Phase I/II Trial of Biweekly Paclitaxel and Cisplatin in
`the Treatment of Metastatic Breast Cancer
`
`By K.A. Gelmon, S.E. O'Reilly, A.W. Tolcher, C. Campbell, C. Bryce, J. Ragaz, C. Coppin, I.H. Plenderleith,
`D. Ayers, B. McDermott, L. Nakashima, D. Healey, and N. Onetto
`
`Purpose: To determine the maximum-tolerated dose
`of escating doses of paclitaxel (Taxol; Bristol-Myers
`Squibb, Princeton, NJ) administered biweekly with a
`fixed dose of cisplatin, to assess the toxicity, and to eval-
`uate the activity of this combination in a phase 1/11 trial
`in metastatic breast cancer.
`Patients and Methods: Twenty-nine women with met-
`astatic breast cancer were enrolled; 27 are assessable
`for response and 29 for toxicity. All but two of the women
`had received prior adjuvant chemotherapy, with 23 re-
`ceiving anthracyclines and six previous cisplatin.
`Results: The initial starting dose of paclitaxel 90 mg/
`m Z iin
`splatin 60 mg/m' became the phase II dose due
`to dose-limiting neutropenia. Responses were seen in
`85% of assessable patients, with three patients (11%)
`achieving a complete response (CR) and 20 patients
`(14%) a partial response (PR), for an overall response
`rate of 85% (95% confidence interval [CI], 66% to 96%)
`time to disease progression for patients who
`The
`
`B REAST CANCER is the single most common malig-
`nancy encountered in North American women. Al-
`though some patients diagnosed with breast cancer are
`cured with surgery or adjuvant chemotherapy and radio-
`therapy, 75% of women with axillary-positive nodes and
`30% of those with axillary-negative nodes will relapse
`with metastatic or recurrent disease and require further
`therapy.' There are a number of drugs with activity in
`metastatic breast cancer, but the duration of response to
`the currently available agents tends to be short.2 Also,
`many cases are either refractory to the most effective
`agents or become resistant after an initial response.
`Paclitaxel (Taxol; Bristol-Myers Squibb, Princeton,
`NJ) is a diterpenoid plant product that interferes with
`microtubular polymerization by promoting abnormal as-
`sembly of microtubules and inhibiting their subsequent
`disassembly and normal function.3 Phase II studies have
`shown paclitaxel to be an active single agent in metastatic
`breast cancer, with reported response rates of 17%
`to
`62%; the variability generally reflects the number of pre-
`the patients have re-
`vious chemotherapy regimens
`ceived.4 7 Promising results have also been reported with
`combinations of paclitaxel with other active agents such
`as doxorubicin, cyclophosphamide, and edatrexate.8 13
`Taxol is now approved for the treatment of breast cancer
`that has progressed after combination chemotherapy for
`metastatic disease or relapsed within 6 months of adjuvant
`chemotherapy in both the original and semisynthetic for-
`mulations.
`
`achieved a CR was 110 to 200 days, and for those with
`a PR, it was 96 to 377+ days, with a median time to
`progression of 7.1 months and a median response dura-
`tion of 7.9 months. Sites of CR were skin, soft tissue, and
`lung, and all occurred in women with previous exposure
`to anthracyclines. Septic events were rare, with two
`grade 3 infections (7%), only one of which required hos-
`pital admission. There was no grade 4 nonhematologic
`toxicity and minimal grade 3 toxicity. A total of 251 che-
`motherapy cycles were given - 16 with paclitaxel alone
`in five patients. Forty-five percent of patients required
`dose reductions, while 52% had delays due to neutro-
`penia.
`Conclusion: Biweekly paclitaxel and cisplatin is an
`active combination in the treatment of metastatic breast
`cancer, including for patients with previous exposure to
`anthracyclines.
`J Clin Oncol 14:1185-1191. © 1996 by American So-
`ciety of Clinical Oncology.
`
`During the early experience at our institution, adminis-
`tering paclitaxel in a 3-week dosing schedule, we ob-
`served that many patients had an abrupt WBC nadir at 8
`days, with recovery of counts by day 15.14 A biweekly
`schedule was proposed with the possibility of increasing
`exposure to paclitaxel. The initial phase I study was
`planned to attempt also to increase the dose-intensity of
`paclitaxel.
`We were also interested in combining the new agent
`with a non-cross-resistant drug with a different spectrum
`of toxicity. Cisplatin seemed to be an appropriate choice.
`First, although it is not an agent used widely in breast
`cancer, its activity in metastatic disease has been docu-
`mented in several studies, with response rates of 47% to
`54%.15-18 Second, it is usually not used in the adjuvant
`setting and, therefore, most patients should not have de-
`veloped resistance to it when they develop metastatic
`disease. The mechanisms of resistance for cisplatin and
`paclitaxel differ, with multiple drug resistance (MDR)
`and tubulin mutations considered the culprits in paclitaxel
`
`From the British Columbia Cancer Agency, Vancouver. Canada;
`and Bristol-Myers Squibb, Princeton, NJ.
`Submitted May 10, 1995; accepted November 6, 1995.
`Address reprint requests to K.A. Gelmon, MD, British Columbia
`Cancer Agency, 600 W 10th Ave, Vancouver, BC, Canada V5Z 4E6.
`© 1996 by American Society of Clinical Oncology.
`0732-183X/1404-0019$3.00/0
`
`Journal of Clinical Oncology, Vol 14, No 4 (April), 1996: pp 1185-1191
`
`1185
`
`Downloaded from ascopubs.org by 73.35.146.70 on December 11, 2016 from 073.035.146.070
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`1 of 7
`
`Celltrion, Inc., Exhibit 1014
`
`

`

`1186
`
`resistance, but not in cisplatin. Third, except for neurotox-
`icity, the toxicities associated with cisplatin do not overlap
`those of paclitaxel. Finally, synergism between paclitaxel/
`cisplatin has been established in preclinical models and
`this has been translated as clear clinical benefits. In fact,
`in ovarian cancer, the association of paclitaxel/cisplatin
`has improved survival when administered as first-line
`therapy." Cisplatin has demonstrated synergism with a
`variety of other cytotoxic drugs, such as fluorouracil
`(5FU) 20 and etoposide. 21'22 Pharmacokinetic interactions
`and sequence analysis of this combination of agents have
`been previously defined with both delayed clearance of
`paclitaxel and more hematologic toxicity associated with
`the sequence of cisplatin preceding rather than following
`a 24-hour paclitaxel infusion.23
`With these theoretic considerations, we designed a non-
`randomized phase I/II dose-escalating study of biweekly
`paclitaxel and cisplatin as first-line chemotherapy treat-
`ment in metastatic breast cancer. The objectives of the
`study were (1) to determine 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/m 2) for patients with
`metastatic breast cancer, (3) to determine the feasibility
`of repeated biweekly administrations, and (4) to evaluate
`the activity of this combination in this disease setting.
`PATIENTS AND METHODS
`Patients with histologically proven metastatic breast cancer (estro-
`gen receptor-positive or -negative) who had received either no
`previous chemotherapy or one adjuvant chemotherapy regimen were
`eligible for study entry. Previous radiotherapy or hormonal therapy
`was also allowed; radiotherapy had to have involved less than 50%
`of the bone marrow and had to have been terminated at least 4 weeks
`before study entry. Patients were nonpregnant, nonlactating women
`18 years of age or older with an Eastern Cooperative Oncology
`Group (ECOG) performance status of 0 to 2 and a life expectancy
`of z 12 weeks. Adequate hematologic, renal, and hepatic functions
`were required, defined as a granulocyte count greater than 1.5 x
`109/L, platelet count greater than 100 x 109/L, bilirubin level less
`than 1.5 times upper normal limit, and creatinine concentration less
`than 1.5 times upper normal limit. Patients with a total bilirubin
`level at baseline between 1.5 and 2.5 times the normal limit due to
`liver metastases were eligible provided liver function was regularly
`monitored. All patients had to be accessible for follow-up evaluation
`and management of complications.
`For the phase II portion of the study, patients were required to
`have clinically or radiologically bidimensional measurable disease,
`defined as a proven malignant manifestation capable of a twofold
`improvement. Initially, a tumor marker (carcinoembryonic antigen
`[CEA] or CA15-3) greater than twice normal was considered as
`measurable disease; however, this was not used in the analysis.
`Patients were excluded if any of the following conditions were pres-
`ent: history of malignancy other than the entry diagnosis (except for
`nonmelanomatous skin cancer or curatively treated cervical carci-
`noma-in-situ), previous anthracycline treatment to a cumulative dose
`
`GELMON ET AL
`
`greater than 450 mg/m 2 with an abnormal serial gated cardiography
`(MUGA) scan, prior chemotherapy regimens for the treatment of
`metastatic breast cancer, history of atrial or ventricular arrhythmias
`or congestive heart failure, and preexisting motor sensory neurotox-
`icity (World Health Organization [WHO] z grade II). Patients who
`were receiving concurrent treatment with other experimental drugs
`were also ineligible for the study.
`All of the patients who entered the trial gave written informed
`consent. The protocol was approved by the British Columbia Cancer
`Agency (BCCA) and the University of British Columbia ethics com-
`mittees. Paclitaxel was provided by Bristol-Myers Squibb and cis-
`platin was provided from the commercial supply by the BCCA phar-
`macy.
`All patients underwent a pretreatment evaluation that consisted
`of a history and physical examination; determination of hematology,
`chemistry, and tumor marker levels (CEA and CA15-3); ECG; and
`radiologic evaluation of all measurable and assessable disease within
`14 days of enrollment.
`
`Treatment
`
`The planned dose-escalation scheme was cisplatin at a fixed dose
`of 60 mg/m2 with a paclitaxel starting dose of 90 mg/m2 increasing
`by increments of 10 mg/m 2 (eg, 100 mg/m2, 110 mg/m2, 120 mg/m2,
`etc). Escalations were planned in cohorts of three or more patients to
`a maximum of 130 mg/m2. The dose could also be adjusted down
`in an individual patient depending on tolerance to a minimum dose
`of 70 mg/m 2.
`Paclitaxel and cisplatin were administered sequentially, each by
`3-hour infusion, with paclitaxel preceding cisplatin. This sequence
`was based on previous reports of severe neutropenia in patients
`who received cisplatin before paclitaxel. 23 To avoid hypersensitivity
`reactions, the following standard premedication package was admin-
`istered: dexamethasone 20 mg orally 12 and 6 hours before paclitaxel
`infusion, dexamethasone 10 mg intravenously 30 minutes before
`infusion followed by diphenhydramine 50 mg intravenously, and
`cimetidine 300 mg intravenously over 10 minutes. Treatment cycles
`were given every 2 weeks; treatment delays and dose modifications
`were based on complete blood cell counts taken the day before the
`next planned treatment (day 14) (Table 1).
`Concomitant supportive therapy, including analgesics and anti-
`emetics, was allowed and recorded on the case report forms. Patients
`all received ondansetron 8 mg orally before cisplatin, and most
`continued to take oral ondansetron 8 mg and dexamethasone 4 to 8
`mg every 8 to 12 hours for 48 to 72 hours after treatment. Cytokine
`support was not given.
`Toxicity was assessed at the biweekly visits and recorded ac-
`cording to WHO toxicity criteria.24 Complete blood cell counts were
`performed three times per week for the first 4 weeks and then weekly
`
`Table 1. Dose Modifications by Day 14 Counts (day before treatment)
`
`Granulocytes
`(x 10'/L)
`
`Delay
`
`No
`Yes*
`Yes*
`
`Platelets (x 109/L)
`> 75
`> 0.75
`and
`< 0.75
`< 75
`or
`Febrile
`or
`Severe bleeding or > 2
`neutropenia
`platelet transfusions
`*Delay until hematologic recovery, defined as granulocytes > 0.75 and
`platelets > 75. Complete blood cell count to be performed 3 times per
`week.
`
`Dose Level
`
`Same
`-1
`-2
`
`Downloaded from ascopubs.org by 73.35.146.70 on December 11, 2016 from 073.035.146.070
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`2 of 7
`
`Celltrion, Inc., Exhibit 1014
`
`

`

`PACLITAXEL AND CISPLATIN FOR BREAST CANCER
`
`for the remaining treatments. Dose escalation was stopped if two of
`- grade 3 nonhematologic toxicity, or if
`six patients experienced
`the same number of patients could not receive the first three treat-
`ments on time due to hematologic toxicity as defined in Table 1. All
`patients who received one cycle of chemotherapy were considered
`assessable for toxicity.
`Patients were assessed every 2 weeks by physical examination
`for response and every 4 weeks with radiologic evaluation. All pa-
`tients in the phase II portion of the study who received at least two
`courses of chemotherapy were considered assessable for response.
`Responses were confirmed by monitors, with a complete response
`(CR) defined as the complete disappearance of all measurable and
`assessable disease and a partial response (PR) as a greater than 50%
`reduction in the sums of the product of two perpendicular diameters
`of the tumor. Stable disease (SD) was considered for all patients
`who had less than a PR but no evidence of progressive disease (PD).
`All responses had to be confirmed at least 4 weeks after the initial
`assessment. PD was defined as an unequivocal increase of - 25%
`in the sums of the product of measured lesions and/or the appearance
`of significant new lesions.
`It was planned that patients would be treated for four cycles past
`a CR, two to four cycles after a PR, or until SD with an initial
`assumption of eight cycles. This was later modified to allow patients
`to continue treatment until progression or toxicity.
`
`Statistical Analysis
`Statistical analysis was performed by Bristol-Myers Squibb using
`the SAS software package (Statistical Analysis System; SAS Insti-
`tute, Cary, NC). All 29 patients who received at least one cycle of
`chemotherapy were considered assessable for toxicity. All 27 pa-
`tients who met the phase II criteria and received at least two courses
`of therapy were included in the efficacy analysis.
`Duration of overall response was calculated from the first day of
`treatment to the date of first observation of PD for all responding
`patients (PRs and CRs). Time to progression was calculated for all
`patients from the day of first treatment until PD was first noted.
`Three patients had not progressed at the time of the analysis and
`were censored at their last follow-up evaluation.
`No formal statistical tests were performed on the data from this
`phase I/II trial. For time-to-event data (ie, duration of response, time
`to progression, and survival), the cumulative proportion of patients
`who had not yet experienced the event was plotted as a function of
`time by means of the Kaplan-Meier product-limit approach.
`
`RESULTS
`
`Patient Characteristics
`
`Twenty-nine patients were enrolled onto the study and
`all are assessable for toxicity. Twenty-seven patients had
`bidimensionally measurable disease and are assessable
`for response.
`Characteristics of the 29 patients entered are listed in
`Table 2. Twenty-seven patients had received prior adju-
`vant chemotherapy. Four patients had been treated with
`cyclophosphamide, methotrexate, and 5FU (CMF), and
`the remaining 23 patients had received an anthracycline-
`based chemotherapy in the form of doxorubicin/cyclo-
`phosphamide (AC) for eight patients, doxorubicin/cyclo-
`
`1187
`
`Table 2. Patient Characteristics (N = 29)
`
`Characteristic
`
`No. of Patients
`
`Age, years
`Median
`Range
`ECOG performance status (at entry)
`0
`1
`2
`Estrogen receptor status
`Negative
`Positive
`Unknown
`Prior therapy
`Adjuvant chemotherapy
`CMF
`AC
`CAF
`ACMF
`Quartet
`Adluvant radiotherapy
`Hormonal therapy
`Disease sites
`Bone
`Lung
`Liver
`Skin
`Soft tissue
`No. of disease sites
`1
`2
`>2
`Time to relapse after diagnosis, months
`Median
`Range
`
`47
`29-67
`
`11
`14
`4
`
`18
`10
`1
`
`27
`4
`8
`7
`2
`6
`26
`22
`
`11
`13
`6
`8
`13
`
`10
`14
`5
`
`18
`6-58
`
`phosphamide/5FU (CAF) for seven patients, doxorubicin/
`cyclophophamide/methotrexate/5FU (ACMF) for two pa-
`tients, and a dose-intensive doxorubicin-based protocol
`of cyclophosphamide, doxorubicin, methotrexate, 5FU,
`cisplatin, etoposide, and prednisone (Quartet) for six pa-
`tients with extreme risk or locally advanced disease. De-
`spite a previous exposure to cisplatin in the adjuvant
`setting with a total cisplatin dose of 150 mg/m2, these
`patients are included in the analysis and are mentioned
`specifically in the response and toxicity sections. Only
`two patients had not received any prior chemotherapy.
`
`Drug Delivery
`
`A total of 251 cycles of chemotherapy were given
`during this study, with 236 consisting of paclitaxel/cis-
`platin. Five patients in 15 cycles were treated with single-
`agent paclitaxel starting at cycles 7, 8, 10, 11, and 17.
`Cisplatin was eliminated in these patients for neuropathy
`in three, diarrhea in one, and fatigue in one. A median
`
`Downloaded from ascopubs.org by 73.35.146.70 on December 11, 2016 from 073.035.146.070
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`3 of 7
`
`Celltrion, Inc., Exhibit 1014
`
`

`

`1188
`
`of eight cycles were administered, with a range of three
`to 20.
`Patients were not treated to progression but rather treat-
`ments were stopped at best response, toxicity, or many
`at eight cycles due to the original study design. Table 3
`lists cycle delays and dose reductions. Overall, 13 patients
`(45%) required dose reductions (six required one reduc-
`tion and seven, two reductions.) for hematologic toxici-
`ties. Figure 1 shows the timing and number of dose reduc-
`tions for the first eight cycles.
`Only five patients received all of their treatments every
`2 weeks. Nine other patients had delays for reasons other
`than neutropenia, and these included fatigue in six pa-
`tients, bone fracture in one, and infections not associated
`with neutropenia in three, including pneumonia, recurrent
`otitis media, and a wound infection. Twelve of 22 patients
`who had eight or more treatments had no delays for neu-
`tropenia. All treatment delays were for -1 week.
`
`Toxicity
`
`The biweekly schedule of paclitaxel and cisplatin was
`well tolerated. Neutropenia was dose-limiting and pre-
`cluded escalation of the paclitaxel from the initial dose
`of 90 mg/m 2; thus, all of the reported results are at that
`dose level. Hematologic toxicity is listed in Table 4 and
`ranked according to WHO toxicity using the worst toxic-
`ity on study for individual patients. Hemoglobin counts
`ranged from 76 to 120 g/dL (median, 99). WBC nadirs
`ranged from 700 to 4,000/ML (median, 1,900). Absolute
`neutrophil counts ranged from 100 to 1,800/pL (median,
`500), with the median day of nadir being day 14 (range,
`8 to 15). There was only one episode of significant sepsis,
`which occurred in a woman with a large open axillary
`recurrence who required a brief hospital admission for
`intravenous antibiotics. During the febrile period, this pa-
`tient also experienced grade IV thrombocytopenia, which
`resolved within 2 days following treatment of the infec-
`tion.
`Nonhematologic toxicity data for the 29 assessable pa-
`tients are listed in Table 4. There was limited grade III
`and no grade IV nonhematologic toxicity. The major non-
`
`Table 3. Dose Reductions and Delays
`
`Variable
`
`Any delays, any cause
`Delays due to neutropenia
`Delays due to fatigue
`Dose reductions
`
`0
`
`5
`14
`22
`16
`
`1
`
`12
`6
`3
`6
`
`Days
`
`2
`
`5
`3
`3
`7
`
`NOTE. Total number of treatments is 251, with a median of 8 treatments
`per patient (range, 3 to 20)
`
`3
`
`4
`3
`
`> 3
`
`3
`3
`
`Hemoglobin
`WBC
`ANC
`Platelets
`
`GELMON ET AL
`
`o90
`0180
`*70
`[ off Tx
`
`iij
`CL
`g_
`)
`
`n.
`
`08
`
`Ez
`
`3z
`
`1
`
`2
`
`3
`
`5
`4
`Cycle
`
`6
`
`7
`
`8
`
`Fig 1. Dose administered per patient per cycle.
`
`hematologic toxicity was nausea and vomiting, which is
`frequently reported with cisplatin administration. No se-
`vere hypersensitivity reactions occurred with the 3-hour
`paclitaxel infusion, although 16 patients (55%) experi-
`enced mild reactions in 38 courses (15%). The most fre-
`quently occurring reaction was flushing in 12 patients.
`Hypertension, agitation, and somnolence were reported
`in three patients, respectively. General fatigue was re-
`ported in 29 patients and was grade 3 in six (21%). Alope-
`cia was common but not universal. Arthralgias and myal-
`gias were seen in 13 and 12 patients, with one patient
`reporting grade 3 arthralgias. Parathesias were reported
`
`Table 4. Toxicity by Worst Grade on Study (N = 29)
`
`WHO Grade
`
`4
`
`% Grade 3 or 4
`
`24
`66
`
`7 3
`
`17
`
`10
`
`3
`
`3
`7
`
`14
`59
`76
`7
`
`0
`0
`0
`
`0 0 0 0 0 0 0 0
`
`0
`0
`
`0
`3
`12
`1
`
`3
`
`7
`19
`2
`
`1 5 0 3 1 0 1 1
`
`1
`2
`
`4
`14
`10
`1
`
`2
`
`14
`2
`4
`
`0 6 1 2 4 2 4 3
`
`4
`7
`
`8
`6
`3
`0
`
`1
`
`8
`2
`5
`
`7
`14
`
`6 2 8
`
`10
`18
`9
`
`7
`7
`
`10
`5
`4
`2
`
`Toxicity
`
`Asthenia
`Alopecia
`Infection (any)
`
`Constipation
`Nausea/vomiting
`Anorexia
`Diarrhea
`
`Arthralgia
`Myalgia
`Parasthesia
`Bone pain
`
`Chest pain
`Respiratory discomfort
`
`NOTE Signs and symptoms reported in at least 24% of patients regard-
`less of relationship to study drug
`Abbreviation: ANC, absolute neutrophil count.
`
`Downloaded from ascopubs.org by 73.35.146.70 on December 11, 2016 from 073.035.146.070
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`4 of 7
`
`Celltrion, Inc., Exhibit 1014
`
`

`

`1189
`
`duration of overall response for the 24 responding patients
`was 7.9 months (range, 96 to 377+ days).
`
`DISCUSSION
`
`After observing a brief WBC nadir when paclitaxel
`was delivered on the 3-week schedule, we initiated a
`trial of biweekly paclitaxel and cisplatin to try to take
`advantage of the 14-day recovery period of the WBCs
`and to try to increase the dose-intensity of the drugs. This
`study confirms that paclitaxel lends itself to this type of
`frequent scheduling, as the majority of patients were able
`to be treated with this type of dose-intense regimen.
`Due to hematologic dose-limiting toxicity, we were
`unable to escalate the paclitaxel dose and treatment con-
`tinued at a dose of 90 mg/m2 . The level of hematologic
`toxicity in this study was greater than expected for the
`dose of paclitaxel administered and not typical of cisplatin
`alone. Studies of the pharmacokinetics of paclitaxel and
`cisplatin have suggested a sequence dependence,22 with
`more significant neutropenia occurring when cisplatin
`preceded paclitaxel, but these studies used a 24-hour infu-
`sion of paclitaxel. The observed neutropenia in this study
`may be explained by the decreased clearance of paclitaxel
`caused by the cisplatin increasing drug exposure. This
`may also enhance the cytotoxic effect and explain the
`provocative response rate. To investigate this, we plan to
`perform pharmacokinetic studies of patients receiving a 3-
`hour infusion of paclitaxel and cisplatin in both sequence
`alternatives and compare these results with the published
`data on the 24-hour infusion. In addition to dose-limiting
`neutropenia, we observed fatigue, nausea, and peripheral
`neuropathy. The majority of these side effects were mild,
`reversible, and tolerable.
`The dose of paclitaxel used in this study translates into
`a dose-intensity per week of 45 mg/m 2 or equivalent to
`the 3-week dose of 135 mg/m2. With this rather modest
`dose, we observed a response rate of 85%, whereas a
`previous study that used 135 mg/m2 every 3 weeks over
`3 hours in a more heavily pretreated group reported a
`21% response rate.25 This response rate suggests that the
`paclitaxel/cisplatin biweekly schedule is an active combi-
`nation in the treatment of metastatic breast cancer. This
`is significant, as our patient population differs from many
`of the other current studies of paclitaxel couplets, which
`are enrolling previously untreated patients or patients not
`previously exposed to anthracyclines. All but two of the
`women in our trial had been treated with previous adju-
`vant chemotherapy, and 23 of 29 patients had previous
`exposure to anthracyclines. Few agents have been re-
`ported to give significant responses after exposure to an-
`thracyclines. Also, although we were unable to deliver
`
`PACUTAXEL AND CISPLATIN FOR BREAST CANCER
`
`in 23 patients (79%), but only one patient experienced
`dose-limiting symptoms.
`Cumulative toxicity was not common, with only three
`patients withdrawing from the trial for cumulative para-
`sthesias, two for progressive fatigue, and one with an
`increasing creatinine concentration. These withdrawals
`occurred at cycles 9, 9, and 14 for patients with neuropa-
`thy, 7 and 8 for fatigue, and 8 with the increased creatinine
`level. Two of the patients with cumulative peripheral neu-
`ropathy had been previously treated with cisplatin adju-
`vantly. This was the only toxicity that was more common
`in this group of patients.
`Overall, there were two hospital admissions for toxic-
`ity, one episode of febrile neutropenic episode described
`earlier, and one upper gastrointestinal hemorrhage associ-
`ated with a small Mallory-Weiss tear diagnosed endo-
`scopically, which resolved on the day of admission.
`
`Responses
`
`Twenty-seven patients were assessable for response;
`three (11%) had a CR and 20 (74%) a PR, for an overall
`response rate of 85% (95% confidence interval [CI], 66%
`to 96%) Sites of CR included skin, soft tissue, and lung.
`All three patients with a CR were previously treated with
`anthracycline-containing adjuvant regimens. Of the seven
`patients with previous exposure to cisplatin in the Quartet
`regimen, one had a CR, four had PRs, and one had PD.
`Omitting those patients from the analysis, the response
`rate remained high at 90%, with responses in 19 of 21
`assessable patients. All completely responding patients
`have relapsed with a time to disease progression of 110
`to 200 days (median, 5.8 months [176.9 days]). Figure 2
`depicts time to progression for the 27 patients who were
`assessable for response (median, 7.1 months). The median
`
`z0 a
`
`-
`0a
`C
`
`C0 2 a
`
`53
`S,
`)E
`
`MONTHS
`
`4
`
`Fig 2. Time to progression. All patients, N = 27; no progression,
`n = 24; Median time to progression, 7.1 months (95% CI, 6.3 to 9.7).
`(-) All patients; (0) censored.
`
`Downloaded from ascopubs.org by 73.35.146.70 on December 11, 2016 from 073.035.146.070
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`5 of 7
`
`Celltrion, Inc., Exhibit 1014
`
`

`

`1190
`
`GELMON ET AL
`
`consistently the full planned dose on schedule in all the
`patients, the activity of this combination was maintained.
`The response rates seen in this trial are particularly
`intriguing when they are compared with other trials of
`paclitaxel and cisplatin. One study from New York Uni-
`versity (NYU) used a 3-week schedule of paclitaxel 200
`mg/m 2 over 24 hours and cisplatin 75 mg/m 2 with granu-
`locyte colony-stimulating factor (G-CSF) 5 pg/kg subcu-
`taneously from day 3. Although 16 of 40 patients had not
`received prior chemotherapy, the overall response rate
`was 44% and significant neuropathy was observed (J.L.
`Speyer, personal communication, January 1995). The dif-
`ferences in the two trials include the duration of the infu-
`sion (3 hours in our study and 24 hours at NYU) and the
`biweekly schedule, which may contribute to the response
`rates if repetitive exposure is important. Schedule is less
`likely implicated, as neuropathy is more commonly ob-
`served with a 3-hour than a 24-hour infusion of paclitaxel
`(BMS 071 preliminary data; personal communica-
`tion).26
`27 The higher dose in the NYU study may explain
`,
`the increase in the incidence and severity of neuropathy,
`which resulted in 17 patients discontinuing the study due
`to progressive neuropathy.2s This may partially account
`for the differences in response rate, as our study, with
`less peripheral neuropathy, was able to achieve a greater
`dose rate of cisplatin combined with paclitaxel. In the
`biweekly study, only three patients discontinued treat-
`ment due to neuropathy.
`In an attempt to decrease further the toxicity and to
`ascertain the contribution of cisplatin to the response rates
`of this couplet, we are currently nearing completion of a
`phase I/II study of single-agent biweekly paclitaxel in
`metastatic breast cancer. This will help us to differentiate
`which toxicities were due to each of the drugs used in the
`combination and to define the response rate of biweekly
`paclitaxel as a single agent. Questions of the optimal
`schedule for delivering paclitaxel are being pursued by
`studies comparing various infusion durations, but the fre-
`quency of dosing may also be important.
`Another strategy is to define a less neurotoxic combina-
`tion. Although phase II studies of carboplatin in advanced
`breast cancer have suggested a lower response rate than
`
`with cisplatin, we are initiating a study of this couplet to
`attempt to decrease the neurotoxicity. The combination
`of paclitaxel and carboplatin is active and well tolerated
`in patients with non-small-cell lung cancer and ovarian
`cancer, and may be an option in patients with advanced
`breast cancer.29'3
`Initial studies with paclitaxel were limited in the num-
`ber of cycles due to the short supply of the drug. Many
`centers now treat patients with paclitaxel until disease
`progression. The excellent tolerance of the drug as a sin-
`gle agent without severe cumulative organ toxicity allows
`this long duration of cytotoxic therapy. This study was
`initially designed to give only eight cycles of therapy (ie,
`4 months) and many patients were discontinued at that
`point. Whether the response duration would have been
`longer with continuous treatment and whether the dura-
`tion reported here can be compared with that of trials
`with different end points is speculative. The observed
`response duration of 7.9 months is within the expected
`range for an active combination. However, it may be
`relevant that the smaller dose per cycle and the relatively
`small number of cycles in an outpatient setting may con-
`tribute to the patient's quality of life.
`Although CRs were seen with the combination of pacli-
`taxel and cisplatin, these were not durable. This reflects
`the disappointing fact that a clinical CR in a trial only
`represents a further log kill of cells and, although it is
`associated with a longer survival time, it is not a cure.
`However, the fact that we did have a high response rate
`and did observe CRs suggests that this active couplet may
`have a role in adjuvant treatment. The combination of
`paclitaxel/cisplatin alternating or sequentially with doxo-
`rubicin and cyclophosphamide may provide a non-cross-
`resistant combination and may translate into improved
`survival in the adjuvant setting.
`Paclitaxel and cisplatin on a biweekly schedule appears
`to be an active combination in the treatment of metastatic
`breast cancer in this single-institution phase I/II trial. Fur-
`ther confirmatory trials of this combination and other
`novel schedules of paclitaxel are necessary to further our
`understanding of how to best use this novel agent.
`
`REFERENCES
`Taxol: An active drug in the treatment of metastatic breast cancer.
`1. Early Breast Cancer Trialists' Collaborative Group: Systemic
`J Natl Cancer Inst 83:1797-1805, 1991
`treatment of early breast cancer: Hormonal, cytotoxic and immuno-
`5. Seidman AD, Reichan BS, Crown JPA, et al: Paclitaxel as second
`therapy. Lancet 330:1-15, 71-85, 1992
`and subsequent therapy for metastatic breast cancer: Activity indepen-
`2. Henderson IC: Chemotherapy of advanced disease, in Harris
`dent of prior anthracycline response. J Clin Oncol 13:1152-1159, 1995
`AL Jr, Henderson IC, Hellman S, et al (eds): Breast Disease. Phila-
`6. Reichman BS, Seldman AD, Crown JPA, et al: Paclitaxel and
`delphia, PA, Lippincott, 1987, pp 428-479
`recombinant human granulocyte colony-stimulating factor as initial
`3. Horwitz SB, Cohen D, Rao S, et al: Taxol: Mechanisms of
`chemotherapy for metastatic breast cancer. J Clin Oncol 11:1943-
`action and resistance. J Natl Cancer Inst 15:15-21, 1993
`1951, 1993
`4. Holmes FA, Walters RS, Theriault RL, et al: Phase II trial of
`
`Downloaded from ascopubs.org by 73.35.146.70 on December 11, 2016 from 073.035.146.070
`
`Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
`
`6 of 7
`
`Celltrion, Inc., Exhibit 1014
`
`

`

`PACUTAXEL AND CISPLATIN FOR BREAST CANCER
`
`7. Gelmon K, Nabholtz JM, Bontenbal M, et al: Randomised trial
`of two doses of paclitaxel in metastatic breast cancer after failure
`of standard therapy. Ann Oncol 5:483, 1994 supplyl 5; abstr 493)
`8. Holmes FA, Newman RA, Madden T, et al: Schedule depen-
`dent pharmacokinetics in a phase 1 trial of Taxol and doxorubicin
`as initial chemotherapy for metastatic breast cancer. Ann Oncol
`5:489, 1994 (suppl 5)
`9. Sledge G, Robert N, Sparano J, et al: Paclitaxel (Taxol)/doxo-
`rubicin combinations in advan