‘Jul 25, No 18S Part I of II
`
`June 20, 2007
`
`J URN 0
`CLINIC
`Q NOLOGY
`
`u.vww.jco.org
`
`official journal of the American Society of Clinical Oncology
`
`ASC“”
`
`43rd Annual Meeting
`lune 1-5, 2007
`McCormick Place
`
`Chicago, IL
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`S~R!ALS
`
`MICHIGAN ST,~:iE LIN!VERStTY
`LIBRAR!ES
`
`43rd
`Annual Meeting of the
`American Society of Clinical Oncology
`June 1-5, 2007
`Chicago, Illinois
`2007 Annual Meeting Proceedings Part I
`
`(a supplement to the Journal of Clinical Oncology)
`
`Periodical Reading Room
`DO NOT CIRCULATE
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`Copyright 2007 American Society of Clinical Oncology
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`Editor: Steven M. Grunberg, MD
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`Publisher: Lisa Greaves
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`SUPPLEMENT TO
`JOURNAL OF CLINICAL
`
`O(’t’i cia / +J o ~t t’ n al o 1" t h e A tl~ c r ica ~ Soc Je ~y
`
`ONCOLOGY
`
`Vol. 25, No. 18S
`
`June 20, 2007
`
`Plenary (Abstracts LBA1 - LBA5) ......................................................................................................................................
`
`ls
`
`Breast Cancer-Local-Regional and Adjuvant
`Scheduled presentations (Abstracts 500 - 616) .........................................................................................................
`3s
`Published only (Abstracts 11000- 11107) ..................................................................................................................... 594s
`
`Breast Cancer-Metastatic
`Scheduled presentations (Abstracts 1000- 1115) ................................................................................................... 32s
`Published only (Abstracts 11500- t 1518) ..................................................................................................................... 603s
`
`Cancer Prevention
`ScheduIed presentations (Abstracts 1500 - 1553) .......................................................... ~ ........................................ 61s
`
`Central Nervous System Tumors
`Scheduled presentations (Abstracts 2000 - 2087) ................................................................................................... 75s ’
`Published only (Abstracts 12500- 12536) .................................................................................................................... 605s
`
`Developmental Therapeutics: Cytotoxic Chemotherapy
`Scheduled presentations (Abstracts 2500 - 2580) ................................................................................................... 97s
`Published only (Abstracts 13000- 13020) .................................................................................................................... 8088
`
`Developmental Therapeutics: Immunotherapy
`Scheduled presentations (Abstracts 3000 - 3077) ................................................................................................... 118s
`Published only (Abstracts 13500 - 13518) ..................................................................................................................... lil0s
`
`Developmental Therapeutics: Molecular Therapeutics
`Scheduled presentations Abstracts 3500 - 3604) ................................................................................................... 138s
`Published only (Abstracts 14000 - 14156) .................................................................................................................... 6128
`
`Gastrointestinal (Colorectal) Cancer
`Scheduled presentations (Abstracts 4000 - 4138) .................................................................................................... 164s
`Published only (Abstracts 14500 - 14603) ..................................................................................................................... li25s
`
`Gastrointestinal (Noncolorectal) Cancer
`Scheduled presentations (Abstracts 4500 - 4649) ................................................................................................... 198s
`Published only (Abstracts 15000 - 15190} .................................................................................................................... 6348
`
`Genitourinary Cancer
`Scheduled presentations (Abstracts 5000 - 5156) .................................................................................................... 2358
`Published only (Abstracts 15500- 15649) .................................................................................................................... 650s
`
`Gynecologic Cancer
`Scheduled presentations (Abstracts 5500 -5599) ................................................................................................... 274s
`Published only (Abstracts 16000- 16081 ). ................................................................................................................... 6628
`
`(continued on following page)
`
`lournal of Clinical Oncotogy (ISSN 0732-183X) is pub|ished ]6 times a year, three times monthly, by American Society of Clinical Oaco!ogy, 1900 Duke St, Sake 200, Alexandria,
`VA 22314. Periodicals postage is paid at Alexandria, VA, and at additional mailing offices. Publication Marl Agreement Number 863289.
`F.,ditotial correspondence should be addressed to Daniel G. Hailer, MD, [ournat ofC~it~ica~ O~colog~, 330 ~ohn Carly]e St, Suite 300, Alexandria, VA 22314. Telephone: (703)
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`POSTMASTER: ASCO members send change of address to American Society of Clinical Oncotogy’, 1900 Duke St, Suite 200, Alexandria, VA 22314. Nonmembers send change
`ef address to ~ourna! of CIi~icat Ontology Customer Service, 3~0 Iohn Carlyh St, Suite ~00, Aiexandrla, VA 22314.
`2007 annual subscription rates, effective September 1, 20(16: United States and possessions: individual, $487; single issue, $~5. |nternational: individual $678; single issue, $45.
`Institutions: Tier 1:$670 US, $950 Int’l; Tier 2:$780 US, $L060 Int’l; Tier 3~ $t,130 US, $1,410 Int’l; Tier 4:$1,24,5 US; $1,525 [nt’l; Tier 5: contact ~’CO for a quote. See
`htlp:t/vocw.jco.org/suhscriptioes/tieredpridag.shtml for descriptions of each tier. Student and resident: United States and possessions: $240; ai~ other countries, $336. To receive
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`
`Head and Neck Cancer
`Scheduled 3resentations Abstracts 6000 - 6090) ................................................................................................... ~39s
`Published only Abstracts 16500- 16546) ..................................................................................................................... 669s
`Health Services Research
`Scheduled 3resentations Abstracts 6500 - 6638) ................................................................................................... 322s
`Published only Abstracts 17000- 17084) .................................................................................................................... 673s
`Leukemia, Myelodysplasia, and Transplantation (Adult)
`Scheduled 3resentations Abstracts 7000 - 7112) ................................................................................................... 357s
`Published only Abstracts 17500- 17543) ..................................................................................................................... 68~s
`Lung Cancer
`Scheduled 3resentations Abstracts 7500 - LBA7727) ........................................................................................... 385s
`Published only Abstracts 18002 - 18213) .................................................................................................................... 684s
`Lymphoma and Plasma Cell Disorders
`Scheduled 3resentations Abstracts 8000 - 8124) .................................................................................................... 441s
`18500 - 18544) ...................................................................................................................... 70Zs
`Published only Albstracts
`
`Melanoma
`Scheduled 3resentations
`Published only Abstracts
`
`Patient Care
`Scheduled 3resentations
`Published only Abstracts
`
`Abstracts 8500 - 8583) ................................................................................................... 472s
`19000- 19003) .................................................................................................................... 706s
`
`Abstracts 9000 - 9133) ................................................................................................... 493s
`19500 - LBA196841 ............................................................................................................
`
`Abstracts 9500 - 9572) ................................................................................................... 5Z6s
`20000 - 20028) .................................................................................................................... ]23s
`
`Pediatric Cancer
`Scheduled ~resentations
`Published on1¥ Abstracts
`Sarcoma
`Scheduled presentations
`Abstracts 10000 - 10078) ................................................................................................. 545s
`Published onty Abstracts 20500 - 20536) ...................................................................................................................... 726s
`Tumor Biology and Human Genetics
`Scheduled ~resentations Abstracts 10500 - 10615) ................................................................................................ 565s
`Published only (Abstracts 21000 - 21188) .................................................................................................................... 729s
`Indexes
`Disclosure Index ......................................................................................................................................................................... 746s
`Author Index ................................................................................................................................................................................ 822s
`Subject Index ................................................................................................................................................................................ 906s
`
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`

`
`112s
`
`Developmental Therapeutics: Cytotoxic Chemotherapy
`
`2560
`
`General Poster Session (Board #C2), Sun, 8:00 AM - 12:00 PM
`
`2561
`
`General Poster Session (8nard #C3), Sun, 8:00 AM - 12:0~
`
`A phase I study evaluating a novel schedule of oral aniluracil (EU) combined
`with escalating doses of oral 5-fluorouracil (5- FU). J. R. lnfante, S. F. Jones,
`M. Law’ton, P. WinE,, R. K. Mah’k, W. P. Peters, H. A. Burris III; Sarah
`Cannon Research Institute, Nashville, TIV; Adherex Technologies, Durham,
`NC
`
`Background: 5-FU, a commonly utilized cytotoxic, is rapidly catabolized by
`dihydropyrimidine dehydrogenase (DPD), and requires anabolic conversion
`for anti-tumor activity. It has poor oral bioavailability due to DPD in the GI
`tract and liver, and toxiciLies such as hand-foot skin reaction. ]n addition,
`high levels of DPD are associated with 5-FU resistance. EU is a mechanism-
`base(l irreversible inactivator of DPD. Early studies in combination with oral
`5-FU demonstrated activity: however, 3 Phase 3 studies were negative, due
`to an unrecognized inhibition of 5-FU anabolic activation by EU (Fourie et
`al; 2006 ASCO Proceedings; a 2058). Lower doses of eniluraci] given
`12-20 hrs prior to 5- FU preserves the desired DPD inhibition, without
`inhibiting these anabolic enzymes. Methods: The objectives are to deter-
`mine the dose limiting toxicities (DLTs) and maximum tolerated dose
`(MTD}, safety, tolerability, pharmacokinetics (PK), and DPD activity in
`peripheral blood mononuclear ceils (PBMCs) following administration of a
`fixed dose of EU in combination with escalating doses of 5-FU. The
`combination of ora~ 5.0 mg EU 12 to 20 hours prior to oral 5 FU, is given
`qW for 3 weeks in 28 day cycles, Results: Twenty subjects have been
`enrolled, at 5-FU doses of 30, 40, 50, 60, and 70 rag. A total of 39 cycles
`have been administered, with 4 patients currently on study. The oral
`combination of £U and 5-FU has been well tolerated. All toxicities have
`been grade 1 or 2 with the exception of two grade 3 toxicities reported at the
`50mg dose (anemia and neutropenia). The grade 3 neutropenia is the only
`observed DLT and resulted in a 1 week delay in initiation of cycle 2. No CR
`or PR noted, but 4 patients (2 previously treated with 5-FU) with 4 cycles of
`SD. 95-100% of DPD inhibition achieved at the time of 5-FU dosing and
`PK resu Its demonstrate a dose proportional increase in 5-FU C,,,, and AUC,
`and a haJf life of ~3.5 hours. Conclusions: The oral combination of 5mg of
`[:U 8ivan 12-20 hrs prior to 5-FU has been weft to~erated and achieves futf
`functional inhibition of DPD i.n all patients. The MTD is not yet defined and
`the next cohort isenrollingat the 80rag dose. EU in combination with 5-FU
`may provide a promising therapeutic option for patients with tumors known
`to be resistant to 5-FU due to high levels of DPD.
`
`Phase I trial of combination becatecarin and nxalipiatin in patieets
`advanced solid tumors. S. Manda, C. Mauser, J. Bokar, M. Cooney, J.
`S. Krishnamurthi, P. Sawides, P. Ivy, S. Remick, A, Dowlati; Case
`Reserve University, Cleveland, OH: CTEP National Cancer institute,
`thesda. MD
`
`Background: Becatecarin (rebeccamycin analogue-RA) is an
`antibiotic with inhibitory activity against both topoisomerase .1~ and I
`as DNA intercalating properties. We performed a phase I trial to
`determine the maximum tolerated dose (MTD) of RA in
`oxalipIatin; b) determine the dose limiting toxicities (DLT)
`on pharmacokinetics and (d) observe for any antitumor activity.
`Eligibility criteria included patients with
`to standard therapy; performance status 0-2; adequate
`and liver function. Patients were treated with RA as a 1 hour infusion dai
`5 and oxaliplatin on day 5 only, after RA infusion. Treatment was
`q 21 days. The following dose levels were evaluated: Dose level 1: RA
`mFJm~!d and oxaliplatin 90 mgimZ; Dose revel 2: RA 80 mF=Jm~/d
`oxaliplatin 130 m~/m~; Dose love! 3; RA 1 t0 m~/m~!d and oxalip~atin
`ml~m~. Results: A total of 15 evaluable patients were enrolled. Median
`was 56 (8 mate, 7 female). A variet
`56 cycles were administered. DLT occurred at a dose of RA at
`x 5 days and oxaliptatin at t30 m~m~ and consisted of ivade !
`hypophosphatemia and grade 4 atriat fibrillation. At this dose level 2 of~
`enrolled patients also developed grade 3 neutropenia. The MTD
`recommended phase II dose was RA at 80 m~Vm2/daily x 5 alOnl
`oxaliplatin 130 m~m2 day 5 q 21 days, Three confirmed partial
`were observed in patients with hepatoceltular,
`cancers, Six patients experienced stable disease. Conclusinns: At the
`combination RA and oxaliplatin is well tolerated and given the res
`rate and stable diseases observed, phase II studies are
`Supported by Grants U01 CA62502, MO:t-RR-O0080, 1<23 CAlO9348-
`from the National Institutes of Health.
`
`2562
`
`General Poster Session (Board #Ca,), Sun, 8:00 AM - 12:00 PM
`
`2563
`
`General Poster Session (Board #C5), Sun, 8:00 AM - 12:00
`
`The c~mplste phase Ib clinical trial: A method to accelerate new agent
`development. D. D. Von Herr, J. A. Nieves, L. K. Voci/a, S. D. Weitman,
`Cvitkovic; Translational Genomics Research Institute (TGen), Phoenix, AZ;
`Translational Oncoiogy Team, Houston, TX; Institute for Drug Develop-
`merit, San Antonio, TX; AAI Oncology, Le Kremlin, France
`
`Baok~ound: The usual clinical development plan for a new agent (NA)
`includes a phase I monotherapy trial. However, because many new agents
`are eventuafly developed as part of a combination, additional phase ~ trials
`assessing the new agent in combination with a standard agent are usually
`performed (usually as individual phase Ib studies). Our hypothesis was that
`within a single protocol, several combination phase I trials could be
`conducted simultaneously. Methods: The design of the protocol is (assum-
`ing the new agent is synergistic with an anthracycline, a tubulin interactive
`agent, an antimetabolite, an angiogenesis inhibitor or an antibody to
`EGFR): patients with advanced cancer are treated with t~e combination
`deemed most likely to be of help=with a choice of a) anthracycline + NA; b)
`tubulin interactive + NA; c) antimetabolite + NA; d) angiogenesis inhibito~
`+ NA; e) antibody to EGFR + NA. The standard agent is started at full dose
`with 3 patients placed at 1/3 full dose of NA, 3 patients at 2/3 dose of
`and 3-6 patients at fulJ dose of the NA in the combination. Results: Our
`experience with the comptete phase Ib trial has foond severa~ advantages
`over conducting separate phase I trials. The advantages include: (a) a very
`rapid follow-up on preclinical data in one.study; (b) a saving of time and
`expense in the start up; (c) accrual is rapid because many patients in a
`,practice are tikely to be eligibte (e.g. the standard agent is the standard of
`care); (d) patients are often less pretreated; (el the trial generates
`information for more informed selection of follow-up randomized phase
`or III tria~s. Conclusions: Utilizing a Complete phase Ib trial design is
`feasible. Our initial experience has sup~ested that this approach is safe and
`highly efficient with several potential advantages over multiple sequential
`combination phase Ib studies.
`
`Pharmacokinetic results of a phase I trial of sorafenib (S) in combination ~
`dacarbazine (DTIC) in patients with advanced metastatic
`solid tumors, E. Brendei, E. Zafarana, C. Figuerola, M, Ludwig, C. Lathia, i
`Burk, C. Robert, J, C. Sor~a, ~, P. Armand; Bayer HealthCare
`Wuppertal, Germany; Bayer Pharma S.A.S., Puteaux,
`ration, West Haven, CT; lnstitut Gustave Roussy, Villejuif, France
`
`Background: Sorafenib (S) is a multikinase inhibitor that prevents
`cell profiferation and angiegenesis via receptor tyrosine kinases,
`-2, -3 and PDGFR-a and -/3, and the Raf/MEK!F_RK pathway at the leveh
`Raf kinase. Single-agent studies show S is well tolerated with mana
`and reversible side effects, most commonly, diarrhea, rash, fatigue, a
`hand-foot skin (HFS) reaction. This phase I study assessed the safety a
`pharmacokinetics (PK) of the combination of S and DTIC. Methods~ :
`patients (pts) received a fixed dose of DTIC (!,000 m&/m~ given
`wks) starting on Day ~. of cycle ]. (C1)~ S (400 mg
`2-21 in C1 and continuously thereafter. PK profiles of DTIC and
`imidazole-4-carboxamide (AIC: an inactive D metabolite that is
`an equal proportion to t~e active moiety, diazomethane, that cannot
`analytically measured) were Obtained from day 1 of both C1 and C2 and
`profi}es of S from Day 1 of C2. Results: 23 pts (M;F, 11:12; mean a
`yrs) were treated with S and DT~C. Of these pts, 15 were valid for ~
`analysis. Following simultaneous administration of S, mean AUC and ~
`of DTIC were moderately reduced by 23% and 16%, while mean AUC
`C .... of AIC were increased by 4].% and 45%, respectively. Mean
`(0-].2)~, and Cr~ax.~ of S were 28,3 mg*h/L {84%) and 3.67 m
`respectively, upon concomitant dosing of S and DTIC. These
`exposures are withi n the ra nge of exposures observed in phase I studies
`pts had an increase of either Cry,, or AUC of AtC of at least 70%, and
`the 6 pts, this increase was correlated with grade 4
`Conclusions: The combination of S and DTIC resulted in moderate
`creases of DTIC exposure; however, more pronounced increases in
`exposure were observed. In patients with a distinct increase
`AIC, a correlation between exposure and toxicity cannot be
`however, all toxicities were manageable,
`
`Sandoz Inc. IPR2016-00318
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`
`

`
`11 2s
`
`Developmental Therapeutics: Cytotoxic Chemotherapy
`
`2560
`General Poster Session (Board #C2), Sun, 8:00 AM - 12:00 PM
`A phase i study evaluating a novel schedule ol oral eniluracil (EU) combined
`with escalating doses of oral 5-fluorouracil (5- FLI). J. R. infante, S. F. Jones,
`M. Lawton, P. Wing, R. K. Malik, W. P. Peters, H. A. Burris fit; Sarah
`Cannon Research Institute, Nashville, TN; Adherex Technologies, Durham,
`NC
`
`Background= 5-FU, a commonly utilized cytotoxic, is rapidly catabolized by
`dihydropyrimidine dehydrogenase [DPD}, and requires anabolic conversion
`for anti-tumor activity. It has poor oral bioavailability due to DPD in the GI
`tract and liver, and toxicities such as hand-foot skin reaction. In addition,
`high ~evets of DPD are associated with 5-FU resistance, EU is a mechanism-
`based irreversible inactivator of DPD. Early studies in combination with orat
`5-FU demonstrated activity; however, 3 Phase 3 studies were negative, due
`to an unrecognized inflibition of 5-FU anabofic activation by £U (fourie et
`hi; 2006 ASCO Proceedings; a 2058), Lower doses of eniluracil given
`12-20 hrs prior to 5- FU preserves the desired DPD inhibition, without
`inhibiting these anabolic enzymes. Methods: The obiectives are to deter-
`mine the dose limiting toxicities (DLTs} and maximum tolerated dose
`(MTO), safety, tolerability, pharmacokinetics (PK), and DPD activity in
`peripheral blood mononuclear cells (PBMCs) following administration of a
`fixed dose of EU in combination with eseafating doses of 5-FU. The
`combination of oral 5.0 mg EU ~.2 to 20 hours prior to oral 5-FU, is given
`qW for 3 weeks in 28 day cycles, Results: Twenty subjects have been
`enrolled, at 5-FU doses of 30, 40, 50, 60, and 70 mg. Atotal of 39 cycles
`have been administered, with 4 patients currently on study. The oral
`combination of EU and 5-FU has been well tolerated. All toxicities have
`been grade 1 or 2 with the exception of two grade 3 toxicities reported at the
`50mg dose (anemia and r~eutropenia). The grade 3 neutropenia is the only
`observed DLT and resulted in a i week delay in initiation of cycle 2. No CR
`or PR noted, but 4 patients (2 previously treateci with 5-FU) with 4 cycles of
`SD, 95-100% of DPD inhibition achieved at the time of 5-FU dosing and
`PK results demonstrate a ~fose proportional increase in 5oFU Cmax and AUC,
`and a half life of -3,5 hours. Conclusions: The oral combination of 5mg of
`EU given 12-20 hrs prior to 5-FU has been well tolerated and achieves full
`functiona~ inhibition of DPD in all patients, The MTD is not yet defined and
`the next cohort is enrolling at the 80rag dose. EU in combination with 5-FU
`may provide a promising therapeutic option for patients with tumors known
`to be resistant to 5-FU due to high levefs ef DPD.
`
`2561
`
`General Poster Session (Board #C3), Sun, 8:00 AM - 12:00 ~
`
`Phase I trial of combination becatecarin and oxaliplatin in patients
`advanced solid tumors..S. Manda, C. Mouser, J. Bokar, M. Cooney, J. Broil,
`S. Krishnamurthi, P. Savvides, P. Ivy, S, Remick, A. Dowlati: Case West~
`Reserve University, Cleveland, OH; CTEP National Cancer Institute, B~
`thesda, MD
`
`Background: Becatecarin (rebeccamycin analogue:RA) is an ant]-tum~{
`antibiotic with inhibitory activity against both topoisomerase II and I
`as DNA intercalating properties. We performed a phase I trial to
`determine the maximum to~erated dose {MTD) of RA in combination wi~
`oxaliplatin; b) determine the dose limiting toxicities (DLT) (c) obtain
`on pharmacokinetics and (d) observe for any antitumor activity. Methl~
`Eligibility criteria included patients with advanced solid tumors refract0~
`to standard tf~erapy; performance status 0-2; adequate hematologic, renal
`and liver function. Patients were treated with RA as a 1 hour infusion dail.~
`5 and oxaliplatin on day 5 only, after RA infusion, Treatment was rebeate
`q 21 days. The following c~ose levels were evaluated: Dose level 1: RAg~
`mgim2/d and oxaliplatin 90 m~im2,, Dose level 2: RA 80 mg/m2/d ant
`oxaliplatin 130 m~jm~; Dose levet 3: RA 110 mgimZid and oxaliplatin [30
`mgim2. Bnsulls: A total of 15 evatuable patients were enrolled. Median ~
`was 56 (8 male, 7 female). A variety of tumor types were enrolled, A total ~f
`56 cyc}es were administered. D LT occurred at a dose of RA at 1 :L 0 mgirn~Id
`2
`x 5 days and oxaliplatin at 130 mg/m and consistec] of grade
`hypophosphatemia and grade 4 atrial fibrillation. At this dose level 2 of 3
`enrolled patients also developed grade 3 neutropenia. The MTD
`recommended phase 11 dose was RA at 80 mg/m2/da]ly x 5 along wi~
`oxaliplatin 130 mg/mz day 5 q 21 days. Three confirmed partial response
`were observed in patients with hepatoeeflular, gallbladder and esopl~age~l
`cancers. Six patients experienced stable disease. Conclusions: At the
`combination RA and oxaliplatin is weft tolerated and given the resp0~
`rate and stable diseases observed, phase II studies are recommende~
`Supported by Grants U01 CA62502, MO1-RR-O0080, K23 CA109348-01
`from the National Institutes of Health.
`
`2562
`
`General Poster Session (Board #C4), Sun, 8:80 AM - ] 2:00 PM
`
`2563
`
`General Poster Session (Board #C5), Sun, 8:00 AM - 12:00
`
`The complete phase Ib clinical trial: A method to accelerate new agent
`development. D: D. Von Huff, J. A. Nieves, L. K. Vocita, S. D. Weitman, E.
`Cvitkovic; Translational Genomies Research Institute (TGen), Phoemx, AZ;
`Translational Oncology Team, Houston, TX~ Institute for Oru~ Develop-
`ment, San Antonio, TX; AAI Oncolegy, Le Kremlin, France
`
`Background.. The usual clinical development plan for a new agent (NA)
`includes a phase I monotherapy trial. However, because many new agents
`are eventually developed as part of a combination, additional £hase I trials
`assessing the new agent in combination with a standard agent are usually
`performed (usually as individua~ phase Ib studies). Our hypothesis was that
`within a single protocol, several combination phase I trials could be
`conducted simultaneously. Metheds; The design of the protocol is (assum-
`ing the new agent is synergistic with an antflracyctine, a tubulin interactive
`agent, an antimetabolite, an angiogenesis inhibitor or an antibody to
`EGFR)= patients with advanced cancer are treated with the comb}nation
`deemed most likely to be of help-with a choice of a) anthracycline + NAI b)
`tubolin interactive + NA; c) antimetabolite + NA; d) angiogenesis inhibitor
`+ NA; e} antibody to EGFR + NA. The standard agent is started at full dose
`with 3 patients placed at 1/3 full dose of NA, 3 patients at 2/3 dose of NA,
`and 3-6 patients at full dose of the NA in the combination. Results: Our
`experience with the complete phase Ib trial has found several advantages
`over conducting separate phase I trials. The advantages include: (a) a very
`rapid follow-up on preclinical data in one studyl (b) a saving of time and
`expense in the start up~ (c) accrual is rapid because many patients in a
`practice are likely to be eligible (e.8. the standard agent is the standard of
`care); (d) patients are often less pretreated; (e) the trial generates
`information for more informed selection of follow-up randomized phase II
`or III trials. Conclusions: Utilizing a Complete phase Ib trial design is
`feast bin. Our in itial experience h~s suggested that th is approach is safe a n d
`highly efficient with several potential advantages over multiple sequential
`combination phase Ib studies.
`
`Pharmacokinetic lesults ol a phase i trial of sorafenih (S) in
`dacarbazine (DTiC) in patients with advanced metastatic melanoma
`selid tumors. E. Brende!, E. Zafarana, C. Figuerol& M, Ludwig, C~ Lathia,~
`Burk, C. Robert, J. C. Sofia, J. P. Armand; Bayer HealthCare
`Wuppertai, Germany; Bayer Pharma S.A.S., Puteaux, France; B~
`ration, West Haven, CT; Institut Gustave Roussy, Villejuif, France
`
`Background: Sorafenib (S) is a mu(tikinase inhibitor that prevents
`cell proliferation and angiogenesis via receptor tyrosine kinases, VEGFR-]
`-2, -3 and PDGFR-a and -/~, and the Raf/MEKiERK oathway at the level~
`Raf kinase. Single-agent studies show S is wel~ tolerete~ with
`and reversible side effects, most commonly, diarrhea, rash, fatigue,
`hand-foot skin (HFSI reaction. This phase I study assessed the safet
`pharmacokinetics (PK) of the combination of S and OTtC. Me~ods:
`pat{ents (pts) received a fixed dose of DTIC (1,000 mgim2 given
`wks) starting on Day I of cycle ] (C1). S {400 mg bid) was given ca
`2-21 in C1 and continuously thereafter, PK profiles of DTIC and
`imidazole-4-carbexamide (AIC; an inactive D metabolite that is formede
`an equal proportion to the a~tive moiety, diazomethane, that cannot
`analytically measured) were obtained from day ~. of both C1 and C2
`profiles of S from Day ~. of C2. Results: 23 pts (M:F, 11:12; mean age
`yrs) were treated with S and DTIC. Of these pts, 15 were valid for
`analysis. Following simultaneous administration of S, mean AUC and O
`of DTIC were moderately reduced by 23% and 16%, while mean AUC~
`C .... of AIC were increased by 41% and 45%, respectively. Mean
`(0-12),~ and Cr~,,,, of S were 28,3 mg*htL (84%} and 3.67 m
`respectively, upon concemiLant dosing of S and DTIC. These
`exposures are within the range of exposures observed in phase I
`pts had an increase of either C~, or AUC of AIC of at least 70%. and in 4~
`the 6 pts, this increase was correlated with grade 4 thromboc
`Conclusions: The combination of S and DTIC resulted in
`creases of DTIC exposure; however, more pronounced increases in
`exposure were observed. In patie£ts with a distinct increase (=70%)~
`AIC, a correlation between exposure and toxicity cannot be
`however, all toxicities were manageable.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1098-0007