Memorial Sloan-Kettering Cancer Center Experience With
`Paclitaxel in the Treatment of Breast Cancer
`
`Andrew D. Seidman, Clifford A. Hudis, David Fennelly, George Raptis, Jose Baselga. and Larry Norton
`
`Paclitaxe l (T axol; Bristol-Myers Squibb Company,
`Prince ton, NJ) is the most important new cytotoxic
`agent to be intr oduced for the management of breast
`cancer in many years. During this decade, investigators
`at Memorial Sloan-Kettering Cancer Center have con(cid:173)
`ducted multiple clinical and laboratory investigations
`aimed at optimally integrating this agent into therapeu(cid:173)
`tic strategies for b reast cancer. These studies address
`both single-agent and combination r egimens in the
`m e tastatic and adjuvant settings. This re port will re(cid:173)
`view p revious results, but focus on active studies and
`future avenues of research.
`Copyright © 1995 by W.8. Saunders Company
`
`A FTER the initial demonstration of the safety
`
`and important antitumor activity of pacli(cid:173)
`taxcl (T axol; Bristol-Myers Squibb Company,
`Princeton, NJ) against metasratic breast cancer, 1
`we performed a series of phase II clinical trials
`characterizing its potentia l as single-agent therapy
`for merastatic breast cancer. T hese trials used vari(cid:173)
`ous doses and schedules in patients without prior
`chemmherapy for stage IV disease as wel l as chose
`with moderate and extensive prior therapy2-~ (Ta(cid:173)
`ble I). In heavily pretreated patients, we have per(cid:173)
`formed forma l, parallel investigation of quality of
`life parameters to better assess the impact of pacl i(cid:173)
`taxel among patients rece iving this agent with pal(cid:173)
`liative incenc. 5
`7 T hese efforts are continuing pro(cid:173)
`·
`spectively in an ongoing study that addresses
`economic variables (charges/costs) in addition tO
`qua lity of life and standard tumor response and
`mxicity outcomes for patients receiving paclitaxcl
`by various infusion schedu les. Motivated by pre(cid:173)
`clinica l data suggesting schedule-dependent cyto(cid:173)
`kinetic variability in resisrance profi les to taxan.ess.12
`
`From ihe Breast and Gynecologic Cancer Med1c111e Service. Divi(cid:173)
`sion of Solid Tumor Oncology, Department of Medicine. Memonal
`Sloan-Keuermg Cancer Cemer, and Come/I Unwersrty Medical
`College, New York, NY.
`Ors Seidman and Baselga have received Career Developmenr
`Awards from the American Socre1y of Clmrcal Oncology ; Dr H11d1s
`has received a Career Developme1lf Award from !he Amencan Can(cid:173)
`cer Society.
`Address repr1111 requesis w Andrew D. Seidman, MD, Breast and
`Gynecologic Cancer Medicine Service, Memorial Sloan-Kectenng
`Cancer Cemer. 1275 York Ave, New York, NY 10021 .
`Copyrighi © 1995 by \'(I B. Sa11nders Company
`0093-7754/95/2205-1224$05 .00/0
`
`and the demonstrated activity and safety of a 96-
`hour infusion schedule against anthracycline- re(cid:173)
`fractory breast cancer, 13 we have conducted a
`phase 11 and pharmacologic trial, evaluating the
`efficacy and safety of this prolonged infusion sched(cid:173)
`ule in patients with demonstrated d isease progres(cid:173)
`sion du ring brief taxane exposure. 14 Efforts to bet(cid:173)
`ter characterize clinically relevant mechanisms of
`resistance to paclitaxel in studies involving human
`breast cancer tissue are under way.
`Paclitaxel combinations wirh various cytotoxic
`agents are being actively explored and are ad(cid:173)
`dressed elsewhere in this supplement. At our insti(cid:173)
`tution, we arc investigating the combination of
`paclitaxel and edatrexate, a dihydrofolate reduc(cid:173)
`tase inhibitor with precl inical advantages over
`methotrexate 15 and documented single-agent ac(cid:173)
`t ivity against metastatic breast canccr. 16
`17 T he
`·
`trial design derives from schedu le-dependent syn(cid:173)
`ergy observed in vitro in mammary carcinoma
`
`ccl ls. 18•19 A novel area of potentially fru itfu l futu re
`clinical research pertains to the observed synergy
`bnwf'en p~cliraxc- 1 and monoclonal antibodies
`(MoAbs) d irected at various growth factor recep(cid:173)
`tor antibodies in human breast ca rc inoma xeno(cid:173)
`grafts.20·2 1 Studies addressing possible mechanisr ic
`explanations for chis effect are ongoing.
`T h e activity of paclitaxel and the potentia l for
`non-cross-resistance with anthracycline has moti(cid:173)
`vated its evaluation as a component of an adjuvant
`sequential chemotherapy regimen for node-posi(cid:173)
`tive srage 11/111 resecrable breast cancer. 22 We are
`presently evaluating the optimal integration of
`paclitaxel
`into doxorubicin/cyclophosphamide(cid:173)
`based adjuvant therapy in a randomized clinical
`trial. T his report wil l address the past, present,
`and futu re investigations with paclitaxel in the
`treatment of breast cancer at Memoria l Sloan-Ket(cid:173)
`tering Cancer Center (MSKCC) .
`
`SINGLE-AGENT TRIALS
`
`Impressed by an early report from the M.0. An(cid:173)
`derson Cancer Center (Houston, TX) of the prom (cid:173)
`ising antitumor activity of paclitaxel (a 56% re(cid:173)
`sponse proportion [95% confidence interval (CJ),
`35% to 76%] was seen among patients with min i(cid:173)
`mal prior rherapy 1
`), we performed a confirmarory
`
`108
`
`Semmors in Oncology. Vol 22. No S, Suppl 12 (October). 1995: pp I 08-116
`
`1 of 9
`
`Celltrion, Inc., Exhibit 1010
`
`

`

`MSKCC: PACLITAXEL IN BREAST CANCER
`
`109
`
`Table I. Summary of Memorial Sloan-Kettering Cancer Center Phase II Single-Agent Trials
`
`Trial
`No.
`
`Prior Therapy
`(Stage IV)
`
`Dose
`(mg/m1
`)
`
`Infusion Duration
`(hr)
`
`I
`2
`3
`4
`5
`6
`
`0
`2:2
`I
`- 2
`0
`1.2•
`
`250
`200
`250
`175
`250
`140
`
`24
`24
`24
`3
`3
`96
`
`G-CSF
`
`Yes
`Yes
`Yes
`No
`No
`No
`
`Response Rate. %
`(95% Cl)
`
`No. of
`Patients
`
`(4 1-80)
`62
`27.5 (1 1-42)
`44
`(24-65)
`20.8 (7-42)
`32
`(15-53)
`26.9 ( 12-48)
`
`26
`SI
`25
`24
`25
`26
`
`• Must include prior paclitaxel via 3-hour infusion o r docetaxel via I -hour infusion.
`
`phase I I trial of paclitaxel as init ial chemotherapy
`of metastatic breast cancer.2 In this study, 28 pa(cid:173)
`tients without prior chemotherapy for metastatic
`disease received pacl itaxel 250 mg/m2 via 24-hour
`infusion every 3 weeks. Significant myelosuppres(cid:173)
`sion was observed in the first two patients we
`treated on this protocol and indeed was dose lim(cid:173)
`iting in the previous trial. 1 The protocol was there(cid:173)
`fore amended such that a ll subsequent patients re(cid:173)
`ceived granulocyte colony-stimulating factor (G(cid:173)
`CSF) 5 µg/kg/d subcutaneously on days 3 through
`10 of each cycle. A 62% response race (95% CI,
`41% co80%)2 was noted, includ ing three complete
`responses (CRs). Responses were seen in 10 of 16
`patients (63%) who had received prior adjuvant
`chemotherapy, including one CR and fou r partial
`responses (PRs) among eigh t patients who had re(cid:173)
`ce ived prio r doxorubicin-based adjuvanc chemo(cid:173)
`therapy.
`Treatment was well tolerated. Adverse effects
`included generalized alopecia in all patients; grade
`~3 nonhematologic toxicities were uncommon.
`Of 178 cycles administered, there were eight ad(cid:173)
`missions ( 4%) for feb rile neutropenia, involving
`six of 28 patients ( 21 % ). Admin istration of recom(cid:173)
`binanc human G-CSF resulted in a median of 2
`days with an absolute neutrophil count less than
`500 cells/ µL, shorter than that previously reported
`(7 days) 1 withouc concomitant growch factor sup(cid:173)
`port. Notably, 58% of cycles were delivered at a
`reduced dose, most frequently 180 or 200 mg/m2
`•
`T he most common reason for dose reduction was
`an absolute neutrophil nadir less than 250 cel ls/µL
`and/or febri le neucropenia. Because of drug supply
`consideracions, response duration was not a valid
`end poinc of this tria l; the clinical trial design
`specified a length of treatment to two cycles be-
`
`yond the best response ro a maximum of lO cycles
`per patient.
`After this confirmatio n of pacl itaxel's signifi cant
`anti wmor activity in patients with minimal prior
`treatment, we next focused on pa tients who h ad
`received extensive prior chemotherapy for meta(cid:173)
`static breast cancer. 3 We enro lled 51 patiencs who
`had previously received a minimum of two prio r
`che motherapy regimens fo r metastatic disease (me(cid:173)
`dian, 3; range, 2 to 6; a ll with prior anthracycline)
`into our second phase II trial. The median Karnof(cid:173)
`sky performance score for these patients was 70%
`(range, 60% to 90%). Of these patients. 14% had
`received prio r high-dose chemotherapy regimens
`sufficiently myelotoxic to require re infusion of au(cid:173)
`tologous bone marrow and/or peripheral blood pro(cid:173)
`genitor cells; two thirds of these patients had re(cid:173)
`ceived radiocherapy for metastatic disease.
`Paclitaxel was administered at 200 mg/m2 via
`24-hour infusion every 3 weeks with G-CSF sup(cid:173)
`port, as prev iously described. (The lower starting
`dose was chosen in anticipation of more significant
`toxicity in this group of patiencs.) Fourteen PRs
`were observed (27.5%; 95% C l, 16% to 42%), with
`a median response duration of 7 months. Febrile
`neutropenia resulting in hospitalization occurred
`in 24 of the first 312 cycles (8%) and in nine of
`51 pa tients (18%). No patient was removed from
`the trial due ro toxicity. Our next trial eva luated
`the higher, 250-mg/m2 dose, again via 24-hour in(cid:173)
`fus ion every 3 weeks, in patients who had received
`just one prior chemotherapy regimen for meta(cid:173)
`static disease (with or without prior adj uvant ther(cid:173)
`apy) .3 Nine PRs and two C Rs were noted in 25
`evaluable patiencs (44%; 95% C l, 24% ro 65%).
`Significantly, in this and the previous trial, prior
`demonstrated sensiciviry or resistance to anthracy-
`
`2 of 9
`
`Celltrion, Inc., Exhibit 1010
`
`

`

`110
`
`SEIDMAN ET AL
`
`Response by anthracycllne experience
`
`S1ageNdOX
`responsllie
`
`Su190Nd0x ··-
`
`S1ageNdOx
`te$<$1MI
`
`Paditaxel tesponse
`
`. No
`
`l!!JYas
`
`No. of patients
`
`Fig I. Lack of clinical cross-resistance between paclitaxel
`and doxorubicin (dox). (Reprinted with permission.' )
`
`cline did not pred ict fo r the likelihood of subse(cid:173)
`quent response to paclitaxel (Fig 1 ). This lack of
`significant clinical cross-resisrance between pacli(cid:173)
`raxel and doxorubicin, an observarion corrobo(cid:173)
`rated by ochers, was gratifyi ng, as preclinical data
`suggest significant in vitro cross-resistance between
`pacl icaxel and ocher agents fo r which p-glycopro(cid:173)
`tein-med iaced multidrug
`resistance
`is
`(mar)
`25 These observations
`thought co be relevant. 23
`'
`have motivated our ongoing studies in which pre(cid:173)
`and post-paclitaxel human tumor tissue biopsies
`are characterized for mdr expression, tubuli n alter(cid:173)
`ations, and genomic changes (MSKCC IRB proto(cid:173)
`col 94-7). Such stud ies should allow a greater un(cid:173)
`derstanding of clinica lly relevant mechan isms of
`raxane resistance, wh ich may guide the efficient
`development of srrategies to overcome resistance
`and/or analogue developmenc.
`
`Dosing Schedule Issues
`
`Wirh renewed interest in the shorter, more con(cid:173)
`venient, 3-hour infusion schedu le, our next two
`phase 11 trials addressed the safety and efficacy of
`chis schedu le as "salvage" chemotherapy in heavily
`treated patients and as initial chemotherapy for
`stage IV disease. For previously rreared patients
`(two or more prior regimens for merastatic disease,
`including anthracycline), paclitaxel was adminis(cid:173)
`tered via 3-hour infus ion every 3 weeks, at a start(cid:173)
`ing dose of 175 mg/m 2
`. Prophylactic G-CSF was
`nor adm inistered, as 3-hour infusions had been
`shown to be associated with less significant myelo(cid:173)
`suppression rhan 24-hour infusions. Visceral-domi(cid:173)
`nant disease was present in 64% of patients, and
`the median Karnofsky performance score was 70%.
`After delivery of the first 111 cycles (median per
`patient, three; range, one to eight), five PRs were
`
`observed in 24 evaluable patients (20.8%; 95% C l,
`7% co 42%),4 with a med ian response duration of
`4 months (range, 2 to 11 ). Treatment was well
`tolerated; che only grade c:: 3 nonhemarologic cox(cid:173)
`icicies noted were myalgia ( 4%) and mucositis
`(4%). Grade 2:3 neucropenia was seen in one third
`of patients, grade 2:] thrombocyropenia was noted
`in 8%, and grade 2:3 anemia was observed in 13%.
`Dose reduction was requi red in 21%, with dose
`escalation possible in only 4%.
`We rhen evaluated a 250-mg/m 2 starting dose
`via 3-hour infusion, again without prophylactic G(cid:173)
`CSF, as initial chemotherapy for metastatic breast
`cancer. One CR and seven PRs have been noted
`among 25 evaluable paciencs (32%; 95% Cl, 15%
`co 53%).4 Myalgias, archralgias, an<l neuropachy
`appeared co be more significant in chis trial than
`in our prior experience with this dose delivered
`over 24 hours to a similar group of patients. Several
`patients experienced the phenomenon of pho(cid:173)
`topsia26 at doses ;;:: 250 mg/m2 over 3 hours, which
`may represent an optic neuropathy. 27 Additionally,
`six patients experienced intense pruricus and hy(cid:173)
`pereschesia as a manifestation of neurocoxicicy; chis
`symptom was alleviated with the administration of
`tricyclic antidepressants in four patiencs.28 This
`trial has provided pi lot data for the design of ra n(cid:173)
`domized trials of the Cancer and Leukemia Group
`B and the National Surgica l Adjuvant Breast
`Project.
`Supported by in vitro data demonstrating less
`resistance to paclitaxel in p-glycoprotein overex(cid:173)
`pressing MCF-7 breast cancer cells with longer
`drug exposure time,8 other preclinical studies,<1·12
`and encouraging clinica l experience in patients
`with anthracycline-resisrant breast cancer, 13 we
`designed a phase JI clinical and pharmacologic trial
`co evaluate the possibility of schedule-dependent
`activity by administering pacliraxel via 96-hour
`continuous infusion, specifically ro patients with
`disease of demonstrated clinical resistance
`to
`"short taxane exposure. " 14 Twenty-seven patients
`who experienced disease progression wh ile receiv(cid:173)
`ing either 3-hour paclicaxel (n = 24), I-hour do(cid:173)
`cetaxel (n = 2), or both (n = l) received pacli(cid:173)
`taxel 140 mg/m2 (35 mg/m2/d X 4) via 96-hour
`infusion with a starting dose of 120 mg/m 2 for pa(cid:173)
`tients with impaired hepatic function. As early
`data suggested that the om ission of steroid and Hi(cid:173)
`receptor antagonist premedicacion was not associ(cid:173)
`ated with significant hypersensitivity reactions
`
`3 of 9
`
`Celltrion, Inc., Exhibit 1010
`
`

`

`MSKCC: PACLITAXEL IN BREAST CANCER
`
`I ll
`
`with this dose and schedule,13 these agents were
`not given in our study. With 173 cycles adminis(cid:173)
`tered, seven PRs have been noted in 25 evaluable
`patients (28%; 95% Cl, 12% ro 49%), with accept(cid:173)
`able hematologic and nonhematologic toxicity and
`no significant hypersensitivity reactions.
`Paclitaxel serum concentrations were assayed in
`23 patients by high-performance liquid ch romatog(cid:173)
`raphy during the infusions at 24, 48, 72, and 96
`hours. The median steady-state paclitaxel concen(cid:173)
`tration (C$$) was 0.047 µmol/L (range, 0.023 to
`0. 176 µmol/L); for 11 patients experiencing grade
`4 neutropenia it was 0.068 µmol/L (range, 0.032
`to 0. 176 µmol/L), compared with 0.039 µmol/L
`(range, 0.023 ro 0.098 µmol/L) in 12 patients with
`less severe neutropenia (P < .05). Median Cs. and
`absolute neutrophil nad irs were 0.094 µmol/L
`(range, 0.074 to 0.176 µmol/L) and 300 cells/µL,
`respectively, in four patients with baseline eleva(cid:173)
`tion of hepatic transarninases versus 0.041 µmol/
`L (range, 0.023 to 0.102 µmo l/L) and 800 cells/
`µL, respectively, in 19 patients with normal trans(cid:173)
`aminases (C"' P < .01; absolute neutrophil count,
`not significant).' 4 To further define the signifi(cid:173)
`cance of duration of drug infusion for paclitaxel,
`we are presenrly randomizing patients with refrac(cid:173)
`tory metastatic breast cancer to receive 3- versus
`96-hour infusion schedules in a multi-institution
`trial led by Dr F.A. Holmes at the M.D. Anderson
`Cancer Center. As there are greater pharmacologic
`diffe rences between 3- and 96-hour schedules com(cid:173)
`pared with 3- and 24-hour infusion schedules, and
`preclinical data suggest the importance of pacli(cid:173)
`taxel exposure duration in breast carcinoma cells,
`this trial should provide important information re(cid:173)
`garding the impact of paclitaxel infusion duration
`on efficacy and toxicity.
`
`Quality of Uf e Considerations
`As the therapeutic goals in rhe management
`of metastatic breast cancer extend beyond classic
`bidimensional measurement of tumor response to
`include relief of tumor-related symproms and, ide(cid:173)
`ally, maintenance or enhancement of quality of
`life, we performed a paralle l prospective and com(cid:173)
`prehensive assessment of these parameters in con(cid:173)
`junction with our clinical trials of 24-hour pacli(cid:173)
`raxel infusion with G-CSF support in previously
`treated patients with metastatic disease. Patients
`completed a series of validated instruments de(cid:173)
`signed to caprure the many dimensions that con-
`
`tribute to global qua lity of life prior to treatment
`and at 9-week (three-cycle) intervals during pacli(cid:173)
`taxel therapy. We have shown the feasib ility of
`quality of life assessment in patients with advanced
`cancer receiving investigational therapy in a phase
`II clinical trial setting, 5 and are encouraged by
`ongoing investigations addressing these important
`issues in parallel with randomized phase III trials
`of paclitaxel alone and in combination. Although
`limited by sample sizes, our single- institution expe(cid:173)
`rience suggests a potential palliative benefit for
`paclitaxel in patients with responsive disease (PR
`or minor response) .6
`7 Multivariate analysis and lo(cid:173)
`·
`gistic regression models also have demonstrated
`the independent prognostic va lL1e of baseline
`scores of two quality of life instruments, the Global
`Distress lndex29 (a 10-irem subscale of the recently
`validated Memorial Symptom Assessment Scale)
`and the Functional Living Index- Cancer,30 in
`·7
`predicting survi val.6
`
`COMBINATIONS: PRESENT AND FUTURE
`Paclitaxel combinations with doxorubicin3' ·36
`and cisplatin37·38 have been reported. Nor surpris(cid:173)
`ingly, these combinations show impressive antitu(cid:173)
`mor activity against metastatic breast cancer, but
`not without appreciable toxicity. Randomized tri(cid:173)
`als such as the Eastern Cooperative Oncology
`Group srudy of paclitaxel (P) versus doxorubicin
`(0) versus P + D ( + G-CSF) are important to
`gauge the re lative worth of such combinations over
`single-agent therapy with pacliraxel alone.
`Edatrexate (E) is a methotrexate analogue that
`competes avidly for the folate binding site of the
`enzyme dihydrofolate reductase. It thus indirectly
`blocks nuc leoride synthesis. Edatrexare possesses
`potential precl inical ad vanrages over methotrexate
`in that it demonstrates greater selective entry and
`intracellular conversion to polyglutamate forms in
`neoplastic cells compared with other antifolates. 15
`Additiona lly, it has shown promising single-agent
`activity against metastatic breast cancer in previ(cid:173)
`·17 In vitro data from our center
`ous clinical trials.16
`have demonstrated that the sequence of edatrexate
`fo llowed by paclitaxel (24 to 27 hours later)
`showed marked synergism
`in
`inhibiting
`the
`growth of SKBR-3 human breast adenocarcinoma
`eel ls. 18
`19 The reverse schedule showed antagonism.
`•
`We are presenrly evaluating the sequential combi(cid:173)
`nation of "E ~ P" in a phase I/II clinica l trial in
`patients with stage IV breast cancer. 39 Thus far,
`
`4 of 9
`
`Celltrion, Inc., Exhibit 1010
`
`

`

`112
`
`SEIDMAN ET Al
`
`Thiotepa
`
`Thio1epa
`
`.
`.
`.
`~
`.
`:
`·-- -- . -- . -·
`
`700
`
`700
`:
`. --·----·
`
`Pac1<1axel
`
`a 8
`l
`
`P~taxet
`
`G-CSF
`PBPC
`
`G·CSF
`PSPC
`
`l
`
`:-·················:
`1 3,000 1
`~ ................. J
`
`.....................
`.
`.
`L. .. ~:~ ... .J
`
`P8C11taxel
`
`Pachtaxel
`
`G ·CSF
`P6PC
`
`1
`
`G-CSF
`PBPC
`
`l
`
`edatrexare doses of up ro 300 mg/m2 have been
`well tolerated in combination with paclitaxel ar
`175 mg/m 2 via 3-hour infusion without hematopoi(cid:173)
`etic growth facror support, with both agenrs recy(cid:173)
`cled every 21 days. At this early juncture, eight
`responses (three CRs and five PRs) have been
`noted among the first 12 evaluable patients (eda(cid:173)
`trexate dose range, 180 ro 270 mg/m2). As only one
`patient has experienced grade 3 mucositis, dose
`escalation of edatrexate continues.
`ln patients with responding metastatic breast
`cancer, single-cycle, conventional high-dose che(cid:173)
`motherapy regimens with autologous stem cell sup(cid:173)
`port have produced CRs in approximately 50% of
`patients, yet disease recurs in the majority of these
`patients. Applying the concepts of the Norton(cid:173)
`Simon hypothesis and the Gompertzian model of
`breast cancer kinetics,40 and motivated by the ap(cid:173)
`parent failure of a single high-dose application of
`chemotherapy to eradicate all viable malignant
`cells in prior clinical rrials, we have performed a
`series of studies evaluating the del ivery of mu ltiple
`courses of high-dose alkylating agenrs at short in(cid:173)
`tertreatment intervals in patients with responsive
`42 Notably, our group
`metastatic breast cancer.41
`'
`has demonstrated that the addition of paclitaxel
`(250 mg/m2) to high-dose cyclophosphamide (3
`g/m2
`) does not compromise the mobi lization of
`CD34+ peripheral blood progenitor cells (median,
`16.22 E6/kg/leukapheresis) compared with 3 g/m 2
`cyclophosphamide alone (2.64 E6/kg/leukapher(cid:173)
`esis).43 Hence, we are presently evaluating the in(cid:173)
`corporation of pacliraxel into our present high(cid:173)
`dose sequentia l regimen in responsive metastatic
`breast cancer, consisting of tandem cycles of high(cid:173)
`dose cyclophospham ide plus paclitaxel followed by
`tandem cycles of high-dose thiotepa plus paclitaxel
`with peripheral blood progenitor cells for hemato(cid:173)
`logic rescue, with 14-day treatment intervals
`(Fig 2).
`
`Growth Faeto1· Studies
`A greater appreciation of autocrine and para(cid:173)
`crine growth factor regulation of breast cancer cell
`growth has led to new avenues of investigation.
`Major advances have been made since the mid(cid:173)
`l 980s in the undersranding of the role that certain
`oncogenes, growth factors, and growth factor re(cid:173)
`ceptors play in breast cancer.44.4 5 Among the best(cid:173)
`studied growth factor receptor systems in breast
`cancer has been the one constituted by the epider-
`
`Fig 2. Seque ntial high-dose regime n. Cycles are at 14-day
`in tervals; dose in milligrams per square m e ter. PBPC, periph(cid:173)
`eral blood progeni tor cells.
`
`mal growth factor receptor (EGFR) and the closely
`related HER-2/neu receptor. Monoclonal antibod(cid:173)
`ies directed against both these receptors inhibit
`the growth of breast cancer cells. 45 Since 1992,
`we and others have developed strong experimental
`data suggesting that combin ing maximally toler(cid:173)
`ated doses of chemotherapeutic agents with
`MoAb-mediated blockade of either EGFR or HER-
`2/neu receptors can erad icate well-established hu(cid:173)
`man rumor xenografts that were resistant to either
`21
`treatment given singly. 20
`46.47 Striking antitumor
`•
`•
`effecrs are observed when paclitaxel is given in
`human breast cancer xenografts in combination
`with either anci-EGFR or anri- HER-2 MoAbs.
`This strong synergy is achieved with no increased
`roxicity in the animal model. C linical trials with a
`chimeric anti-EGFR MoAb and with a humanized
`anci-HER-2/neu MoAb (rhMoAb HER-2) are cur(cid:173)
`rently under way at MSKCC. ln a recently com(cid:173)
`pleted phase II study, significant responses with
`rhMoAb HER-2 were observed in patients who
`had been heav ily pretreated.48 While mechanisms
`for the apparent synergy are being explored,47 these
`dara provide a lead for translation into the clinic.
`Indeed, future clinical trials combin ing pacl itaxel
`with anti-growth factor receptor MoAbs are being
`planned.
`
`ADJUVANT THERAPY
`Motivated by the significant activity and safety
`of paclitaxel noted in our own and others' trials
`in patients with advanced disease, we have incor(cid:173)
`porated paclitaxe l into a poscoperative adjuvant
`chemorherapy regimen for patients with node-pos(cid:173)
`itive resectable stage II/III breast cancer. The supe(cid:173)
`riority of sequential versus alternating scheduling
`
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`

`MSKCC: PACLITAXEL IN BREAST CANCER
`
`113
`
`090 mg/m2
`
`P 250 mg/m2
`
`C 3g/m 2
`
`Fig 3. The MSKCC adiuvant
`treatme nt regime n 0
`... P - C.
`Radiothe rapy/tamoxifen
`foll ow
`a s approp r iate. SC, subcu tane (cid:173)
`ously; RT, rad iothe rapy.
`
`0
`
`-
`
`2
`
`4
`
`6
`
`G-CSF 5 µg/kg SC days 3-10
`
`I
`8
`
`I
`10
`Weeks
`
`12
`
`- -I
`
`I
`14
`
`I
`16
`
`(RT)
`
`(Tamoxifen) -I
`
`of active therapeutic components in the adjuvanr
`setting has been suggested by mathematical models
`of rumor kinetics40 and substantiated by clinical
`trial.'9 We have previously demonstrated the feas i(cid:173)
`bility of sequential administration of doxorubicin
`and high-dose cyclophosphamide as adjuvant ther(cid:173)
`apy for patients with resectable stage 11/l l I breast
`cancer with four or more involved axillary lymph
`nodes.50 The recurrence-free survival curve noted
`thus far is encouraging; with a med ian fo llow-up
`time of 36 months, a 62% recurrence-free survival
`proportion has been noted among 71 patients with
`a median of nine involved axillary nodes. This
`experience, combined with paclitaxel's activity
`and partial non- cross-resistance with doxorubicin,
`led us to incorporate it into an adjuvant chemo(cid:173)
`therapy regimen for women of the same risk cate(cid:173)
`gory.
`Forty-two patients with four or more positive
`axillary lymph nodes (median, eight; range, fou r
`to 25) have received che regimen of rapidly se(cid:173)
`quenced doxorubicin (90 mg/ml), paclitaxel (250
`
`mg/ml, 24 hours), and high-dose cyclophospha(cid:173)
`mide (C) (J g/m2
`), all administered with G-CSF
`support, as shown in Fig 3.51 Two patients did
`nor complete the regimen due to nonhematologic
`toxicity experienced afcer the second cycle of high(cid:173)
`dose cyclophosphamide. The median delivered
`dose intensity for each component of this regimen
`(D __. P--> C) has been I 00% of planned. Hemato(cid:173)
`logic toxicities are shown in Table 2. The more
`frequent grade } nonhematologic toxicities in(cid:173)
`cluded fatigue (24%), bone pain (24%), stomatitis
`(l 7%), dermatologic (17%; grade 4, 2%), neuro(cid:173)
`sensory (15%), nausea ( 12%), and diarrhea (7%).
`Serial radionuclide gated heart scans showed no
`decline in cardiac ejection fraction. and no clinical
`cardiotoxicity was noted. At a median follow-up
`of 448 days after surgery (range, 82 to 632 days),
`7% of patients have relapsed. 52
`l nan effort to optimally integrate paclitaxel into
`adjuvant system ic therapy, we are presently ran(cid:173)
`domizing patients to receive a slightly mod ified
`version of the sequential regimen described above
`
`Table 2. H em atologic Toxicity: D oxorubicin/Paclitaxe l/Cyclophosphamide Adiuvant Re gime n
`
`Median nadir (range)
`WBC X IO'lµ L
`ANC X 101/µL
`Platelets X 10'/µL
`Hgb (g/dl)
`Median therapeutic interval (d)
`Range
`Percenr of patients
`Admissions
`RBC transfusion
`Platelet transfusion
`
`D x 3 (125 Cycles)
`
`P x 3 (123 Cycles)
`
`C x 3 (12 Cycles)
`
`1.2 (0.5-5)
`0.4 (0-2.9)
`102
`(19-234)
`9.4 (7.5-11.6)
`14
`
`13-30
`
`44
`10
`0
`
`3.3 (0.2-16.5)
`2.1 (0-7.5)
`126
`(53-292)
`8.3 (5.6-1 O}
`14
`
`11-35
`
`24
`22
`0
`
`0.4 (0-3.3)
`0. 1 (0-2.6)
`(8-240)
`72
`7.3 (4.4-9}
`14
`12-36
`
`42
`54
`10
`
`Abbreviations: WBC. white blood cell count: ANC, absolute neutrophil count; Hgb. hemoglobin; RBC. red blood cell.
`
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`114
`
`SEIDMAN ET AL
`
`- All cycles q1 4d
`
`days 3-10 all cycles
`
`I 1 1 0 0 0 '"w'
`I I I I I I
`-G-CSF 5 µg/kg SC
`0 0 0 12wk
`I D: 80mg/m2
`I
`0
`
`P: 200 mg/m2/24 hr
`
`C: 3 g/m 2
`
`Fig 4. Randomized adjuvant
`phase II trial 94-85: D - P - C
`(PC). R.adiot he rapy/
`ve rsus D -
`tamoxifen follow as appropriate.
`
`(Fig 3) versus single-agent doxorubic in X 3, fol(cid:173)
`lowed by concomitant paclitaxel and high-dose cy(cid:173)
`clophosphamide (Fig 4). ln a different approach,
`an Intergroup trial will evaluate the efficacy of
`four cycles of paclitaxel administered via 3-hour
`infusion after delivery of one of three dose levels
`of doxorubicin/cyclophosphamide (60/600, 75/
`600, o r 90/600 mg/m2
`) as adjuvant chemotherapy
`for node-positive early stage breast cancer.
`
`SUMMARY
`
`ln this decade many large multicenter tria ls will
`answer important questions regarding the optimal
`application of single-agent paclitaxel (dose and
`schedule), its role in relation to other active agents
`and regimens, its comparative impact on quality
`of life, and the potential of combination regimens
`conta ining paclitaxel. Studies at MSKCC and else(cid:173)
`where are attempting co characterize in vivo resis(cid:173)
`tance mechanisms to this class of agents. These
`efforts may result in mechanism-directed strategies
`to overcome resistance; they may a lso guide ana(cid:173)
`logue development. T ranslat ional research involv(cid:173)
`ing growth factors and their receptors promises to
`capitalize on an expanding knowledge of autocrine
`and paracrine pathways and the ability to perturb
`them. ln the c linic and the laboratory, there are
`many reasons for optimism in the future applica(cid:173)
`tio n of paclitaxel against breast cancer.53
`
`REFERENC ES
`
`I. Holmes FA, Walters RS, Theriault RL, et al: Phase 11
`trial of Taxol, an active drug m the treatment of metastatic
`breast cancer. J Natl Cancer lnsc 83:1797-1805, L99i
`2. Reichman BS, Seidman AO. Crown JPA, et al: Taxol
`and recombinant human granulocyce colony sumulatmg factor
`
`as initial therapy for metastatic breast cancer. J Clin Oncol
`11: 1943-195 1. 1993
`3. Seidman AD, Reichman BS, Crown JPA, et al: Paclicaxel
`as second and subsequent therapy for metastatic breast cancer:
`Act1vity independent of prior anthracycline response. J Clm
`Oncol 13:1152-1159, 1995
`4. Seidman AD, T ierscen A, Hudis C, et al: Phase II trial
`of paclitaxel by three-hour infusion as initial and as salvage
`chemotherapy for metastatic breast cancer. J Clin Oncol
`13:2575-2581, 1995
`5. Seidman AD, McCarthy J, Anthony V, et al: Pain and
`quality of life assessment in patients receiving Taxol and recom·
`binant human granulocyte colony stimulating factor for meta(cid:173)
`static breast cancer. Proceedings of the 2nd National Cancer
`lnsmute Workshop on Taxol and Taxus, September Z3-24,
`Alexandria, VA, 1992 (abstr 1-1)
`6. Seidman AD, Lepore J, Yao T-J, et al: Prognostic value
`of baseline quality of life (QOL) assessment in patients receiv(cid:173)
`ing Taxol + G-CSF for refractory metastatic breast cancer.
`Proc Am Soc Clin Oncol 13:434, 1994 {abscr)
`7. Seidman AD, Porcenoy R, Yao T-J, et al: Quality of life
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`dictive value in advanced breast cancer patients created with
`paclitaxel plus recombinant human granulocyte colony stimu(cid:173)
`lating factor. J Natl Cancer Inst 87:13 16-1322, 1995
`8. Zhan Z, Kang Y-K, Regis J, et al: Taxol resistance: In
`vitro and in vivo studies in breast cancer and lymphoma. Proc
`Am Assoc Cancer Res 34:2 15, 1993 (abm)
`9. Lopes NM, Adams EG. Pitts TW, et al: Cell kinetics and
`cell cycle effects of Taxol on huma n and hamster ovarian cell
`lines. Cancer Chemorher Pharmacol 32:235-242, 1993
`JO. Liebmann JE, Cook JA, Lipschultz D, et al: Cytotoxic
`studies of paclitaxel (Taxol) in human tumor cell lines. Br J
`Cancer 68: 1104-1109, 1993
`l I. Kelland LR, Abel G: Comparative m vitro cycotoxicity
`ofTaxol and Taxotere against c1splarin-sens1t1ve and -resistant
`human ovarian carcinoma cell lines. Cancer Chemorher Phar·
`macol 30:444-450, 1992
`12. Georg1ad1s MS, Russell E, Johnson BE, et al: Prolonging
`the exposure of human lung cancer cell lines co paclitaxel
`improves the cytotoxicity. Proc Am Assoc Cancer Res 35:341,
`1994 (abstr)
`
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`MSKCC: PACLITAXEL IN BREAST CANCER
`
`115
`
`13. Wilson WH, Berg S, Bryant G, et al: Paclitaxel in doxo·
`rubte1 n-refractory or mitoxanrrone-refractory breast cancer: A
`phase 1/11 mal of96 hour infusion. J Clin Oncol l2:16Zl-