination is tolerable and manageable and is better than what was
`observed with IR) monotherapy.
`
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`
`

`
`306d
`
`1174
`
`GASTROINTESTINAL CANCER
`
`Proceedings of ASCO Volume 1 8 1999
`
`Phase I/ll Study of lrinotecan combined with Mitomycin-C in Patients with
`Advanced Gastric Cancer. Yamao I, Kazami, A., Handa, T., Koizumi, K.,
`Kai, 8., Takemoto, N., Maruyama, M., Shlrao, K., Muro, K., Yamada,
`)’.,
`Sugano, K., Matsumura,
`l’., and Shimada,
`1’. Cancer institute Hospital,
`Tokyo, Japan, National Cancer Center Hospital, Tokyo, Japan.
`lrinotecan (CPT-11) is a new active drug for advanced gastric cancer (AGC).
`Preclinical synergism has been reported in combination of CPT-11 and
`mitomycin-C (MMC) in human gastric cancer cell lines. To determine the
`maximum tolerated dose (MTD),
`the dose limiting toxicity (DLT), and
`preliminary anti-tumor activity, we conducted a dose escalation study of
`CPT-11 and MMC in patients with AGC. MMC was administered as i.v.
`bolus, and then immediately followed by intravenous infusion of CPT-11
`over 90 minutes. The treatment was repeated every other week. Granisetron
`was administered to prevent nausea and vomiting. The prophylactic use of
`granulocyte colony-stimulating factor was not planned. The planned dose
`escalation schedule for MMC/CPT«11 (mg/m2) of each dose level was as
`follows;
`|evel—1, 5/100;
`level—2, 5/125;
`level-3, 5/150;
`leve|—4, 7/150;
`|evel—5, 10/150. MTD is determined when the incidence of critical toxicity
`(either grade 4 neutropenia 2 4 days, febrile grade 4 neutropenia, non-
`hematological toxicity 2 grade 3, or treatment delay due to any toxicity >7
`days) exceeds 50% (2/3 or 3/6 patients). At the present 15 patients was
`entered (3 at
`level-1, 7 at
`level—2, 5 at
`level-3, respectively) and 14
`patients were evaluable for toxicity. Patient characteristics were following;
`median age 60 yrs [range 37-73]; sex 13 male, 2 female; PS 0-3, 1-11,
`2-1; macroscopic type; diffuse -3, non—diffuse -12; microscopic type;
`diffuse -9, intestinal -6. At |evel—1 no critical toxicity was observed. At
`level-2, the critical toxicity was observed in 2 of 7 patients (administration
`delay due to persistent leukopenia and grade 4 diarrhea). At the present,
`level-3 is under evaluation for toxicity and response and the maximum
`tolerated dose of CPT»11 and MMC has not yet been determined. Partial
`response was achieved in five of 10 patients evaluated. The treatment
`could be continued on the outpatient—basis in all patients.
`
`CPT-11/MMC
`100/5
`125/5
`150/5
`
`n
`3
`7
`5
`
`neutropenia
`(Grade 4)
`
`Diarrhea
`(Grade 3,4)
`O
`1
`1
`
`Delay
`O
`1
`0
`
`Level
`1
`2
`3
`
`1176
`
`A Phase II Trial of NEUTREX|N®, 5-Fluorouracil and Law Dose Leucovorin
`(NFLL) in Patients with Metastatic colorectal cancer (CR8). Kai-Yiu Yeung,
`Harvey l. Katzen, David J. Haldalr, Rita Gupta, Jacquline M. Greer, Joyce
`Saunders. 0nco/og,v—Hematolog/Associates, P.A., Clinton, MD.
`The incorporation of sequential Neutrexin (Trimetrexate, TMTX, a non-
`classical antifolate, 110 mg/m2) infusion on day 1
`into the standard
`regimen of IV bolus 5-Fluorouracll (5-FU, 500 mg/m2) and Leucovorin (LV,
`200 mg/m2) on day 2; followed by oral LV rescue (15 mg every 6 hr) of 7
`doses beginning 6 hr after 5-FU administration (NFL regimen) by Blanke,
`et al. has improved a response rate (RR) to 42% in a phase II trial on 36
`intent to treat (ITT) patients (pts) with stage IV CRC. Each cycle consists of
`6 weekly treatments followed by 2 weeks rest. Kreuser, et al. reported a RR
`of 32% in a similar phase II trial of 34 l1'l' pts. The results of these two
`phase ii studies prompted two ongoing phase ill multi-institutional
`randomized trials to compare NFL vs. FL regimen in US and Europe. Grade
`3 & 4 diarrhea, however, has been observed in 58%