’‘ Clinical cancer research : an official jo
`v.7, no. 11, suppl. (Nov. 2001)
`DUP - General Collection
`W1 CL672
`
`2001-11-15
`Lmmcol
`Coincer
`Research
`
`An Official Journal
`_
`WW
`American Association
`for
`Cancer Research
`
`AmerzfcanAssrmiatiori
`76rCa"cerResearCh
`
`I
`
`I
`
`E 0 C
`European Oigani/.alion for Re5(3dl'Cl”l
`and Tf(’i'lll‘l'lE|1l0iCi1ll(.'(-.'l’
`
`AACR-NCI-EORTC International Conference
`
`Molecular Targets and
`Cancer Therapeutics:
`DlSCOU67j/, Biology, and Clinical Applications
`
`October 29-November 2, 2001 - Fontainebleau Hilton Hotel - Miami Beach, Florida
`
`_?=-
`
`PROPERTY OF THE
`
`NATIONAL
`LIBRARY OF
`«H MEDICINE
`
`éxlovember 2001 - Volume 7 - Supplement
`36533-38523 - ISSN 1078-0432
`
`This material w.a5»i:i:ipiEd
`Ett7l'|EHll.l'|.l1 and maybe
`
`1
`
`AVENTIS EXHIBIT 2224
`Mylan v. Aventis IPR2016-00712
`
`

`
`#282 Phase l and pharmacokinetics (PK) study of RPR 116258A given
`as a weekly 1-hour infusion at day 1, day 8, day 15, day 22 every 5 weeks
`in patients (pts). with advanced solid tumors. P. Fumoleau, J. Trigo, M.
`Campone, J. Baselga. F. Sistac, P. Gimenez. L. Manos. H. Fontaine. D. Semi-
`ond, G. Sanderink, D. Perard, M. Besenval. Ctr Rene Gauducheau, Nantes,
`France; Hosp Vail d'Hebron, Barcelona, Spain: Aventls Pharma Spain, Barce-
`lona. Spain: Aventis Pharma France, Antony, France; Aventls Pharma France,
`Alforvi/ie, France.
`'
`RPR 116258A is a new taxoid with a broad spectrum of activity: activity on
`mdr-1 expressing tumor cells in vitro and against B16/TXT resistant melanoma
`and ability to cross blood brain barrier. This new compound was tested in phase
`I study using Simon's design 4A. The drug was administered as a weekly 1-hour
`infusion during 4 consecutive weeks (D1, D8. D15 and D22) every 5 weeks,
`without premedication. The dose-limiting toxicities (DLTs) were evaluated after
`cycle 1 (5 weeks) to establish the Maximum Tolerated Dose (MTD). PK samples
`were collected during the first 48 or 72 hours post infusion at day 1 and day 22
`of cycles 1 and 2 when possible. Twenty-five patients (6 males. 19 females,
`median age: 52) were included. Most of pts presented advanced breast cancer
`(15/25 pts). Seventeen patients were treated in the dose escalation phase at 1.5
`(1 pt), 3 (1 pt), 6 (4 pts), 8.4 (5 pts) and 12 mg/m2 (6 pts). A total of 48 cycles (1 -8)
`was administered with treatment duration ranges from 2 to 40 weeks. The MTD
`was reached at the 12 mg/m2 dose level at which 2 out of 6 pts experienced
`DLTs at cycle 1. These DLTs consisted of diarrhea gr 3 (timeof occurrence: day
`7-18/duration: 3-4 days). At the subsequent cycles, other DLTs were reported
`at 12 mg/m‘?: 2 fatigue gr 3. 1 diarrhea gr 3, 1 neutropenia gr 4 > 5 days, 1
`
`febrile neutropenia and at 8.4 mg/m2: 1 fatigue gr 3. Eight additional patients
`were treated at 8.4 mg/m2 to well establish the recommended dose for future
`phase ii studies. Neutropenia was the main hematologic toxicity and reached gr
`3 (1 pt) at the dose of 8.4 mg/m‘*’. The main non hematologic toxicities were:
`diarrhea: 36.4% pts including 3 gr 3, fatigue: 36.4% pts including 3 gr 3 and
`neurosensory: 22.7% pts with only 1 gr 3. No neurocentral toxicity was re-
`ported. Only 3 cases of mild hypersensitivity reaction (gr 1) were observed. The
`preliminary PK results indicated that AUC(0-t) increased proportionally with the
`dose from 1.5 to 12 mg/m2 on day 1 at cycle 1. At 8.4 mg/m"’. the drug had a
`high total body clearance (50 L/h/m"’). a very large volume of distribution (1424
`um?) and a quite long terminal half life (31h). There was a trend towards higher
`plasma levels at later sampling times on day 22 than on day 1 at cycle 1.
`However. no drug was detected at predose on day 22. Two confirmed partial
`responses in breast cancer patients after taxold failure were reported at 8.4 and
`.12'_mg_/m'*’ dose levels and 12 stable diseases were observed in different“
`Indications. such as: breast (7 pts). gastric. ovary, cholanglocarcinoma, carci.-._j
`noid tumor. NSCL cancers. An intermediate dose level of 10 mg/m2 is being
`explored.
`
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`37105 p(,Ste,. 535540,, B, (_~()ntif1;(ed Clinical Cancer Research 0 Volume 7 0 November 2001 (Supplement)
`febrile neutropenia and at 8.4 mg/m2: 1 fatigue gr 3. Eight additional patients
`PK l‘.1r-amctcr Estimates
`were treated at 8.4 mg/m2 to well establish the recommended dose for future
`phase II studies. Neutropenia was the main hematologic toxicity and reached gr
`3 (1 Pi) at the dose of 8.4 mg/ma. The main non hematologic toxicities were:
`diarrhea: 36.4% pts including 3 gr 3, fatigue: 36.4% pts including 3 gr 3 and
`neurosensory: 22.7% pts with only 1 gr 3. No neurocentral toxicity was re-
`ported. Only 3 cases of mild hypersensitivity reaction (gr 1) were observed. The
`preliminary PK results indicated that AUC(0-t) increased proportionally with the
`dose from 1.5 to 12 mg/m2 on day 1 at cycle 1. At 8.4 mg/ma, the drug had a
`high total body clearance (50 L/him”), a very large volume of distribution (1424
`Umz) and a quite long terminal half life (31 h). There was a trend towards higher
`plasma levels at later sampling times on day 22 than on day 1 at cycle 1.
`However, no drug was detected at predose on day 22. Two confirmed partial
`responses in breast cancer patients after taxoid failure were reported at 8.4 and
`"l2‘mg‘/m2 dose levels and 12 stable diseases were observed in different
`indications, such as: breast (7 pts), gastric, ovary, cholangiocarcinoma, carci-
`EX
`.
`hDFl)[fO1rl;:Ij’l0l', NSCL cancers. An intermediate dose level of 10 mg/m2 is being
`
`130 (1)
`
`215 (6)
`
`325 (2)
`
`#281 Inhibition of H-ras membrane binding and topoisomerase-1 in a
`phase I trial of topotecan combined with the farnesyl transferase inhibitor,
`R115777 (Zarnestra). H. Hochster, L. Liebes, M. Buckley, J. Sorich, D. Fry, A.
`Hamilton, J. Wright, F. Muggia. New York Univ Sch of Medicine, New York, NY,’
`CTEP, NCI, Bethesda, MD.
`Pre—clinica| studies have suggested synergistic activity of the farnesyl trans-
`ferase inhibitor, R115777, when given together with topotecan, a topoisomer—
`ase—1 inhibitor. This phase I study combined topotecan given on a daily x 5
`regimen (days 1-5) together with R115777 given orally bid days 1-21 every 28
`days. Methods: Eligibility included histologically documented, advanced can»
`cer, :3 prior chemotherapy regimens, RT to less than 25% of bone marrow,
`ECOG PS 0-2. Organ function had to meet typical criteria and bowel function
`had to be normal. Twelve patients were entered including 8M, 4 F; PS 1 =9, 2 -
`3; median age 54 (range 35-67 years); disease sites: colon 4, pancreas 2,
`gastric 2, NSCLC, MM, sarcoma, peritoneal @1; prior RT = 3, prior chemo 12
`(1 prior = 3, 2 = 3, >3 = 6). Dose levels were (topo/FTI) = 1.0/200, 1.25/200
`and 1.0/300. Dose limiting neutropenia and thrombocytcpenia was seen at
`levels II and Ill. PK and PD studies were performed for topotecan blood levels,
`PBMC free topo-1, and PBMC membrane-bound fraction of H—ras. Studies
`were performed on day 1 (topotecan alone) and compared to day 5 (topotecan
`plus Fi115777, which was started on day 2 of treatment first cycle). Topotecan
`blood levels and PBMC topo-1 were determined by published methods (Liebes,
`et. al. Clinical Cancer Res. 4:545-557, 1998). To determine fraction of mem—
`brane~bound ras, PBMCS were pelleted and then phase separated using Tri-
`ton—X 1% to isolate cytoplasmic vs membrane fractions. These were quanti-
`tated by scanning densltometry from Western Blots using anti-H—ras 259
`antibody (Santa Cruz Biotech). Results: 1) PK modeling of topo-1 AUC showed
`no difference for day 1 (topotecan alone) compared to day 5 (topotecan plus
`R115777); 2) AUG (4-hour sampling) for free topo-1 (in PBMCs) decreased from
`mean value of 11.4 x 105 copies per cell on day 1 compared to 3.5 on day 5
`(n=10, p<0.001, paired Host); and 3) Membrane bound H-ras decreased from
`mean value of 48:11% (day 1) to 24:7% (day 5) (p<0.001 paired t-test, Fl=5l-
`Conclusions: 1) Enhanced myelosuppression was seen when a topo-1 inhibitor
`was combined with R115777, such that neither drug could be given at full
`doses; 2) Inhibition of topo-1 is dramatically increased on day 5 compared to
`day 1, which may be due to cumulative topotecan effect or enhancement of
`topotecan binding to cleavable complex by the FTI. This is not accounted for by
`a pharmacologic interaction; and 3) R115777 plus topotecan causes inhibition
`of ras farnesylation by approximately 50% as evidenced by the decrease in the
`ratio of membrane bound compared to cytoplasmic H-ras. We are continuing
`these studies using topotecan administered by the less myelosuppressive
`21~day infusion with R115777 given orally x 21 days. Supported in part by P30
`CA16087, M-O1 FlR0OO96, and U-01 76642.
`
`#282 Phase I and pharmacokinetics (PK) study of RPR 116258A given
`as a weekly 1-hour infusion at day 1, day 8, day 15, day 22 every 5 weeks
`in patients (pts) with advanced solid tumors. P. Fumoleau, J. Trigo, M.
`Campone, J. Baselga, F. Sistac, P. Gimenez, L. Manos. H. Fontaine, D. Semi—
`ond, G. Sanderink, D. Perard, M. Besenval. Ctr Fiene Gauducheau, Nantes,
`France; Hosp Vail d'Hebron, Barcelona, Spain; Aventis Pharma Spain, Barce-
`lona, Spain; Aventis Pharma France, Antony, France: Aventis Pharma France,
`Alforville, France.
`RPR 116258A is a new taxoid with a broad spectrum of activity: activity on
`mdr-1 expressing tumor cells in vitro and against B16/I’XT resistant melanoma
`and ability to cross blood brain barrier. This new compound was tested in phase
`I study using Simon‘s design 4A. The drug was administered as a weekly 1-hour
`infusion during 4 consecutive weeks (D1, D8, D15 and D22) every 5 weeks,
`without premedication. The dose-limiting toxicities (DLTs) were evaluated after
`cycle 1 (5 weeks) to establish the Maximum Tolerated Dose (MTD). PK samples
`were collected during the first 48 or 72 hours post infusion at day 1 and day 22
`of cycles 1 and 2 when possible. Twenty-live patients (6 males, 19 females,
`median age: 52) were included. Most of pts presented advanced breast cancer
`(15/25 pts). Seventeen patients were treated in the dose escalation phase at 1.5
`(1 pt), 3 (1 pt), 6 (4 pts), 8.4 (5 pts) and 12 mg/m2 (6 pts), Atotal of 48 cycles (1-8)
`was administered with treatment duration ranges from 2 to 40 weeks. The MTD
`was reached at the 12 mg/m2 dose level at which 2 out of 6 pts experienced
`DLTs at cycle 1. These DLTs consisted of diarrhea gr 3 (time of occurrence: day
`7-18/duration: 3-4 days). At the subsequent cycles, other DLTs were reported
`at 12 mg/m2: 2 fatigue gr 3,
`1 diarrhea gr 3, 1 neutrcpenia gr 4 > 5 days,
`1
`
`#283 A phase I/pharmacologic study of UCN-O1 in combination with
`5«fluorouraci| in patients with advanced solid tumors. M. A. Shah, J. Kort-
`mansky, D. P. Kelsen, C. Hseuh, A. Kaubisch, D. Spriggs, M. Gonen, W. Tong,
`S. Endres, G. K. Schwartz. Memorial Sloan Kettering Cancer Ctr, New York, NY.
`Background: UCN-01 (UCN) is a potent inhibitor of protein kinase C and
`cyclin dependent kinases. Single agent Phase I toxicities have included head-
`ache and hyperglycemia (HG). We have previously reported that, UCN signifi-
`cantly cnhances the induction of apoptosis by 5-F|uorouraci|(F) in vitro, asso-
`C|ZtI0d’W|tl’I_ a decrease in the transcription factor E2F-1, and a subsequent
`reduction in thymidylate ‘synthase expression [Clinical Cancer Res,1998].
`Therefore, to initiate the clinical evaluation of this novel drug combination, we
`began a Phase I clinical trial of UCN in combination with F. Methods: Escalating
`doses of'weel<ly 24 hour infusional F (250~>260O mg/m2) were given in combi-
`nation with a fixed monthly dose of UCN (45 mg/m2/d), Based on the single
`agent maximum tolerated dose, UCN infusion began on day #2 of each 28 day
`cycle over 72 hours for cycle 1 and over 36 hours for subsequent cycles.
`Peripheral blood samples were taken for thymidylate synthase assessments.
`Results: 24 patients have enrolled thus far; 22 are evaluable for toxicity and 18
`for pharmacology. UCN associated toxicities have included grade 3 headache
`In 1 patient and grades/4 HQ (1 and 2 patients). All incidents of grade 3/4 HG
`occurredin patients with a history of diabetes mellitus, and those with grade 4
`HG required continuous insulin infusions. We have therefore modified the
`inclusion criteria to exclude diabetic patients, and since have seen no further
`episodes of grade 3/4 HG. UCN peak plasma concentrations (Cmax) did not
`change from cycle 1 to cycle 2 and did not change with increasing F. As UCN
`is tightly bound to serum (X'1 acid glycoprotein (AGP), AGP levels were meas-
`ured. As shown below, we found a significant linear correlation between serum
`AGP and UCN Cmax (spearmanls rank correlation, r:0.79, p=0.0015). The
`regression line is estimated as Cmax=0.09*AGP+5.53.
`In addition. plasma
`UCN’concentrations achieved (20.2-53.5 pM) are associated with potentiation
`of F in vitro. Thus far, we have observed 3 patients with stable disease (range
`4-7 months duration), and a minor respone in 1 patient with colon cancer
`refractory to irinotecan and F. Conclusions: From the regression analysis UCN
`Cmax can be predicted from AGP determinations. This allows for UCN deter-
`minations by a simple protein immunoturbidity assay. Since we have yet to
`reach the maximal tolerated dose for this exciting drug combination_ accrual
`continues with escalating F doses. TS assessments will be presented. Sup-
`ported by Grant UO1 CA6985-6.
`
`8
`
`
`
`
`
` BUCN-01Cmax(mcg/ml)
`
`o5
`
`‘lm
`
`150
`
`ZD
`
`230
`
`AGP (mg/(ll)
`
`#284 Changes in plasma levels of hypoxia-induced secreted proteins
`as markers of response to a tirapapzamine-containing regimen: Molecular
`endpoints of a California Cancer Consortium phase I trial of tirapazamine
`(TPZ) plus carboplatin/paclitaxel. P. C. Mack, P. N. Lara,
`l. V. Galvin, D. H.
`Lau,_ H. J. Lenz, J. H. Doroshow, D. Fl. Gandara, P. H. Gumerlock. Univ of CA,
`Dav/s Cancer Ctr, Sacramento, CA,‘ Univ of Southern CA, Los Angeles, CA; City
`of Hope, Duarte, CA.
`‘ Tumor-related hypoxia is associated with increased resistance to conven-
`tional anticancer therapies, and thus, patients may benefit from combining an
`
`Proceedings of the 2001 AACR—NCI—EORTC international Conference
`
`3