Biweekly Paclitaxel (Taxol) and Cisplatin
`in Breast and Ovarian Cancer
`
`Karen A. Gelmon
`
`Two trials are being conducted to evaluate paclltaxel
`(Taxol; Bristol-Hyers Squibb Company, Princeton, NJ)
`combined with clsplatln In previously treated and un(cid:173)
`treated breast and ovarian cancer. Preliminary results
`are presented. The objectives of these nonrandomlzed
`trials are (I) to determine the toxicity of paclitaxel/
`clsplatln In a biweekly schedule, (2) to establish the
`maximum tolerated dose of paclitaxel In combination
`with a fixed dose of clsplatln (60 mg/m1
`) , (3) to deter(cid:173)
`mine the feasibility of repeated biweekly admlnlstra(cid:173)
`dons, and ( 4) to evaluate the efficacy of the comblnadon
`In these diseases. In the breast cancer study, 22 patients
`have been enrolled to date and eight patients have
`completed treatment. Dose-limiting neutropenla, which
`occurred with the starting dose of paclitaxel (90 mg/
`m1) followed by 60 mg/m1 clsplatln, has precluded any
`attempts to escalate the paclltaxel dose. Overall, the
`regimen has bee n well tolerated at the doses just de(cid:173)
`scribed. There has been little arade Ill and no grade IV
`nonhematoloalc toxicity. Amona 16 patients currently
`evaluable for response, four had a complete response
`and 11 had a partial response, for an overall response
`rate of 94,.. In the ovarian cancer study, 14 patients
`have been enrolled thus far. Padltaxel/clsplatin appears
`to be well tolerated, althouah It Is still too early to assess
`response rates or to define the HTD. Patients continue
`to be accrued in both trials.
`Copyrliht <Cl 1994 by W.8 . Saunders Company
`
`B REAST CANCER is the single most com(cid:173)
`
`mon malignancy encountered in North
`American women. Although some breast cancer
`patients are cured with surgery or adjuvant che(cid:173)
`motherapy and radiotherapy, many patients re(cid:173)
`lapse with metastatic disease. Moreover, the du(cid:173)
`ration of response to currently available drugs
`tends to be short. Many cases are refractory to
`the most effective agents, whereas relapsers who
`initially respond subsequently become resistant
`to these agents. Thus, the search continues for
`new, effective treatments for metastatic breast
`cancer.
`Ovarian cancer represents 4% of all cancers en(cid:173)
`countered in women in the United States, ranking
`
`From rhe Deparrmenr of Medical Oncology, British Columbia
`Cancer Centre, Vancouver, BC, Canada.
`Address reprint requests ro Karen A Gelmon, MD, FRCPC,
`Department of Medical Oncology, British Columbia Cancer
`Cenrre, 600 W !Och Ave, Vancouver, BC, <:;anada V5Z 4E6.
`Copyrighc © 1994 by W.B. Saunders Company
`0093. 7754 /94/2105-0805$05.00/0
`
`it £fth among the most common cancers.1 In 1992,
`over 20,000 new cases of ovarian cancer and 13,000
`related fatalities were expected. 1 Although this dis(cid:173)
`ease typically responds well to treatment measures
`including primary cytoreductive surgery, radiation
`therapy, and/or chemotherapy, it remains the most
`common cause of death in women who develop
`gynecologic malignancies. Because a reliable method
`of early detection for ovarian cancer has not yet
`been established, almost 75% of cases are in the
`advanced stage when diagnosed.2
`Paclitaxel (T axol; Bristol-Myers Squibb Company,
`Princeton, NJ) is a diterpenoid plant product that
`interferes with microtubular polymerization by
`promoting abnormal assembly of microtubules and
`inhibiting their subsequent disassembly and normal
`function. Phase II studies have shown paclitaxel to
`be an active agent in ovarian and breast cancer.3.a
`It also has shown potential in chemotherapeutic
`combinations using non-cross-resistant cytotoxic
`agentsll- 12 such as alkylating agents and anthracy(cid:173)
`clines. One such agent, cisplatin, has many com(cid:173)
`plementary features for use with paclitaxel. Myelo(cid:173)
`suppression, the dose-limiting toxicity of paclitaxel,
`has not been associated with cisplatin use. 0
`11 Cis(cid:173)
`•
`platin has achieved response rates of 47% to 54%
`in metastatic breast cancer, although it is not com(cid:173)
`monly used in this disease. It has also demonstrated
`synergism with a variety of other cytotoxic drugs.
`This paper presents preliminary results of two
`ongoing dose-finding studies in which pacliraxel
`is being given in combination with cisplatin on a
`biweekly basis to patients with breast and ovarian
`cancer.
`
`PHASE I STUDY IN BREAST CANCER
`
`The objectives of this nonrandomized phase I/
`II trial in metastatic breast cancer are (1) to de(cid:173)
`termine the toxicity of paclitaxel and cisplatin in
`a biweekly schedule, (2) to establish the maximum
`tolerated dose of paclitaxel in combination with
`
`a fixed dose of cisplatin (60 mg/ m2) for patients
`with metastatic breast cancer, (3) to determine the
`feasibility of repeated biweekly administrations,
`and (4) to evaluate the efficacy of this combination
`in this disease setting.
`
`24
`
`Seminars in On<ology. Vol 21, No S, Suppl 8 (October). 1994: pp 24-28
`
`1 of 5
`
`Celltrion, Inc., Exhibit 1018
`
`

`

`PACLITAXEL/OSPLATIN IN BREAST & OVARIAN CANCTR
`
`25
`
`Table I. Dose Levels of Paditaxel and Cltplatln
`
`Level
`
`Step - 2
`Step - 1
`Step 0 (starting)
`Step I
`Step 2
`Step 3
`Step 4
`
`Paclluxel
`(mg/m')
`
`Ospl.cln
`(mg/m')
`
`70
`80
`90
`100
`110
`120
`130
`
`60
`60
`60
`60
`60
`60
`60
`
`PATIENTS AND METHODS
`Patients with histologically proven metastatic breast cancer
`(estrogen· or progesterone-positive or · negative) who have re·
`ceived either no previous chemotherapy or one adjuvant che·
`motherapy regimen are eligible for entry into the study. Pre·
`vious radiotherapy or hormonal therapy is also allowed;
`radiotherapy has to have involved less than 50% of the bone
`marrow and have been terminated at least 4 weeks prior to
`scudy entry. Patients must be nonpregnant, nonlactating
`women 18 years of age or older with an Eastern Cooperative
`Oncology Group performance status of 0-2 and a life expec·
`tancy of 12 weeks or longer. Adequate hematologic, renal,
`and hepatic functions are required, as is written informed
`con sent. For the phase II portion of the study, patients must
`have clinically or radiologically measurable disease, defined as
`a proven malignant manifestation capable of a twofold im·
`provement.
`Patients are excluded if any of the following conditions are
`present: past history of malignancy other than the entry di·
`agnosis (except for nonmelanomatous skin cancer or curatively
`created cervical carcinoma in situ), previous anthracycline
`t:reatment to a cumulative dose ~450 mg/m1 with an abnormal
`MUGA scan, prior chemotherapy regimens for the treatment
`of metastatic breast cancer, history of atrial or ventricular ar·
`rhythmias or congestive heart failure, and pre-existing motor
`sensory neurotoxicity (World Health Organization grade II or
`higher).
`Dose levels are shown in Table I. Cisplatin is given at a
`fixed dose of 60 mg/m1
`; the starting dose of paclitaxel, 90 mg/
`rn2 , is subsequently adjusted up to a maximum of 130 mg/m1
`or down to a minimum of 70 mg/m1
`, depending on patient
`tolerance. Both drugs are given sequentially by 3-hour infusion,
`
`with paclitaxel preceding cisplatin administration. This se·
`quence is based on previous reports of severe neutropenia in
`patients receiving cisplatin before paclicaxel.9 To avoid hyper·
`sensitivity reactions, the following standard premedication
`regimen, used in other trials of paclitaxel in metastatic breast
`cancer, is administered: dexamethasone 20 mg orally 12 hours
`and 6 hours prior to paclitaxel infusion, and 30 minutes prior
`to infusion, dexamethasone 10 mg inttavenously, diphenhy·
`dramine SO mg intravenously, and dmetidine 300 mg intra·
`venously over 10 minutes. Treatment is given every 2 weeks;
`treatment delays and dose modifications are made based on
`complete blood cell counts taken the day before the next
`planned treatment (day 14) (Table 2).
`Dose-limiting toxicity is defined according to the following
`schedule: if at least one of three patients receiving a given
`dose has a treatment delay because of toxicity, three more
`patients are enrolled; if at least two of six patients experience
`dose· limiting toxicity at the same dose level, that dose is defined
`as the maximum tolerated dose.
`All patients are treated at the British Columbia Cancer
`Agency and screened within 14 days of enrollment.
`
`RESULTS
`As of the time of this report, 22 patients have
`been enrolled in the study and eight patients have
`completed treatment. Of the 22 patients, 18 are
`presently evaluable for toxicity and 16 for re(cid:173)
`sponse (two of the latter patients are unevaluable
`because of unmeasurable disease).
`Characteristics of the 22 patients entered are de·
`scribed in Table 3. Only two patients did not receive
`previous chemotherapy. Three patients were pre·
`viously treated with cyclophosphamide/ methotrex·
`ate/ 5-fluorouracil (5-FU) (CMF); the remaining 17
`patients received anthracycline-based chemotherapy
`in the form of doxorubicin/ cyclophosphamide (AC)
`(eight patients), cyclophosphamide/ doxorubicin/ 5-
`FU (CAF) (four patients), doxorubicin/ cyclophos·
`phamide/ methotrexate/5-FU (ACMF) (one patient),
`or Quartet (four patients). (Quartet is a dose-inten(cid:173)
`sive, doxorubicin-based protocol for extreme-risk
`adjuvant patients.)
`We have been unable to escalate the dose of pa(cid:173)
`clitaxel as planned in the phase I part of the study
`
`Table 2. Dose Modification: Day 14 Counts (Day lkfor• Next Planned Tr.atnMnt)
`
`,
`
`Granulocytes (XI O' /L)
`
`... 0.15
`< 0.75
`Febrile neutropenla
`
`and
`or
`or
`
`Platelets (X I O' /L)
`
`.,_75
`< 75
`Severe bleeding: > 2 platelet
`transfusions
`
`Delay
`
`No
`Yes•
`Yes•
`
`Dose Level This Cycle
`
`Same
`- I
`- 2
`
`• Delay until hematologk recovery, deflned as granulocytes ;o 0.75 X 10'/L and platelets ;o 75 X 10'/L Complete blood cell count to be
`done three times per week.
`
`2 of 5
`
`Celltrion, Inc., Exhibit 1018
`
`

`

`26
`
`KAREN A. GELMON
`
`Table l. Patient Characteristics (n G 22)
`
`Table 4. Cyde Delays (Patients Evaluable - 18)
`
`Characteristic
`
`No. of Patients
`
`No. of Delays•
`
`No. of Patients
`
`Median age (yr)
`Range
`ECOG performance status (at entry)
`0
`I
`2
`ER status
`Negative
`Positive
`Prior therapy
`Adjuvant chemotherapy
`Adjuvant radiotherapy
`Hormonal therapy
`Radiotherapy for treatment
`Disease sites
`Bone
`lung
`Liver
`Skin
`Soft tissue
`No. of disease sites
`I
`2
`> 2
`Median time to relapse after diagnosis (mo)
`Range
`
`48.5
`38-67
`
`8
`II
`3
`
`13
`9
`
`20
`19
`17
`5
`
`8
`10
`4
`6
`10
`
`10
`8
`4
`20
`8-50
`
`Abbreviations: ECOG, Eastern Cooperative Oncology Group;
`ER, estrogen receptor.
`
`because of dose-limiting neutropenia occurring with
`the starting dose of 90 mg/m2 paditaxel followed
`by 60 mg/m2 cisplatin; thus, these doses were con(cid:173)
`tinued for the phase 11 trial, and all the results for
`toxicity and response reported here use this starting
`dose. Patients received an average of eight cycles of
`treatment each. Tables 4 and 5 describe cycle delays
`and dose reductions, respectively. Overall, 11 pa(cid:173)
`tients required dose reductions (six patients required
`one reduction and five patients, two reductions).
`We tried to identify which patient subsets required
`dose reductions but were unable to establish a con(cid:173)
`sistent pattern, with the exception of patients re(cid:173)
`ceiving prior treatment with Quartet plus radio(cid:173)
`therapy, of whom two of four required two dose
`reductions.
`Overall, paclitaxel/cisplatin has been well tol(cid:173)
`erated. Nonhematologic toxicity data for the 18
`evaluable patients appear in Table 6. There has
`been little grade llI and no grade IV nonhema(cid:173)
`tologic toxicity. The major nonhematologic tox(cid:173)
`icity has been nausea and vomiting, which is most
`
`0
`I
`2
`3
`4
`
`4
`6
`3
`2
`3
`
`I • Total no. of cycles delayed = 30.
`
`likely related to cisplatin administration. No se(cid:173)
`vere hypersensitivity reactions have occurred with
`the 3-hour paclitaxel infusion, although some pa(cid:173)
`tients have experienced mild (grades I/II) reactions
`consisting mainly of rash and flushing. General
`fatigue has been reported by 77.8% of patients,
`but in only one patient has this been severe (grade
`III). Alopecia has been common. Cardiovascular
`complaints have been minimal, although two pa(cid:173)
`tients had premature ventricular contractions that
`were considered asymptomatic. Arthralgias and
`myalgias have been seen in 22% and 44% of pa(cid:173)
`tients, respectively, but only 5% of these reactions
`have been severe (grade Ill). There have not been
`any severe infections.
`Hematologic toxicity is described in Table 7,
`and ranked according to World Health Organi(cid:173)
`zation grading in Table 8. Hemoglobin counts
`have ranged from 79 to 125 g/d.L (median, 104 g/
`dL). White blood cell counts have ranged from
`700 to 4,000/ µL (median, 1,950/ µL). Absolute
`
`Table S. Dose Reductions (Patients Evaluable ~ 18)
`
`No. of
`Reductions• No. of Patients
`
`0
`I
`2
`
`7
`6
`5
`
`Other reasons for delay
`Holiday
`Wrist fracture
`fatigue
`
`I
`I
`I
`
`% of Dose Delivered
`
`No. of Patients (Planned)
`
`90
`> 90
`80-90
`< 80
`
`7
`5
`5
`I
`
`• Total no. of dose reductions • 16.
`
`3 of 5
`
`Celltrion, Inc., Exhibit 1018
`
`

`

`PACLITAXEL/ CISPLATIN IN BREAST & OVARIAN CANCER
`
`27
`
`Table 6. Nonhematolo1lc Toxicity by World Health
`Ol'lanlzatlon Grade (Patients Ewaluable • 18)
`
`Table 7. Hematolop: Toxicity (Patients
`En.luable - 18)
`
`Grade
`
`I
`
`2
`
`3
`
`4
`
`Total (%)
`
`Gastrointestinal
`Nausea
`Vomiting
`Diarrhea
`Heartburn
`Mucosltls
`Change of um!
`Blood per rectum
`Eplstaxls
`Hypersensitivity
`Flushing
`Rash
`Bllster
`Congestion
`Chest tightness
`Dizziness
`Dyspnea
`Chills
`Restlessness/ jltteriness
`Drowsiness
`Swelling knee
`General
`Fatigue
`Skin
`Alopecla
`RedneJS In RT area
`Cardiovascular
`Increased blood
`pressure
`Arrhythmia {PVC)
`Swelling In ankles
`Musculoskeletal
`Arthralgla
`Myalgla
`Fluid in knees
`Painful foot
`Swelling In arm
`Neuro logic
`Headache
`Tingling
`Numbness
`Tinnitus
`Depression
`Infection
`
`10
`4
`
`2
`I
`I
`
`I
`
`9
`
`I
`I
`2
`I
`I
`I
`3
`2
`2
`
`10
`
`3
`
`I
`2
`I
`
`3
`7
`2
`I
`I
`
`2
`B
`5
`2
`2
`I
`
`I
`I
`2
`
`I
`I
`
`I
`
`I
`2
`
`3
`
`3
`
`I
`
`8
`
`I
`
`I
`
`I
`
`I
`
`11 (61.1)
`6 (33.3)
`3 ( 16.7)
`2 ( I I. I)
`I (S.6)
`I (5.6)
`I (5.6)
`I (S.6)
`
`10 (55.6)
`2 ( 11 .I)
`I (5.6)
`I (5.6)
`2 {I I. I)
`I (5.6)
`I (5.6)
`I (5.6)
`3 (16.7)
`2 (I I.I)
`2 (I I.I )
`
`14 (77.8 )
`
`11 (6 1. 1)
`3 ( 16.7)
`
`I (5.6)
`2 ( I I. I)
`I (5.6)
`
`4 (22.2)
`8 (« .5)
`2 {II . I)
`I (5.6)
`I (5.6)
`
`2 ( I I.I)
`8 («.S)
`s (27.8)
`2 ( I I.I )
`2(11. 1)
`3 ( 16.7)
`
`Abbreviations: RT, radiotherapy; PVC, premature venulcular
`contr•ction.
`
`neutrophil counts, which were measured three
`times per week for the first month of treatment,
`have ranged from 100 to 1,800/ µL (median, 500/
`µL), and have not been associated with any sig(cid:173)
`nificant septic complications; median duration of
`
`Hemoglobin
`WBC
`ANC
`Plateleu
`
`Median (Range)
`
`104 g/dl (79· 125)
`1,950/"L (700-4,000)
`500/ l'L ( 100- 1,800)
`142,SOO/l'L (20,000-275,000)
`
`Abbreviations: WBC, white blood cells; ANC, absolute neu-
`trophil count.
`
`the absolute neutrophil count nadir was 2 days.
`One patient experienced grade IV thrombocy(cid:173)
`topenia of short duration that was not associated
`with bleeding.
`Complete response (CR) and partial response
`(PR} are measured from time of response to time
`of relapse and progression, respectively, and not
`from time of initiation of treatment. Sixteen pa·
`tients are currently evaluable for response; four
`patients (25%) have had a CR and 11 patients
`(69%) a PR, for an overall response rate of 94%
`(Table 9). One patient has had stable disease, and
`no patients have had initial disease progression
`while receiving treatment. Sites of CR include
`skin, liver, soft tissue, and lung in one patient
`each. All CRs were previously treated with an(cid:173)
`thracyclines (one with AC, one with CAF, one
`with ACMF, and one with Quartet). Duration of
`response thus far is 32+ to 208+ days (median,
`108 days} for CRs and 33+ to 199+ days (median,
`72 days) for PRs. One PR relapsed in the lung
`after 148 days of treatment.
`
`PHASE I STUDY IN OVARIAN CANCER
`The phase I study of biweekly paclitaxel/cis·
`platin as initial therapy for ovarian cancer has been
`
`Table 8. H ematolo1lc Toxldty by World Health
`Ol'lanlzation Grade (Patients Evaluable = 18)
`
`Grade
`
`I
`
`7
`3
`2
`
`2
`
`3
`5
`3
`
`3
`
`I
`7
`5
`
`4
`
`2
`8
`I
`
`Total (%)
`
`11 (61.1 )
`17 (94.4)
`18 ( 100)
`I (S.6)
`
`Hemoglobin
`WBC
`ANC
`Platelets
`
`Abbreviations: WBC, white blood cell count; ANC, absolute
`neutro phll count.
`
`4 of 5
`
`Celltrion, Inc., Exhibit 1018
`
`

`

`28
`
`KAREN A. GELMON
`
`Table 9. Response In Evaluable Patients ( Patlents
`Evaluable ~ 16)
`
`Best Response
`
`CR
`PR
`SD
`PD
`Sites of CR
`Skin
`Liver
`Soft tissue
`Lung
`
`No. of Patients(%)
`
`4 (25)}
`11 (69) 94 %
`I (6)
`0
`
`I
`I
`I
`I
`
`Abbreviations: SD, stable disease; PD, progression of disease.
`
`initiated as a National Cancer Institute of Canada
`study at three sites in Canada. Dr Kenneth Swe(cid:173)
`nerton is the principal investigator. Patients with
`high-risk, residual-positive ovarian carcinoma are
`being entered who have an Eastern Cooperative
`Oncology Group performance status of 0 or 1
`and good organ function. The objectives of this
`study, as well as dosing, premedication, dose es(cid:173)
`calation, and other procedures, are identical to
`those described in the breast cancer study.
`Currently, 14 patients have been enrolled, with
`three at dosing level 0, nine at level 1, and two at
`level 2 (see Table 1). One patient has experienced
`dose-limiting neutropenia, and there has been one
`withdrawal due to grade II neurotoxicity and oto(cid:173)
`toxicity. Paditaxel/cisplatin appears to be well tol(cid:173)
`erated. It is still too early to assess response rates or
`to define the maximum tolerated dose in this disease
`setting; patients continue to be accrued.
`
`DISCUSSION
`Both studies are ongoing, and reports will be
`published when the studies are completed. Study
`results so far indicate that paclitaxel/cisplatin can
`be given biweekly in both ovarian and metastatic
`breast cancer. At this early time, it is difficult to
`discuss the high overall response rate or duration
`of response achieved with paclitaxel/cisplatin in
`patients with metastatic breast cancer. Biweekly
`scheduling may provide some pharmacologic
`benefit, but this is not yet confirmed.
`Given every 2 weeks, the combination has been
`well tolerated without serious toxicity, including
`no cardiac toxicity and only mild neurotoxicity.
`Toxicities seen in breast cancer patients differ
`slightly from those encountered in ovarian cancer
`
`patients. Marrow toxicity prevented us from es(cid:173)
`calating the dose of paditaxel above 90 mg/m2 in
`breast cancer patients. Future studies may help
`further define this combination's activity in these
`and other disease settings and whether the high
`response rates seen are related to biweekly dosing.
`In addition, follow-up will determine whether the
`duration of the responses is favorable.
`
`REFERENCES
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`C A Cancer J C lin 42:19, 1992
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`11. Holmes FA, Frye D, Valero V, et al: Phase I study of
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`Oncol 11:60, 1992 {abstr 66)
`12. Fisherman), McCabe M, Hillig M, et al: Phase I study
`of Taxol and doxotubicin (Dox) with G-CSF in previously
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`13. Kolavic K, Roch A: Phase II clinical trial of cisdichlo·
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`Cancer Chemother Pharmacol 11:108-112, 1993
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`
`5 of 5
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`Celltrion, Inc., Exhibit 1018
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