Paclitaxel Couplets With Cyclophosphamide or Cisplatin in
`Metastatic Breast Cancer
`
`Anthony W. Tolcher
`
`Determining active combinations containing paclitaxel
`(Taxol; Bristol-Myers Squibb Company, Princeton, NJ)
`to treat metastatic breast cancer has been the focus of
`recent clinical development. Paclitaxel combined w ith
`eithe r cyclophosphamide or cisplatin has several poten(cid:173)
`tial advantages: cisplatin and cyclophosphamide are ac(cid:173)
`tive single age nts against previously untreated meta·
`static breast cancer, colony-stimulating factors can
`modulate overlapping toxicities like myelosuppression,
`and no mechanisms of cross-resistance between pacli(cid:173)
`taxel and these agents are yet known. Major questions
`include the optimal schedule of administration and the
`sequence dependence of toxicities with these combina(cid:173)
`t ions. Paclitaxel schedules with cisplatin include either
`two dose levels using the 24.hou r infusion o r a novel
`biweekly l·hour infusion. The sequence in the three
`available studies was paclitaxel followed by cisplatin.
`Hem atologic toxicities were dose limiting with the bi(cid:173)
`weekly and low-dose 24-hour paclitaxel/cisplatin com·
`binations; with granulocyte colony-stimulating factor,
`neurotoxicity became a prominent cumulative toxicity
`of the high-dose paclit axel/cisplatin combination. Re·
`sponse rates in the first-line treatment of metastatic
`breast cancer ranged from 49% to 85%. In the three
`completed studies with cyclophosphamide, paclitaxel
`has been administered over eithe r 72, 24, or 3 hours.
`Paclitaxel followed by cyclophosphamide had greater
`he matologic toxicity than the opposite schedule or con(cid:173)
`current administration. Pharmacokinetic factors do
`not see m to account for this sequence-depe ndent toxic·
`ity. As expected, dose-limiting toxicity in all studies has
`been hematologic. However, granulocyte colony-stim(cid:173)
`ulating factor has ameliorated myelosuppression and
`allowed considerable dose escalation of cyclophospha·
`mide. This combination has demonstrated activity in
`pre viously treated patients with m etastatic breast can(cid:173)
`cer, including the anthracycline-refractory subpopula·
`t ion that will be reviewed.
`Copyright © 1996 by W.B. Saunders Company
`
`P ACUTAXEL (Taxol; Bristol-Myers Squibb
`
`Company, Princeton, NJ) is an active single
`agent in the treatment of metastatic breast cancer
`with reported response rates up to 62% in first-line
`therapy and up to 30% in extensively pretreated
`patients. H The logical progression for the clinical
`development of this agent includes combination
`studies of paclitaxel and other drugs that possess
`proven activity against breast cancer. Cyclophos(cid:173)
`phamide and cisplatin are two such agents: both
`have proven activity in rhe treatment of breast
`cancer and neither has any known mechanisms of
`cross-resistance with paclitaxel.
`
`A lthough seldom used in treating breast cancer,
`cisplatin is active, with single-agent response rates
`of 47% to 54%5
`6 as first-line therapy for metastatic
`·
`breast cancer. A paclitaxcl/cisplatin combination
`has several potential advantages: patients generally
`have nor received adjuvanr cisplatin and, with the
`exception of peripheral neuropathy, overlapping
`toxicities for the two drugs are uncommon and are
`not usually hematologic.
`Cyclophosphamide is the standard alkylating
`agent used in both the adjuvant and palliative treat(cid:173)
`ment of breast cancer. Considerable cl inical experi(cid:173)
`ence has been ga ined from its past 30 years of use
`against this disease. Single-agent activity, reported
`from the earliest clinica l trials, ranged from 25% to
`45% in patients with advanced disease.7
`8 Myelosup(cid:173)
`'
`pression, particularly neutropenia, is the major over(cid:173)
`lapping toxicity of cyclophosphamide and pacli(cid:173)
`taxel; this can now be diminished with the use of
`colony-stimulating factors.
`Combining two chemotherapy agems with dis(cid:173)
`tinctly different mechanisms of action and charac(cid:173)
`teristics into a couplet represents a challenge. The
`optimal dose and schedule of both agents in combi(cid:173)
`nation needs to be determined, which requires bal(cid:173)
`ancing the combined, and at times unexpected,
`clinical toxicities against the need for maximum
`cytotoxicity from each agent. Similarly, the optimal
`sequence of administration may need tO be deter(cid:173)
`mined. Potential sequence-dependent toxicities and
`cytotoxic activity have been associated with other
`chemotherapy combinations
`in clinical oncol(cid:173)
`ogy.9·t0 If sequence dependence is clinically signifi(cid:173)
`cant, phase I evaluation must determine whether
`pharmacokinetic or biologic factors are responsible.
`
`PACLITAXEL/CISPLATIN COUPLET
`Preclinical and Clinical Sequence Rationale
`Paclitaxel/cisplatin combinations have demon(cid:173)
`strated additive and synergistic cytotoxicity in
`
`From rhe British Columbia Cancer Agency, Uni••ersity of British
`Columbia, Vancouver, BC, Canada.
`Addre.1.1 reprint r~quests co Anthony W. Tolcher, MD , FRCPC,
`Bricish Columbia Cancer Agi'llC)', University of British Columbia,
`600 \~ 10th Ave, Vancouver, BC V7C IY4 , Canada.
`Copyright© 1996 by W .B. Saunders Company
`0093-7754196/2301-0113$05.0010
`
`Seminors in Oncology, Vol 23. No I. Suppl I (February). 1996: pp 37-43
`
`37
`
`1 of 7
`
`Celltrion, Inc., Exhibit 1013
`
`

`

`38
`
`Table I. Paclitaxel/Clsplatin In Breast Cancer:
`Dose and Schedules
`
`Investigator
`
`Dose (mg/m'}nnfusioo Length
`
`Low dose
`
`BU
`
`High dose
`
`NYU
`
`I
`
`Biweekly
`
`BCCA
`
`Paclicaxel I 35121 hr
`Cfsplatin 75
`Paclicaxel 200121 hr
`Cisplatin 75
`G·CSF
`Paclicaxel 90/3 hr
`Cispladn 60
`
`Abbreviations: BU. Brown University; NYU. New York Uni-
`versity: BCCA. British Columbia Cancer Agency.
`
`some cell lines in vitro.it.ii Sequence analysis of
`this combination has been studied in vitro by many
`investigators. n·14 Paclitaxel followed by cisplatin
`appears to produce maximal cytotoxicity in many
`cell lines, whereas the reverse sequence has dem(cid:173)
`onstrated antagonism_ l).l 4 Paclitaxel is a cell cycle
`phase-specific agent, and perturbations of the cell
`cycle by cisplatin have been hypothesized as a bio(cid:173)
`logic explanation for this sequence-dependent an(cid:173)
`tagonism.14·1 5
`In an elegant phase I and pharmacokinetic
`study, Rowinsky et al examined the sequence-de(cid:173)
`pendent clinical toxicities of the paclitaxel/cis(cid:173)
`plarin combination. In this study, cisplatin admin(cid:173)
`istered before a 24-hour paclitaxel infusion was
`associated with significantly increased granu locyte
`toxicity compared with the reverse sequence of
`paclitaxel fol lowed by c isplatin.16 Pharmacokinetic
`analysis of these sequences suggested that adminis(cid:173)
`tering cisplatin first significantly delayed clearance
`of the myelosuppressive agent paclitaxel compared
`with the alternate sequence and that the delayed
`clearance was responsible for the increased granu(cid:173)
`locyre toxicity. Based on this compelling labora(cid:173)
`tory and clinical evidence, paclitaxel followed by
`cisplatin has become the standard sequence of ad(cid:173)
`ministration in clinical investigation.
`
`Clinical Scudies
`Interim results from three phase 11 studies are
`available for analysis. Table 1 lists the doses and
`schedules, which are illustrated in Fig 1.
`trial.
`New York University Medical Cencer
`Wasserheit et al studied paclitaxd 200 mg/m2 by
`24-hour infusion followed immediately by cisplatin
`
`- ---------------+- -
`-
`P135mg/m2 -
`
`ANTHONY W . TOLCHER
`
`22
`
`22
`
`t
`
`t
`
`G-CSF
`
`t
`
`t
`
`15
`
`•
`
`t
`
`P200mg/m2
`C 75mg/m2
`
`NYU
`
`BU
`
`,
`
`,
`
`C7Smgtm2
`
`C60mg/m2
`
`BCCA P90mg/m2 •
`
`,
`
`t
`
`Fig I. The schedule and sequence of the three phase II stud(cid:173)
`ies of paclitaxel (P) in combination with cisplatin (C). N YU ,
`N ew York University; BU, Brown University; BCCA, British
`Columbia Cancer Agency; G·CSF, granulocyt e colony-stimulat(cid:173)
`lng factor.
`
`75 mg/m 2 every 3 weeks (C. Wasserheit, MD, prin(cid:173)
`cipal investigator, unpublished data, July 1995).
`Based on previous clinical trial experience with
`paclitaxel in ovarian cancer and, as a single agent,
`in breast cancer, neutropenia was anticipated to
`be dose limiting. Thus, granulocyte colony-stimu(cid:173)
`lating facror (G-CSF) was administered to all pa(cid:173)
`tients following chemotherapy.
`Open to women with metastatic breast cancer
`the study has treated 44 patients. Prior adjuvan;
`chemotherapy was permitred and three patients
`had received prior chemotherapy for metastatic
`disease. Twenty-three patients had prior adjuvanr
`chemotherapy and 19 had received anchracyclines.
`Tahle 2 summarizes patient characteristics.
`Although G-CSF modified hematologic toxic(cid:173)
`ity, instances of febrile neutropenia and one toxic
`death were recorded. Neuropathy was a prominent
`nonhemaLOlogic and dose-limitingcumulacive tox(cid:173)
`icity in chis study. Peripheral neuropathy grade 2
`o r greater occurred in 88% of patients over a me(cid:173)
`dian of five cycles. Periphera l neuropathy was dose
`limiting in the phase I study of pacliraxel/cisplatin
`and G-CSF due to rhe G-CSF-relaced ameliora(cid:173)
`t ion of the usually dose-limiting neutropenia and
`
`Table 2. PaclitaxeVClsplatln in Breast Cancer:
`Patient Characteristics
`
`NYU BU BCCA
`
`No. of patients
`Median age (yr)
`Median no. of disease siles
`No. of patients with prior chemotherapy
`Anthracycline containing
`
`44
`49
`2
`23
`19
`
`16
`53
`2
`13
`12
`
`29
`47
`2
`27
`23
`
`Abbreviations- NYU. New York University: BU. Brown Uni-
`versity; BCCA, British Columbia Cancer Agency.
`
`I
`
`2 of 7
`
`Celltrion, Inc., Exhibit 1013
`
`

`

`PACUTAXEL W ITH CJSPlATIN OR CYCLOPHOSPHAMIDE
`
`39
`
`the consequent increased dose delivery of these
`two neurotoxic agents. 17
`This schedule of paclitaxel/cisplatin at these
`doses was active, with five complete responses
`(CRs) and 15 partial responses (PRs) of 41 evalu(cid:173)
`able patients, for an overall response rate of 49%.
`Brown University Hospitals study. Browne and
`colleagues initiated a phase II study of paclitaxel
`135 mg/m2 by 24-hour infusion followed immedi(cid:173)
`ately by cisplatin 75 mg/m2 in women with meta(cid:173)
`static breast cancer (M. Browne, MD, principal
`investigator, unpublished data, July 1995). The
`doses and schedule were derived from phase I stud(cid:173)
`ies in ovarian cancer. Granulocyte colony-stimu(cid:173)
`lating factor was used only as indicated clinically.
`Only patients with untreated metastatic breast
`cancer were eligible, although prior adjuvant che(cid:173)
`motherapy was allowed. Sixteen patients have
`been entered to date, 13 of whom had received
`prior adjuvant chemotherapy.Twelve patients' ad(cid:173)
`juvant therapy contained anthracycline. Table 2
`summarizes patient characteristics. The largely he(cid:173)
`matologic clinical toxicities have been tolerable.
`Nonhematologic toxicities have included alopecia,
`rash, nausea and vomiting, and fatigue, all which
`were anticipated in a cisplatin-containing regimen.
`Peripheral neuropathy has been tolerable and con(cid:173)
`sistent in frequency with the incidence reported
`in ovarian cancer trials.
`Two CRs and six PRs have been observed with
`this pacliraxel/cisplarin dose and schedule in 15
`patients evaluable for response, for an interim re(cid:173)
`sponse rare of 53%. This level of activity is encour(cid:173)
`aging considering that most of the women had
`received anthracyclines.
`British Columbia Cancer Agency trial. This
`phase I/II study (K. Gelmon, MD, principal inves(cid:173)
`tigator, unpublished data, Ju ly 1995) was planned
`to deliver biweekly pacliraxel by 3-hour infusion
`followed immediately by cisplatin. The biweekly
`schedule of paclitaxel combined wirh cisplatin was
`based on the results of the European and Canadian
`study of single-agent paclitaxel in refractory ovar(cid:173)
`ian carcinoma, which compared the 3- and 24-
`hour infusion schedules at dose levels of 135 and
`18 In this comparative study, the major(cid:173)
`175 mg/m 2•
`ity of patients who received paclitaxel by the 3-
`hour infusion at both dose levels had neutrophil
`recovery to greater than 1,500/ µL by day 15, sug(cid:173)
`gesting that biweekly administration of a 3-hour
`paclitaxel infusion was possible. The paclitaxel/
`
`cisplatin combination in a biweekly schedule was
`hypothesized to be tolerable due to the modest
`myelosuppression associated with cisplatin. The
`schedules and sequence of the agents are demon(cid:173)
`strated in Fig l.
`The starting dose level in the phase I portion
`of the study in metastatic breast cancer cou ld not
`be escalated, however, because the patients' granu(cid:173)
`locyte counts had not recovered to greater than
`750/µL by day 14. The phase !I dose level was thus
`determined to be paclitaxel 90 mg/m 2 by 3-hour
`infusion followed by cisplatin 60 mg/m2 adminis(cid:173)
`tered every 2 weeks. The use of G-CSF was not
`permitted. The study was open to patients with
`chemotherapy-naive metastatic breast cancer, al(cid:173)
`though prior adjuvant chemotherapy was permissi(cid:173)
`ble. Twenty-nine patients were entered, 27 of
`whom were evaluable for response in the phase II
`portion. Twenty-seven patients had received prior
`adjuvant chemotherapy, 23 with anthracycline(cid:173)
`containing regimens. Table 2 summarizes patient
`characteristics.
`Hematologic toxicity was common, although
`brief grade 4 neutropenia, median 2 days' duration
`(range, 0 to 7), was observed in only 34% of pa(cid:173)
`tients. One patient was admitted for febrile neutro(cid:173)
`penia and bacteremia was documented. During the
`septic episode, which responded to antibiotic man(cid:173)
`agement, this same patient experienced the only
`case of grade 4 thrombocytopenia.
`Mild nonhematologic toxicities were common.
`Alopecia, nausea and vomiting, and fatigue, al(cid:173)
`though frequent with this combination, were gen(cid:173)
`erally not dose limiting. Arthralgia and myalgia
`occurred in 41 % of patients but were dose limiting
`in only one. Mild sensory changes were observed,
`but only one patient experienced grade 3/4 periph(cid:173)
`eral neuropathy with this schedu le.
`This combination and schedule have been asso(cid:173)
`ciated with a provocative level of activity. Three
`patients have achieved CRs and 20 achieved PRs,
`for an overall response rate of 85% in a patient
`population exposed to prior adjuvant, mostly an(cid:173)
`thracycline-based, chemotherapy. A confirmatory
`phase II study is presently being performed.
`
`Summary of Paclitaxel/Cisplatin Couplet Trials
`The pacliraxel/cisplarin combination has dem(cid:173)
`onstrated an encouraging level of antitumor activ(cid:173)
`ity in women with metastatic breast cancer and
`has an acceptable level of toxicity. These response
`
`3 of 7
`
`Celltrion, Inc., Exhibit 1013
`
`

`

`40
`
`ANTHONY W. TOLCHER
`
`rates occurred despite previous adjuvant chemo(cid:173)
`therapy, in many cases with anchracyclines. The
`use of G-CSF permits higher doses of the drugs
`to be delivered, but peripheral neuropathy then
`becomes a prominent dose-limiting toxicity.
`The differenc response rates in these phase II
`trials should be interpreted with caution. Results
`with the biweekly schedule generate several ques·
`tions. Is the antitumor activity schedule depen(cid:173)
`dent? A phase I/II study of biweekly paclitaxel
`alone is presently under way to determine whether
`frequent dosing of the 3-hour paclitaxel infusion
`alone is associated with a high level of activity.
`An alternate explanation for the high level of anti·
`tumor response includes the different cisplatin
`dose intensity. Nonetheless, the actual difference
`in cisplatin dose intensity between the studies is
`quite small (30 v 25 mg/m2/wk). The biweekly
`schedule also allowed treatment on day 15 if the
`granulocyte count was at least 750/µL and the
`platelets had recovered to at least 75,000/ µL.
`Given this same level of hematologic recovery,
`would a similar level of activity be observed with
`the other regimens if treatment was also initiated
`earlier than day 21? It is hoped that some of these
`questions will be answered should results of the
`confirmatory study support the biweekly paclitaxel/
`cisplatin schedule.
`
`PACLIT AXEU CYCLOPHOSPHAMIDE
`COUPLET
`
`Preclinical RatioTlllle
`
`Combinations of paclitaxel and alkylating
`agents have demonstrated additive but also antago(cid:173)
`nistic cyrotoxicity in vitro. Preclinical pacl itaxel/
`cyclophosphamide sequence data were not avail(cid:173)
`able before phase l tria ls of this combination be(cid:173)
`gan. Recently, however, in vitro results with some
`cell lines have demonstrated that the sequence of
`an alkylating agent before paclitaxel is associated
`with reduced cell kill compared with the reverse
`sequence, much like the in vitro results with the
`cisplatin/paclitaxel combination. 14 This finding
`was not universal, however; other cell lines did
`19
`not demonstrate sequence dependence. 14
`•
`
`Phase I Clinical Studies
`
`Results of three phase l stud ies are mature. The
`dose and schedules used in each of these studies
`
`are summarized in Table 3 and illustrated in
`Fig 2.
`Johns Hopkins Oncology Center trial. Kennedy
`et al initiated a phase I study of paclitaxel/cyclo(cid:173)
`phosphamide with G-CSF in patients with anthra(cid:173)
`cycline-refractory metastatic breast carcinoma. 1
`'.I
`Table 4 briefly summarizes the patient characteris(cid:173)
`tics.
`Paclitaxel was administered by a 24-hour infu(cid:173)
`sion with intravenous bolus cyclophosphamide
`(Fig 2). The elegant clinical trial design incorpo(cid:173)
`rated sequence analysis of toxicity for al l dose lev(cid:173)
`els when possible. All patients received both drug
`administration sequences. The use of G-CSF per(cid:173)
`mitted considerable dose escalation of this combi(cid:173)
`nation, with nine dose levels (paclitaxel l35 to
`200 mg/m2 and cyclophosphamide 750 to 2,000
`mg/m 2
`). Dose-limiting toxicity was neutropenia
`(one patient) and typhlitis (one patient) in two
`of four patients. The ma,'<imum tolerated dose was
`considered to be paclitaxel 200 mg/m2 and cyclo(cid:173)
`phosphamide 1,600 mg/m2 while
`the recom(cid:173)
`mended doses for phase II investigation were 200
`and 1,250 mg/m2
`respectively. Dose-limiting
`,
`thrombocytopenia was uncommon, occurring in
`on ly two patients. Myalgias and neuropachy were
`uncommon nonhemarologic dose-limiting toxici(cid:173)
`ties, occurring in only five patients. The dose-lim(cid:173)
`iting toxicity of typhlitis with this combination
`and schedule had been observed in a phase l study
`of the paclitaxel/doxorubicin combination and
`
`Table 3. Padit:axel/Cyclophosphamide
`in Breast Canc,er
`
`Dose (mg/m'}/lnfusion Length
`
`NCI
`Pacliaxel 160172 hr
`Cyclophosphamide 2,700 (divided dose)
`G-CSF
`JHOC
`Pacliaxel 200124 hr
`Cyclophosphamide 1,600
`G-CSF
`Bellinzona
`Pacliaxel 20013 hr
`Cyclophosphamide 1,250
`
`Abbreviations: NCI, National Cancer Institute: JHOC, Johns
`Hopkins Oncology Center. Bellinzona, Ospedale San Giovanni.
`Bellinzona, Switzerland.
`
`4 of 7
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`Celltrion, Inc., Exhibit 1013
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`

`

`PACLITAXEL WITH CISPLATIN OR CYCLOPHOSPHAMIDE
`
`41
`
`may represent a unique, albeit an uncommon, tox(cid:173)
`icity for paclitaxel combinations.20
`Sequence-dependent toxicities were observed.
`Paclitaxel fo llowed by cyclophosphamide was asso(cid:173)
`ciated with greater neutrophil and platelet tox icity
`compared with the alternate sequence, as con(cid:173)
`firmed by the rates of admission for febrile neutro(cid:173)
`penia (27% v 11 %, respectively). The pharmacol(cid:173)
`ogy of these agents did not differ significantly with
`either sequence. Therefore, and in contrast to the
`paclitaxel/cisplatin data, a ltered pharmacokinetics
`does not explain the observed difference in hema(cid:173)
`tologic toxicity, and a biologic explanation for se(cid:173)
`quence-dependent cytotoxicity may apply.
`ln this phase I study of heavily pretreated, doxo(cid:173)
`rubicin-refractory patients, the overall response
`rate of 28% demonstrated encouraging activity.
`Phase 11 data will clarify the true activity of this
`schedule and combination .
`Currently, the Johns Hopkins group is evaluat(cid:173)
`ing the same combination using the 3-hour pacli(cid:173)
`taxel infusion schedu le with G-CSF.
`Ospedale San Giovanni, Bellinzona, phase I trial.
`Sessa and Pagani (0. Pagani, MD, principa l inves(cid:173)
`tigator, unpublished data, July 1995) and their col(cid:173)
`leagues initiated a phase I study of pacliraxel by
`3-hour infusion combined with cyclophosphamide.
`The characteristics of the 43 patients are summa(cid:173)
`rized in Table 4. Dose levels of paclitaxel 175 to
`200 mg/m2 and cyclophosphamide 750 to 1,250
`mg/m 2 without G-CSF were explored. Further dose
`escalation ro 1,750 mg/m 2 cyclophosphamide was
`possible with the use of G-CSF. Grade 4 neutro(cid:173)
`penia for greater than 7 days limited further dose
`escalation. Nonhemarologic toxicities were nor
`dose limiting, and ryphlitis was not observed. Se(cid:173)
`quence-dependent toxicity analysis is planned but
`nor yet avai lable. However, caution is warranted
`
`Table 4. Paclitaxel/Cyclophosphamlde In Breast
`Cancer: Patient Characterist ics
`
`NCI JHOC Bell
`
`No. of patients
`Median age (yr)
`Median no. of disease sites
`No. of patients with prior chemotherapy
`Median no. o f prior chemotherapy
`regimens
`Anthracycline-containing
`Anthracycline-resistant
`
`55
`45
`2
`53
`
`2
`47
`19
`
`37
`so
`2
`37
`
`2
`37
`29
`
`43
`5 1
`2
`36
`
`-
`26
`14
`
`in interpreting the existence of sequence effects for
`the shorter paclitaxel infusion schedule. Sequence
`dependence may be less apparent with concurrent
`or near-concurrent administration of paclitaxel
`and cyclophosphamide. With such schedu les, the
`actual toxicities observed may reflect not the order
`of administration but, rather, the relatively differ(cid:173)
`ent pharmacokinetic half-lives of the two drugs
`and the sequence that this engenders.
`Preliminary activity data demonstrate objective
`responses including CRs at multiple dose levels in
`th is phase I study.
`Medicine Branch, National Cancer lnscicute phase
`I study. This phase I study (A. T olcher, MD, prin(cid:173)
`cipal investigator, unpublished data, July 1995)
`was initiated to determine the tolerability of ad(cid:173)
`ministering paclitaxel by 72-hour continuous infu(cid:173)
`sion (CIVI) in combination with high-dose cyclo(cid:173)
`phosphamide and G-CSF
`in
`the ambulatory
`setting. In vitro data suggest that paclitaxel is a
`cell cycle phase-specific cytotoxic agent. Cytotox(cid:173)
`icity in cell lines in vitro reaches a plateau at a
`threshold paclitaxel concentration beyond which
`increased pacliraxel concentrations do nor yield
`greater cell kill; however, prolonging the duration
`of drug exposure over multiple drug concentrations
`to a maximum of 72 hours has increased cell kill
`22 In the clinical setting,
`further in some assays. 2
`1.
`prolonged infusions of paclitaxel can theoretica lly
`increase the number of cancer cells exposed to
`pacliraxel during the G 2/M phase of the cell cycle,
`in which cells are most vulnerable to this agent's
`cytotoxic effects. Alkylating agents like cyclophos(cid:173)
`phamide are associated with steep dose-response
`relationships in vitro and considerable dose escala(cid:173)
`tion of this agent can be achieved clinically with
`the use of G-CSF. Divided-dose cyclophosphamide
`
`NCI
`
`P 160 mgfm2 72 hr
`C 2,700 mg/m2
`
`JHOC
`
`P 200 mg/m2 24 hr
`C 1,600 mg/m2
`
`Bellinzona P 200 mgtm2 3 hr
`C 1,250 mg/m2
`
`1
`
`2
`
`3
`
`t t
`
`t
`
`G-CSF
`---------.-
`
`1
`
`G-CSF
`
`--------------·
`
`t
`
`t
`
`• G-CSF
`
`-------------·
`
`Fig 2. T he schedule and sequence of the three phase I stud(cid:173)
`ies of paclitaxel (P) in combination with cyclophosphamide (C).
`N CI, N ational Cancer Institute; )HOC, Johns H opkins Oncol(cid:173)
`ogy Cente,r.
`
`5 of 7
`
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`

`

`42
`
`ANTHONY W. TOLCHER
`
`theoretically permits ambulatory administration of
`high doses of this agent, while reducing urotoxic(cid:173)
`ity, emesis, and the risk of cardiotoxicity. The
`schedule of administration for this study appears
`in Fig 2. This phase I study included 55 patients,
`54 of whom are evaluable for toxicity. The patient
`characteristics are summarized in Table 4. Forty(cid:173)
`seven patients had already received doxorubicin
`and 52 had received cyclophosphamide. The study
`was open to patients with metastatic breast cancer
`who had received up to two prior chemotherapy
`regimens (one adjuvant, one for metastasis) and
`the median number of prior regimens was two.
`Dose escalation was completed over 10 levels from
`a starting dose of paclitaxel 135 mg/m1 C IVl and
`cyclophosphamide 600 mg/m2 to paclitaxel 160
`mg/m2 C IVI and cyclophosphamide 3,300 mg/m 2
`•
`Dose-limiting toxicity was reached at the latter
`dose level, with two patients experiencing grade 4
`neutropenia for more than 5 days and one patient
`experiencing both this level of grade 4 neutropenia
`and platelets less than 20,000/ µL. The maximum
`tolerated dose was therefore paclitaxel 160 mg/m1
`C IVI over 72 hours and cyclophosphamide 2,700
`mg/m1 in three divided doses. Febrile neutropenia
`commonly complicated this dose-intense regimen,
`causing at least one hospitalization in 86% of pa(cid:173)
`tients; one patient died of a septic complication.
`Dose-limiting nonhematologic toxicities were
`uncommon. Diarrhea was a cumu lative toxicity,
`occurring in six patients, and may have been re(cid:173)
`lated to the use of broad-spectrum antibiotics for
`febrile neutropenia; in three patients with Clostrid(cid:173)
`ium difficile, toxin was detected. Six patients devel(cid:173)
`oped gross hematuria requiring dose reduction and
`increased hydration. In those patients whose he(cid:173)
`maturia recurred, oral mesna prevented further
`bleeding and permitted ambulatory treatment to
`be continued. Despite a premedication regimen of
`dexamethasone, diphenhydramine, and cimeti(cid:173)
`dine, five patients experienced grade 1 or 2 acute
`hypersensitivity reactions to paclitaxel. Four of
`these patients cou ld be re-treated; the other re(cid:173)
`fused further therapy. No episodes of typhlitis were
`observed with this paclitaxel/cyclophosphamide
`schedule.
`A pilot study of the sequence of paclitaxel by
`72-hour CIVI followed by a single bolus dose of
`cyclophosphamide was
`initiated
`to determine
`whether the sequential schedule was tolerable and
`comparable with the concurrenc schedule (A.
`
`Tolcher, MD, principal investigator, unpublished
`data, July 1995). Dose-limiting toxicity was ob(cid:173)
`served in three patients at the first dose level of
`paclitaxel 160 mg/m2 C IVJ followed by cyclophos(cid:173)
`phamide 1,600 mg/m2 and G-CSF. The sequential
`schedule was associated with intolerable hemato(cid:173)
`logic and gastrointestinal toxicity (grade 4 mucosi(cid:173)
`tis), despite a cyclophosphamide dose that was
`only 60% of the previous maximum tolerated dose.
`These results suggested that the sequence of pacli(cid:173)
`taxel fo llowed by cyclophosphamide was more
`toxic than the concurrent schedule of paclitaxel
`and divided-dose cyclophosphamide. Since data
`from Kennedy at al 19 demonstrated a similar find(cid:173)
`ing and no alterations in pharmacology were ob(cid:173)
`served with these two agencs, one can hypothesize
`that a perturbation of paclitaxel's cell cycle-de(cid:173)
`pendent cytotoxicity may occur to the hemato(cid:173)
`logic and gastrointestinal progenitor cells with the
`concurrent schedule, which is not seen when pacli(cid:173)
`taxel is fo llowed by cyclophosphamide. The pre(cid:173)
`clinical data suggest that this reduction in normal
`tissue toxicity may result from a reduction in the
`number of progenitor cells in the G 2/M phase,
`where paclitaxel exerts its greatest cytotoxicity. 14
`The question remains whether the schedu le and
`sequence of cyclophosphamide also alter rumor re(cid:173)
`sponsiveness to this couplet.
`In this phase I study using a spectrum of dose
`levels, the responses of 44 patients with measurable
`disease were assessed: 23 patients achieved a PR
`and one patient a CR, for an overall response rate
`of 55%. In the doxorubicin-refractory subset, seven
`(54%) of 13 patients evaluable for response ob(cid:173)
`tained an objective response (one CR and six PRs).
`In this heavily pretreated popu lation, this response
`rate is encouraging.
`
`Summary of Pacliraxel/Cyclophosphamide Couplet
`Trials
`In these three phase I studies, the paclitaxel/
`cyclophosphamide combination has demonstrated
`both an acceptable level of toxicity and encourag(cid:173)
`ing anritumor activity in metastatic breast cancer
`patients previously treated with doxorubicin and/
`or cyclophosphamide. Sequence analysis suggests
`that paclitaxel followed by cyclophosphamide is
`associated with greater hematologic toxicity com(cid:173)
`pared with either the opposite sequence or with
`concurrent adm inistration. Based on the Johns
`Hopkins data, 19 altered pharmacokinetics do not
`
`6 of 7
`
`Celltrion, Inc., Exhibit 1013
`
`

`

`PACLITAXEL WITH CISPLATIN OR CYCLOPHOSPHAMIDE
`
`43
`
`cause this sequence dependence. Whether the ad(cid:173)
`ministration sequence of paclitaxel/cyclophospha(cid:173)
`mide wi ll affect amitumor activity, as it does nor(cid:173)
`mal organ toxicity, has yet to be determined. Phase
`11 assessments of the role of this couplet, and the
`schedule and sequence effects, are necessary to de(cid:173)
`termine the place of this combination in the treat(cid:173)
`ment of both early and advanced breast cancer.
`
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