ANALYZED
`
`HEMATOLOGY I
`ONCOLOGY
`CLINICS OF
`NORTH AMERICA
`
`New Directions in Breast Cancer
`Research and Therapeutics
`
`CHARLES L. SHAPIRO, MD, and
`I. CRAIG HENDERSON, MD, GUEST EDITORS
`
`VOLUME S
`
`•
`
`NUMBER 1
`
`•
`
`FEBRUARY 1994
`
`W.B. SAUNDERS COMPANY
`A Division of Harcourt Brace & Company
`PHILADELPHIA LONDON, TORONTO MONTREAL SYDNEY TOKYO
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`W.B. SAUNDERS COMPANY
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`Hematology/Oncology Clinics of North America is covered in Excerpta Medica, Index Medicus,
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`HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA
`Volume 8-Number 1
`February 1994
`
`ISSN 0889- 8588
`
`Copyright C> 1994 by W.B. Saunders Company. All rights reserved. No part of this publi(cid:173)
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`L
`
`BREAST CANCER
`
`CONTENTS
`
`Preface
`
`Charles L. Shapiro and I. Craig Henderson
`
`Advances in Breast Cancer Research
`
`Clinical Relevance of Breast Cancer Biology
`A. M. Oza and I. F. Tannock
`
`Biological properties of breast cancer are reviewed in relation to
`their ability to provide information about etiology, prognosis, or
`response to therapy. The authors suggest guidelines for the rigor(cid:173)
`ous and systematic evaluation of biologic factors in relation to the
`prognosis and treatment of breast cancer.
`
`The Genetics of Breast Cancer
`Briggs W. Morrison
`
`Some of the genetic abnormalities that give rise to human breast
`cancer have been identified. This article reviews the biology of the
`oncogenes c-myc and neu and the antioncogene p53. Data sup(cid:173)
`porting the role of these genes in the pathogenesis of human
`breast cancer are reviewed. Potential diagnostic and therapeutic
`applications that have developed out of our understanding of the
`molecular genetics of breast cancer are also discussed.
`
`Growth Factors and Their Receptors
`Debasish Tripathy and Christopher Benz
`
`Breast cancer represents a type of malignancy that is amenable to
`therapy targeting growth factors and receptors. There is consid-
`
`HEMATOLOGY /ONCOLOGY CLINICS OF NORTH AMERICA
`
`VOLUME 8 •NUMBER 1 ·FEBRUARY 1994
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`xi
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`erable evidence that signaling mechanisms involving growth fac(cid:173)
`tors and their receptors are important in the normal development
`of breast epithelium. Dysregulation of these pathways may con(cid:173)
`tribute to the proliferative, invasive, and metastatic phenotypes of
`breast cancer cells in humans. Approaches being tested in the
`preclinical setting include antibodies or peptides that disrupt
`receptor-ligand interactions as well as other compounds that can
`interfere with downstream signalling.
`
`Angiogenesis and Breast Cancer
`Daniel F. Hayes
`
`Preclinical studies have established an association between angio(cid:173)
`genesis and the oncogenic process for many malignancies. Recent
`studies have suggested that the presence of neovascularization in
`primary breast cancer tissues is correlated with a high risk of
`distant metastases and mortality. Several angiogenic factors have
`been identified. A t least one of these, basic fibroblast growth factor
`(bFGF), can be monitored in human serum and urine, and prelim(cid:173)
`inary studies suggest that circulating bFGF levels are elevated in
`patients with breast cancer.
`
`Overview of the Biologic Markers of Breast Cancer
`Kathleen Porter-Jordan and Marc E. Lippman
`
`The prognostic potential of several of the newer biological mark(cid:173)
`ers of breast cancer are discussed, with emphasis on markers of
`tumor growth, invasion, and tumorigenesis. Reviewed are data
`supporting possible use of ErbB-2 to predict for improved re(cid:173)
`sponse to adriamycin, Hsp 27 to predict for failure of doxorubicin,
`and pS2 or EGFR to provide supplemental information predicting
`response to hormonal therapy.
`
`Estrogen Receptor Molecular Biology
`Myles Brown
`
`Recent advances in estrogen receptor molecular biology and the
`dissection of its important functional and structural domains has
`led to a greater understanding of the factors underlying the hor(cid:173)
`mone responsiveness of breast cancer. A coherent model for the
`partial agonist activity of tamoxifen has been developed. In addi(cid:173)
`tion, the potential mechanisms of tamoxifen resistance can now be
`explored at the molecular level. This has led to the development
`of pure antiestrogens that may be capable of clinical utility.
`
`51
`
`73
`
`101
`
`Advances in Therapeutics
`
`New Directions for Breast Cancer Therapeutic Research
`Michael A. Friedman
`
`113
`
`For the past two decades, attempts to improve chemotherapy for
`patients with breast cancer have emphasized the use of currently
`
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`available agents. Research by drug discovery programs of the
`National Cancer Institute has identified a number of clinically
`promising novel agents. Conceivably, within the next several
`years there could be a doubling of the chemotherapy armamentar(cid:173)
`ium for breast cancer-more than 30 active cytotoxic agents.
`
`Paclitaxel (Taxol) in Breast Cancer
`Susan G. Arbuck, Andrew Dorr, and Michael A. Friedman
`
`121
`
`Paclitaxel (Taxol) is a diterpine plant compound that was isolated
`initially from the bark of the western yew tree, Taxus brevifolia,
`but can now be produced by semisynthesis from a renewable
`source. Paclitaxel is the first new agent in the past decade to have
`confirmed single agent activity in breast cancer in excess of 50%.
`A 28% response rate has been reported in doxorubicin-refractory
`patients. Ongoing studies include attempts to combine paclitaxel
`with other drugs used for breast cancer treatment and with radia(cid:173)
`tion.
`
`Navelbine and the Anthrapyrazoles
`Alison L. Jones and Ian E. Smith
`
`This article reviews the preclinical and early clinical development
`of navelbine and the anthrapyrazoles. The :iifferences in structure
`from the "parent" compounds that may confer clinical advantages
`are discussed. The preclinical data, clinical pharmacology, and
`Phase I trials are reviewed. Further development of these drugs
`in Phase II trials and comparative studies is also discussed.
`
`Bisphosphonates in Breast Cancer Patients
`with Skeletal Metastases
`Charles L. Shapiro
`
`The utility of bisphosphonates is well established in the treatment
`of acute hypercalcemia of malignancy. Bisphosphonates may also
`decrease the complications and morbidity of skeletal metastases.
`This article emphasizes the use of bisphosphonates in breast can(cid:173)
`cer patients with skeletal metastases.
`
`Clinical Controversies and M anagement Issues
`
`Mammography in Women Under 50
`Anthony B. Miller
`
`In this article, the evidence relating to the evaluation of effective(cid:173)
`ness of early detection of breast cancer in women age 40 to 49 is
`reviewed, in light of the considerable controversy that has arisen
`over whether women in this age group should be given routine
`mammography screening. Of necessity, evidence is also provided
`on its effectiveness in older women, to facilitate comparison.
`
`CONTENTS
`
`141
`
`153
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`165
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`Hormone Replacement Therapy in Women with a History
`of Breast Carcinoma
`Claudine J. D. Isaacs and Sandra Meta Swain
`Hormone replacement therapy in women with a history of suc(cid:173)
`cessfully treated breast cancer is felt to be contraindicated. Very
`little direct information is available regarding the effect of such
`therapy in this patient population. This article reviews the evi(cid:173)
`dence both supporting and refuting a causative role for estrogen
`and progesterone in breast cancer. The majority of evidence sup(cid:173)
`ports such a role. The use of tamoxifen as an alternative treatment
`modality is examined.
`
`A Practical View of Prognostic Factors for Staging,
`Adjuvant Treatment Planning, and as Baseline
`Studies for Possible Future Therapy
`Peter M. Ravdin
`
`Recent advances in the basic sciences have led to a number of
`mechanistically important molecules being identified and meas(cid:173)
`ured in normal and neoplastic breast tissue. Although new infor(cid:173)
`mation has potential to improve prognostic assessment of breast
`cancer patients, inappropriate application can be fiscally irrespon(cid:173)
`sible and decrease the accuracy in the prognostic assessment of
`breast cancer patients.
`
`Adjuvant Therapy of Breast Cancer
`Charles L. Shapiro and I. Craig Henderson
`
`This article examines questions about adjuvant systemic therapy,
`especially in premenopausal and postmenopausal women. The
`impact of adjuvant therapy on quality of life is addressed, as is
`the role of doxorubicin in adjuvant chemotherapy. The value of
`high dose adjuvant chemotherapy and late effects of adjuvant
`therapy are also examined.
`
`The Use of Hematopoietic Growth Factors to Support
`Cytotoxic Chemotherapy for Patients with Breast Cancer
`George D. Demetri
`
`The rationale for the uses of hematopoietic growth factors in the
`treatment of breast cancer is reviewed. The historical background
`of development of these novel therapeutic agents is also summa(cid:173)
`rized as it pertains to patients undergoing myelosuppressive treat(cid:173)
`ments. Important areas of controversy in the clinical uses of he(cid:173)
`matopoietic growth factors are identified, and future research
`directions in this field are discussed.
`
`179
`
`197
`
`213
`
`233
`
`Index
`
`Subscription Information
`viH
`
`251
`
`Inside back cover
`
`CONTENTS
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`BREAST CANCER
`
`0889-8588/94 $0.00 + .20
`
`PACLITAXEL (TAXOL)
`IN BREAST CANCER
`
`Susan G. Arbuck, MD, Andrew Dorr, MD,
`and Michael A. Friedman, MD
`
`Thirty years ago, samples of Tax11s brevifolia, the Pacific yew tree, were
`collected from the old growth forests of the Pacific northwest, as part of a
`National Cancer Institute (NCI) program to screen natural products for antican(cid:173)
`cer activity. Preliminary screening indicated that an extract from the tree had
`activity against several murine and human tumor cell lines, including the human
`MX-1 breast cancer xenograft model.30· 57 Paclitaxel, the active component of the
`extract, was isolated in pure form in 1969, and its structure was described by
`Wani, Taylor, and Wall57 in 1971 (Fig. 1). Paclitaxel is a complex diterpene with
`a taxane ring system composed of a four-membered oxetane ring and an ester
`side chain at position C-13 (necessary for cytotoxic activity in mammalian cells).31
`Paclitaxel has a novel mechanism of action. Although relatively little is
`known about mechanisms of clinical resistance in human tumors, a great deal is
`known about clinical toxicity and clinical activity. This article summarizes se(cid:173)
`lected background information and the results of the clinical breast cancer trials.
`Many questions regarding how to optimally incorporate this new active agent
`into treatment for breast cancer patients remain unresolved; studies addressing
`these questions will be described.
`
`MECHANISM OF ACTION
`
`Schiff and Horwitz"2· 43 described paclitaxel's unique mechanism of cytotox(cid:173)
`icity in 1979. In contrast to other antimitotic agents, such as vinca alkaloids and
`colchicine, which inhibit the polymerization of tubulin, paclitaxel promotes the
`assembly of tubulin and stabilizes the resulting microtubules.
`Microtubules are important structural elements in eukaryotic cells. In addi(cid:173)
`tion to forming the mitotic spindle and channels for neurotransmitter secretion,
`
`From the Cancer Therapy Evaluation Program, Division of Cancer Treatment, National
`Cancer Institute, Bethesda, Maryland
`
`HEMA TO LOGY /ONCOLOGY CLIJ\TJCS OF NORTH AMERICA
`
`VOLUME 8 • NUMBER 1 • FEBRUARY 1994
`
`121
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`122
`
`ARBUCK ct al
`
`I
`
`I
`
`r--------------·
`:~i
`: ,
`I
`:
`! ~Cf{O~H ! o
`'----------- --"
`,, ..
`~H
`'
`I/
`
`3'
`
`0
`
`0
`
`:;;;.-
`
`f1t1o
`
`0
`
`PACLITAXEL (TAXOL® )
`
`I
`I
`I
`
`'
`
`r--}oc-----------1
`::;...-
`:
`ONH :
`L---(31:0~
`
`I
`I
`I
`
`: :
`
`I Q
`
`OH
`
`ij
`
`&o 0
`I
`
`DOCETAXB.. (TAXO~)
`
`Figure 1. The structures of paclitaxel and docetaxel. The paclitaxel and docetaxel molecules
`differ at two sites (shown within the boxes).
`
`they regulate cell shape, anchor surface receptors in the plasma membrane, and
`affect motility of cilfa. ln the presence of paclitaxel, tubulin polymerization is
`promoted.12• 19· •1 ~>. 53 Thus, the normal equilibrium of assembly and disassembly
`is shifted toward microtubule formation. Disruption of this equilibrium interferes
`with cell division and normal cellular activities involving microtubules.
`Paclitaxel is a potent inhibitor of eukaryotic cell replication, and it blocks
`cells in late G2-mitotic phase of the cell cycle.42 Mitotic arrest has been observed
`in normal esophagus, stomach, smalJ intestine, colon, liver, skin, bone marrow,
`ahd testis specimens obtained at autopsy from a patient who received paclitaxel
`11 days before death.20
`
`PHARMACOLOGY
`Paclitaxel disposition is characterized by a biexponential process, with a beta
`half-life of 4 to 6 hours. Pharmacokinetic parameters for 3, 6, 24, and 96 hour
`
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`PACLITAXEL (TAXOL) IN BREAST CANCER
`
`123
`
`administration schedules are summarized in Table 1. Peak plasma concentrations
`achieved with all schedules are within the range of drug concentrations reported
`to induce biologic and cytotoxic effects in vitro (0.01 to greater than 1 µ,M).'· ~
`Paclitaxel is extensively bound to plasma proteins (95% to 98%).22
`63 Neverthe(cid:173)
`26
`•
`•
`less, the drug is readily eliminated from plasma.26
`62
`63
`•
`•
`Renal clearance has accounted for an insignificant proportion of total sys(cid:173)
`temic clearance (approximately 5%). The principal mechanisms of systemic clear(cid:173)
`ance have not been defined precisely, suggesting that metabolism, biliary excre(cid:173)
`tion, or extensive tissue binding are responsible for the bulk of systemic
`clearance. High paclitaxel concentrations and hydroxylated metabolites have
`been found in both rat and human bile.28•
`67
`Recently, two groups reported that clearance decreased with increasing dose,
`indicating that paclitaxel elimination was nonlinear.23• 50 With nonlinear elimina(cid:173)
`tion, a small increase in dose or decrease in infusion duration can result in a
`large increase in total drug exposure and toxicity.
`With evidence of increasingly broad clinical activity, a phase I trial was
`initiated to evaluate the toxicity and pharmacokinetics of paclitaxel in patients
`with abnormal liver function. This study will determine whether paclitaxel can
`be used safely in patients with hepatic impairment and, if so, determine neces(cid:173)
`sary dose adjustments.
`
`TOXICITY
`
`Leukopenia
`
`Phase I studies of paclitaxel demonstrated that leukopenia was frequent and
`dose-limiting on all schedules evaluated, whereas thrombocytopenia was rare.
`When administered over 24 hours, doses of 135 to 250 mg/m2 caused grade III
`and IV neutropenia in the majority of patients, usually 8 to 11 days after drug
`administration. Recovery usually occurred by day 15 to 21, permitting re-treat(cid:173)
`ment every 3 weeks.35 Recent data indicate that in addition to being dose-depen(cid:173)
`dent, neutropenia is schedule-dependent, with less neutropenia occurring on the
`3-hour schedule compared with the 24-hour schedule.5' Neutropenia does not
`worsen with repetitive dosing.
`
`Hypersensitivity Reactions
`
`Because of its limited aqueous solubility, paclitaxel is formulated in Cremo(cid:173)
`phor EL and ethanol. Cremophor EL has been associated with bronchospasm,
`hypotension, and other manifestations of hypersensitivity, particularly following
`
`Table 1. PACLITAXEL PHARMACOKINETIC PARAMETERS*
`
`Schedule
`(hr)
`
`3
`6
`24
`96
`
`f1f2~
`(hr)
`
`9.7
`6.4
`3.9
`
`Cl
`(mUmin/m2)
`
`VDss
`(Um')
`
`130-200
`195
`993
`478
`
`59
`55
`
`Cmax•
`(µ.M)
`
`7-12.5
`3-4
`0.7-0.9
`O.OS-0.07
`
`Ref. No.
`
`44
`26,63
`62
`64
`
`•At doses recommended for phase II evaluation
`T1/2p = beta half-life; Cl = clearance; VDss = volume of distribution; Cmax = peak plasma
`conc,entration
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`124
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`ARBUCK et al
`
`rapid administration.JO Although Cremophor EL is used to formulate other drugs,
`the paclitaxel formulation requires the highest Cremophor EL concentration per
`dose.JO
`Hypersensitivity reactions were reported in as many as 18% of patients in
`early phase I trials. Allergic manifestations varied in severity and included ana(cid:173)
`phylaxis, dyspnea, hypotension, flushing, urticaria, rash, and pruritus.61 There(cid:173)
`fore, a routine premedication regimen was adopted: oral or intravenous dexa(cid:173)
`methasone, 20 mg (6 and 12 hours pre-treatment); diphenhydramine, 50 mg; and
`an I-12 blocker (usually cimetidine, 300 mg) intravenously 30 minutes before
`paclitaxel. With routine premedication paclitaxel can be administered safely over
`3 as well as 24 hours.51 In one trial, severe hypersensitivity reactions occurred in
`2.2% of patients treated on the 3-hour schedule and in 1.2% of those on the 24-
`hour schedule.
`Although Cremophor EL may be responsible for the hypersensitivity phe(cid:173)
`nomena, some contribution of paclitaxel itself is possible. Anaphylaxis and angio(cid:173)
`edema have been reported in a teenager who chewed yew needles.6 Hypersensi(cid:173)
`tivity reactions also occur in patients who receive docetaxel (Taxotere), a
`semisynthetic analogue of paclitaxel. that is partially synthesized from 10-deace(cid:173)
`tylbaccatin Ill, isolated from the needles of the European yew, TnXlls bnccatn.32
`Docetaxel is formulated with polysorbate (Tween-80), which also has been asso(cid:173)
`ciated with hypersensitivity and skin reactions. At present, it is not possible to
`determine the relative contribution of the taxanes versus the formulations to the
`hypersensitivity reactions.
`
`Neurotoxlclty
`
`Because neutropenia was dose-limiting in phase I trials, granulocyte colony(cid:173)
`stimulating factor (G-CSF) was added in an effort to administer higher doses of
`paclitaxel.39 At doses of 250 mg/m2 or higher every 3 weeks, peripheral neurop(cid:173)
`athy, characterized primarily by sensory symptoms such as paresthesias and
`numbness in a stocking-glove distribution, become dose-limiting. Symptoms
`often begin 24 to 72 hours after treatment. Although neurotoxicity is usually
`reversible, it is also cumulative. In some cases recovery requires many months.
`Patients who develop grade 3 or worse neuropathy (severe objective sensory
`loss, paresthesias, or weakness with functional impairment) can generally be re(cid:173)
`treated at a lower dose once they recover to grade 1 or less neurotoxicity (mild
`paresthesias, or loss of deep tendon reflexes or subjective weakness with no
`objective findings).
`Transient myalgias are frequent occurrences following moderate to high
`doses of paclitaxel. Typically, patients develop discomfort 2 to 3 days following
`treatment, with resolution in 5 or 6 days. Some investigators have noted more
`troublesome myalgia in association with G-CSF administration.33
`Motor neuropathy has also been reported, generally as a consequence of
`higher paclitaxel doses, and in patients with other risk factors for neuropathy.38
`Possible autonomic neuropathy manifested as hypotension has been reported
`rarely.3•
`37
`
`Cardiac Toxicity
`
`Concerns about anaphylaxis early in clinical development led investigators
`at johns Hopkins Cancer Center to perform continuous cardiac monitoring dur-
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`P ACUT AXEL (f AXOL) £N BREAST CANCER
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`125
`
`ing paclitaxel administration. Sinus bradycardia was documented in 29% of 40
`patients but was rarely clinically significant.27 Other cardiac changes were docu(cid:173)
`mented in 5% of 144 monitored patients. These events included heart block,
`nonsustained ventricular tachycardia, other ventricular and atrial arrhythmias,
`myocardial ischemia, and infarction. A causal relationship between paclitaxel
`and most ischemia and tachyarrhythmia episodes is uncertain.3•
`37 Most arrhyth(cid:173)
`mias were asymptomatic.
`Once cardiac events were reported, patients with potential cardiac risk fac(cid:173)
`tors were excluded from paclitaxel trials to maximize the safety of patients
`receiving this investigational drug. Patients expected to be intolerant of bradycar(cid:173)
`dia, including those with a history of congestive heart failure or angina, and
`those who had sustained a myocardial infarction within 6 months, were deemed
`ineligible. Patients with arrhythmias and those on medications known to alter
`cardiac conduction, including digoxin, calcium channel blockers, and beta-adre(cid:173)
`nergic blockers, were also frequently excluded. The actual risk associated with
`these clinical circumstances remains unknown.
`Toxicology reports from human yew poisonings and structural similarities
`of paclitaxel with taxine B, a known cardiac toxin, support the conclusion that
`paclitaxel has cardiac effects.3 Nevertheless, most of the arrhythmias are asymp(cid:173)
`tomatic, and the incidence of cardiac events is very low in studies performed
`without routine continuous cardiac monitoring. Based on experience to date,
`patients without obvious risk factors do not require continuous cardiac monitor(cid:173)
`ing. Current data are insufficient to make recommendations for patients with
`significant cardiac risk factors, because they have been excluded from most
`paclitaxel trials. In the absence of such information, a treating physician should
`consider potential risks and potential benefit for each patient. Careful vigilance
`by treating physicians and continued reporting of adverse cardiac events to the
`National Cancer Institute (NCI) for NCI-sponsored trials, and to the Food and
`Drug Administration (FDA) when patients have been treated with commercial
`drug, should generate additional information to help determine whether such
`patients are at increased risk of adverse cardiac events or if the concern is
`unwarranted.
`
`Other Toxicities
`
`Complete or nearly complete alopecia occurs in all patients treated with
`paclitaxel. Fatigue and arthralgia, in conjunction with myalgia, are common at
`the higher doses. Mucositis is also frequent at high doses and appears to be more
`common on the 96-hour continuous infusion schedule.65 Nausea, vomiting, and
`diarrhea occur but are rarely severe. Taste and mood alterations, hepatic enzyme
`abnormalities, and seizures have been reported rarely.
`lf infiltration occurs during administration, taxol may cause local erythema,
`tenderness, and induration. Rare reports of local ulceration or cellulitis following
`infiltration have been received. These complications healed with conservative
`management. Cremophor is a known vesicant and may contribute to local reac(cid:173)
`tions.
`
`PHASE II CLINICAL TRIALS IN BREAST CANCER PATIENTS
`
`ln 1986, the first phase II breast cancer trial was initiated at the MD Ander(cid:173)
`son Cancer Center. Twenty-five patients who had received no more than one
`
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`126
`
`ARBUCK et al
`
`prior chemotherapy regimen (as adjuvant therapy or for metastatic disease) were
`treated with paclitaxel by 24-hour infusion every 3 weeks18 (Table 2). Eighteen
`patients were treated with 250 mg/m2, and seven received 200 mg/m2 (due to
`
`predicted poor hematologic tolerance). Fourteen patients had received prior ad(cid:173)
`juvant therapy, and 11 had received one combination chemotherapy regimen for
`metastatic disease. The objective response rate was 56% (including 12% complete
`responses). The investigators noted that in only two patients (8%) did paclitaxel
`fail to cause any regression or stabilization of tumor.
`The median time to best response was 3.5 months (range, 1 to 7 months),
`and the median duration of response was greater than 10 months.'5 The median
`time to disease progression was 9 months (range, 5 to 13+ months), and the
`median survival was 24 months (range, 5 to 34 + months).16
`Dose reductions were required for a neutrophil nadir of less than 250/µ.L or
`for infection associated with granulocytopenia. Most patients had grade 4 neutro(cid:173)
`penia; the median duration was 7 days. Thirty-six percent of patients had febrile
`neutropenia. 15 The median administered dose was 200 mg/m2
`• In future studies
`the investigators recommended dose reductions for febrile neutropenia and not
`for neutropenia in the absence of clinical consequences. They also suggested
`evaluation of hematologic growth factors to determine whether the severity and
`duration of granulocytopenia could be reduced.
`These impressive results stimulated a second phase 11 trial in breast cancer
`at Memorial Sloan-Kettering Cancer Center (MSKCC)." ln this study, eligibility
`was restricted to patients who had no prior chemotherapy for metastatic breast
`cancer. This study differed in that all patients began treatment with paclitaxel,
`
`250 mg/m2, and all patients received G-CSF routinely with each cycle. However,
`dose reductions were still mandated for a neutrophil nadir less than 250/µ.L.
`Twenty-eight patients were entered. Sixty-one percent had received prior
`adjuvant chemotherapy, with a median time interval from completion of adju(cid:173)
`vant therapy to study entry of 20 months (range, 12 to 47 months). Eighty-two
`percent had two or more sites of metastatic disease; 39% had at least three sites.
`The results of this trial were similar to those of the MD Anderson study (see
`Table 2). Sixty-two percent of 26 evaluable patients responded (including 8%
`with complete responses). Responses were observed in all sites of metastatic
`disease, including previously irradiated chest wall disease in one patient. An(cid:173)
`other patient experienced reossification of bony metastases with associated pain
`relief. The median time to first objective response was 6 weeks (range, 1 to 14
`weeks). Because the protocol called for drug discontinuation two cycles beyond
`best response, the response duration on this trial could not be determined; most
`patients proceeded directly to alternative therapies, including high-dose chemo(cid:173)
`therapy with autologous bone marrow support.
`Despite the routine administration of G-CSF in this study, dose reductions
`were necessary for the second cycle in 12 of 26 patients, primarily for granulocyte
`nadir counts less than 250/ µ.L. Febrile neutropenia occurred in 6 of 28 patients
`(21%). G-CSF did not ameliorate the neutrophil nadir, which occurred approxi(cid:173)
`mately 1 week after paclitaxel; however, the median time to recovery to more
`than 500 neutrophils/µ.L was 3.5 days (range, 1 to 8 days), compared with 7 days
`in the previous study without G-CSF."
`These two phase II trials demonstrated paclitaxel's antitumor activity in a
`defined subset of patients with metastatic breast cancer. Both studies were per(cid:173)
`formed in patients with good performance status and organ function, and with
`minimal or no prior treatment for advanced disease. Although these single-agent
`response rates are among the best that have been reported, combination therapies
`also produce similar or sup~rior complete and overall response rates. Further-
`
`12 of 26
`
`Celltrion, Inc., Exhibit 1024
`
`

`

`53 (28-77)
`
`33 (13-59)
`26 (14-40)
`62 (41-80)
`56 (35-76)
`
`%CR+ PR
`
`(95% Cl)
`
`26 (18-35)
`
`27
`
`9
`
`5
`6
`13
`13
`11
`
`NA = not available; G-CSF = granulocyte colony-stimulating factor; CR a complete response; PR = partial response: Cl = confidence interval
`§Patients with predicted poor hematologic tolerance received lower starting dose
`;Preliminary report
`tPrlor therapy refers to the number of prior chemotherapy regimens for metastatic disease
`·Paclitaxel was administered by 24-hour infusion unless otherwise stated
`
`~
`
`3
`
`0
`
`0
`0
`0
`3
`3
`
`117
`
`17
`NA
`5
`18
`51
`26
`25
`
`417
`
`22
`267
`NA
`NA
`51
`28
`25
`
`S1 (77%)
`
`S1 (6 resistant)
`
`~1 (all)
`<!2 (all)
`2 (all)
`~3 (all)
`~2 (all)
`O(NA)
`
`175(3hr)
`
`135 (3 hr)
`
`140 + G-CSF [96 hr)
`
`175
`
`200 + G·CSF
`250 + G-CSF
`
`250 (200)§
`
`150 (135)§
`150 (135)§
`
`Study Groupt29
`Bristol-Myers Squibb
`Phase Ill
`NCI Medicine Branch:r'
`NCI Treatment Referral Center:t:
`MD Anderson;•s
`MO Anderson;•s
`MSKCCt'7
`MSKCC33
`MD Anderson"
`Phase II
`
`PR
`
`CR
`
`No. Entered No. Evaluable
`
`Responses
`
`No.
`
`(Prior Anthracycline)
`Prior Chemotherapyt
`
`Dose (mg/m2)'
`
`Institution (Ref.)
`
`Table 2. PACLITAXEL RESPONSE RATES IN METASTATIC BREAST CANCER
`
`13 of 26
`
`Celltrion, Inc., Exhibit 1024
`
`

`

`128
`
`ARBUCK et al
`
`more, few other drugs have been evaluated as single agents in patients with so
`Jjttle prior chemotherapy.
`These promising results led to additional studies to evaluate paclitaxel's
`antitumor activity in other patient populations, and to explore combination ther(cid:173)
`apies that might produce higher response rates (especially complete responses).
`
`Paclltaxel In Patients with Refractory Metastatic Breast
`Cancer
`
`Table 2 also s ummarizes preliminary results of phase IJ trials in more heav ily
`pretreated patients. In the second MSKCC study, patients who had received at
`least two prior regimens for metastatic disease (including doxorubicin or mitox(cid:173)
`antrone) were treated with paclitaxel, 200 mg/m1 every 21 days.47 G-CSF was
`administered on days 3 to 10. The median age of patients entered on this trial
`was 47 years, with a median Karnofsky performance status of 70 (range, 60 to
`90). ln an interim report of the data as of November 1992, 13 of 51 patients (25%)
`had partial responses, with a median response duration of 16 + weeks (range, 4
`to 28 + weeks). The investigators noted that responses were continuing to evolve
`in 16 patients. The median number of disease sites in this study was three {range,
`one to seven sites). Forty-four of 51 patients had multiple sites of metastasis. The
`distribution of sites of metastasis was bone, 47%; lymph nodes, 43%; liver, 33%;
`skin and soft tissue, 47%; and lung or pleura, 45%. Responses were seen in all
`sites of measurable disease.
`In this second MSKCC trial and in subsequent trials at that institution, the
`paclitaxel dose was decreased for episodes of febrile neutropenia, but not for a
`predetermined degree or duration of neutropenia. Nevertheless, 47% of 51 pa(cid:173)
`tients required a dose reductio n. ln this more heavily pretreated population, nine
`patients had febrile neutropenia, four had grade 3 or 4 mucositis,