Proceedings of ASCO Volume 17 1998
`
`CUNICAL PHARMACOLOGY
`
`225a
`
`*88.5
`
`*868
`
`PHASE I AND PHARMACOKINETIC (PK) STUDY OF THE GLYCINAMIDE RIBO-
`NUCLEOTIDE FORMYLTRANSFERASE (GARIq’) INHIBITOR LY309887 AS A BOLUS
`EVERY 3 WEEKS WITH FOLIC ACID (FA). C. A)~lesworth, $.D. Baker, J.
`Stephenson, P. Monroe, L Sanchez, J. Wafting, R. Johnson, D. Van Hoff and
`E. Rowinsky. Brooke Army Medical Center and Cancer Therapy and
`Research Center, San Antonio, TX; Eli Lilly Pharmaceuticals.
`
`LY309887 is a potent inhibitor of GARFT that catalyzes the first two
`folate-dependent steps of de novo purine biosynthesis. Compared to
`Lometrexol, a "first generation" GARFT inhibitor that induced delayed and
`cumulative clinical toxicity, LY309887 is less extensively polyglutaminated
`and 9-fold more potent at inhibiting GARFT. Also, LY309887 showed
`greater affinity for folate receptor isoforms in malignant compared to liver
`tissue. Co-administration of LY309887 and FA resulted in an increased
`therapeutic index in mice. The objectives of this study were to assess the
`feasibility of administering LY309887 as an iv bolus every 21 days with FA
`5 m~/day for 5 days starting 2 days before LY309887 in patients (pts) with
`advanced solid cancers and to determine the maximum tolerated dose
`(MTD) and both toxicity and PK profiles. To date, 14 pts have received drug
`at the following levels (rag/mS): 1 (3 pts! 8 courses (Cs)), 2 (1 pt/2Cs), 4 (1
`pt/4Cs), 8 (4 pLs/7Cs), 12 (2 pts/2Cs) and 6 (3 pts/6Cs). At 12 m~/m2, no
`toxicity occurred during C1, but C2 was associated with grade 4 neutrope-
`nia and grade 3 thrombocytopenia with recovery at day 64. Subsequent
`experience at 8 m~m2 resulted in grade 4 neutropenia (C1) and grade 4
`thrombocytopenia (C2). Modest neurosensory toxicity has also been noted
`in 4 pts across all dose levels. During C1, both Cmax and AUCo-24h values
`increased linearly with dose. Approximately 63 % of drug was excreted
`unchanged in urine. The t112 and CI were dose-independent with mean
`values of 4.3 hours and 92.7 ml/min, respectively. Increasing levels of drug
`exposure were associated with greater platelet toxicity. Interpatient variabil-
`ity in FA exposure was observed with Cm~ and AUCo-24h values ranging from
`500-2330 ug/ml and 77-220 ug*hr/ml, respectively, which may have
`contributed to large interpatient variability in toxicity. To date, 3 pts have
`received 6 Cs at the 6 mg/m2 without grade 3/4 hematologic toxicity. This
`dose level will be further evaluated to determine the MTD that permits
`repetitive dosing with acceptable toxicity and describe the relationship
`between PK and toxicity.
`
`A PHASE I AND PHARMACOKINETIC (PK) STUDY OF THE MULTITARGETED
`ANTIFOL (MTA) LY231514 WITH FOLIC ACID. L. Hammond, M. Vi/lalona-
`Calero, S.G. Eckhardt, R. Dreng[ler, C. Aylesworth, T. Johnson, M. Hidalg[o,
`G. Rodrig[uez, S. Diab, R Monroe, D. Thornton, D. Von Hoff, and E.
`Rowinsky. Cancer Therapy and Research Center and Brooke Army Med
`Center, San Antonio, TX, and Eli Lilly Company, Indianapolis, IN.
`
`MTA (LY 231514) is a new antifol that inhibits multiple folate-dependent
`enzymes, including thymidylate synthase, dihydrofolate reductase, and
`glycinamide ribonucleotide formyl transferase. Initial phase I trials demon-
`strated major antitumor responses when MTA was given as a 10 min i.v.
`infusion, however, myelosuppression precluded dose escalation above
`500-600 mg/m2. Since preclinical studies indicated that folic acid
`supplementation increases the therapeutic index of MTA, the feasibility of
`administering folio acid 5 mg daily for 5 days starting 2 days before MTA in
`minimally- and heavily-pretreated pts was evaluated to determine if folio
`acid supplementation ameliorates the toxic effects of MTA, permitting
`significant dose-escalation above the recommended phase II dose of MTA
`alone. Thus far, 21 pts with solid cancers have received 55 courses at the
`following dose levels: 600, 700, and 800 mg/m2. Drug-related toxicities
`have included neutropenia, anemia, and thrombocytopenia, which have
`been more severe in heavily-pretreated pts. Other toxicities (grade 1-2)
`include rash, somnolence, fatigue, leg edema, and diminished renal
`function manifested by a decrease in creatinine clearance. One pt taking a
`non-steroidal anti-inflammatory agent experienced severe toxicities at the
`800 mg/m2 dose, which resolved after administration of leucovorin and
`thymidine. One partial response in a pt with metastatic colon cancer has
`been observed. PK and vitamin (folio acid) metabolite profiles were done
`during cycles 1 and 3 at 600 and 800 mg/m2. To date, serum folic acid
`levels do not appear to be related to toxicity, but homocysteine was
`significantly elevated in the pt with severe toxicities at the 800 mg/m2
`dose. Thus far, heavily- and minimally-pretreated patients have tolerated
`MTA at 600 and 800 mg/ms and accrual continues at 700 and 900 mg/m2,
`respectively. These results indicate that folio iicid supplementation appears
`to permit MTA dose escalation.
`
`*887
`
`*868
`
`A PHASE I AND PHARMACOKINEI’IC (PK) STUDY OF TRIMETREXATE (TMTX) IN
`CANCER PATIENTS (PTS) WITH RENAL (RI) OR HEPATIC IMPAIRMENT (HI). M~./.:
`Gi/lisor~, S. O’Rei/ly, R.C. Donehower, D.A. Noe, M. Duerr, L.B. Grochow.
`Johns Hopkins Onco/o~, Center, Baltimore,
`
`The antifolate TMTX is undergoing phase III evaluation with 5FU in colon
`cancer pts. In phase I studies significant interpt variability in toxicity was
`observed and was related to hepatic function. A phase I and pk study was
`performed in pts without and with RI or Hi. Cohorts included: controls
`(creatinine clearance (CrCI) >7OraL/rain total bilirubin (TB) < 1.6rag/alL);
`pts with mild Ri (CrCi 40-60 mL/min); pts with moderate RI (CrCi
`20-4OraL/rain); pts with severe RI (CrCI < 2OraL/rain); and pts with HI
`(TB > 2.0 m~/dL, albumin < 3.6rag/alL). TMTX was given iv over 30 rain
`every 21 days. Doses were escalated from 140 mg/ms in controls and pts
`with mild RI; from 105 m~/ms in pts with moderate RI; and from 70 mg/ms
`in pts with severe RI or HI. Dose limiting toxicities (DLT) were grade IV
`neutropenia, thrombocytopenia, mucositis and rash. Ten DLT occurred in
`3/17 controls who received 62 cycles of TMTX (range 105-275 rag/mS); 27
`DLT occurred in 9/13 RI pts over 61 cycles (range 35-175 rag/mS); and 10
`DLT occurred in 4/11 HI pts over 26 cycles (range 35-105rag/mS). Dose
`was reduced to 35mg/ms in HI pts, after the first 2 pts had severe DLT. Prior
`pelvic irradiation or nitrosourea therapy increased the risk of DLT (p = 0~06).
`Single clinical measures of RI or HI did not correlate with TMTX pk
`(r < 0.5). However, mean TMTX clearance was lower in HI pts compared to
`controls (36.5 vs. 64.3 mL/min; p = 0.016). Increasing hematologic
`toxicity was observed with increasing TMTX AUC in controls and RI pts but
`not in HI pts, suggesting variable metabolism of TMTX. TMTX pk is altered
`in HI pts, for whom a starting dose of 35 mg/m~ is recommended. A dose of
`105mg/ms is recommended for pts with CrCI of 20-6OraL/rain. Subse-
`quent dose escalations may be considered for pts without DLT. Supported
`by grants no. NO1 CM 07302 and CA 01709-03 (NIH)
`
`INTERIM RESULTS OF A PHASE I TRIAL SUGGEST THAT TOMUDEX~ (RALTI-
`TREXED) MAY ACT SYNERGISTICALLY WITH 5-FLUOROURACIL (S-FU) IN PA-
`TIENTS WITH ADVANCED COLORECTAL CANCER (ACC). K.H. Dragnev,
`Schwartz, J. Bertino, N. Kemeny, L. Saltz, A. Sug[arman, D.K. Kelsen, W.
`Tong[, C. Lowery. Memorial Sloan-Kettering[ Cancer Center, New York, NY
`and Zeneca Pharmaceuticals, Wilmington, DE.
`
`’Tomudex’ is a direct inhibitor of thymidylate synthase with activity in ACC.
`Synergy has been demonstrated in cell lines when ’Tomudex’ is followed by
`5-FU. 21 patients were given ’Tomudex’ followed 24 hours later by 5-FU
`every 21 days. All but five had failed prior modulated 5-FU therapy:
`
`Dose, mg/m2
`’Tomudex’/
`5-FU
`
`OR
`(duration
`months)
`
`SD
`(duration
`months)
`
`Mean
`5-FU Cmax
`PD (izM)
`
`Mean 5-FU
`AUC
`(p.M/min)
`
`0.5/900
`1.0/900
`1.5/900
`2.0/900
`2.51900
`3.01900
`
`1 306 -+ 32 10498 -+ 1119
`1 (3.7)
`1PR(5.9)*
`9176 ± 611
`1 278 -+ 52
`2 (3.8, 13-1)
`0
`5362 +- 2591
`1 166 -+ 86
`2 (6.0, 9.6)
`0
`6794 +- 1167
`1 216 -* 27
`1 (6.6)
`1PR(5.2)*
`3 (5.5, 6.5, 3.0) 0 648 -+ 74 19593 -+ 6074
`0
`2 528 +- 136 16360 _+ 1452
`1CR(9.5+) 0
`
`3.011050
`Total
`
`0
`3
`
`1 (3.0+)
`10
`
`2 667 -+ 116 20979 _+ 6046
`8
`
`*received prior 5-FU based therapy, **received no prior therapy
`
`Therapy was well tolerated. There was no grade 3 or 4 mucositis; the most
`common toxicity was neutropenia. Eighteen patients are alive. Clinical
`activity, including disease stabilization, was seen in patients previously
`treated with 5-FU. Pharmacokinetic data suggest synergy between ’Tomu-
`dex’ and 5-FU. At ’Tomudex’ doses above 2.0 mg/ms DLT has not yet been
`reached. Dose escalation continues. Tomudex is a trademark and property
`of Zeneca Ltd.
`
`Sandoz Inc.
`Exhibit 1014-0001
`
`Teva – Fresenius
`Exhibit 1014-00001