Phase II and Pharmacologic Study of Docetaxel as Initial
`Chemotherapy for Metastatic Breast Cancer
`
`By Clifford A. Hudis, Andrew D. Seidman, John P.A. Crown, Casilda Balmaceda, Ronnie Freilich,
`Theresa A. Gilewski, Thomas B. Hakes, Violante Currie, David E. Lebwohl, Jose Baselga, George Raptis, Marc Gollub,
`Marie Robles, Rene Bruno, and Larry Norton
`
`Purpose: Because docetaxel (Taxotere, RP 56976;
`Rhone-Poulenc Rarer, Antony, France) appeared to be
`active against breast cancer in phase I trials, we per-
`formed this phase II study.
`Patients and Methods: Thirty-seven patients with
`measurable disease were enrolled. Only prior hormone
`therapy was allowed, as was adjuvant chemotherapy
`completed a- 12 months earlier. Docetaxel 100 mg/m2
`was administered over 1 hour every 21 days. Diphenhy-
`dramine hydrochloride and/or corticosteroid premedi-
`cation was added after hypersensitivity-like reactions
`(HSRs) were seen in two of the first six patients. Pharma-
`cokinetic studies were performed during cycle 1 for cor-
`relation with toxicity.
`Results: Thirty-seven patients were assessable. Nine-
`teen (51%) required dose reductions, usually for neutro-
`penic fever. The median nadir WBC count was 1.4 x 103/
`/AL. HSRs were noted in 20 patients (54%). At a median
`cumulative dose of 297 mg/m2 (range, 99.6 to 424.5
`mg/m2), 30 patients (81%) developed fluid retention, for
`which 11 (30%) subsequently stopped treatment. The
`
`CHEMOTHERAPY AGENTS, alone or in combina-
`
`tion, can induce objective tumor regression and
`symptom palliation for many patients with metastatic
`breast cancer. Unfortunately, these responses are almost
`always of limited duration and cure is exceedingly rare.'
`Recently, a novel diterpene, paclitaxel (Taxol; Bristol-
`Myers Squibb, Princeton, NJ), derived from the bark of
`the western yew, Taxus brevifolia, was found to be active
`in the treatment of metastatic breast cancer.2'3 Unlike the
`other microtubule toxins in clinical use, such as vincris-
`
`From the Breast and Gynecological Cancer Medicine Service,
`Division of Solid Tumor Oncology, Department of Medicine, and
`Departments of Neurology, Radiology, and Biostatistics, Memorial
`Sloan-Kettering Cancer Center; Department of Medicine, Cornell
`University Medical College, New York, NY; and Department of Drug
`Metabolism and Pharmacokinetics, Rhone-Poulenc Rorer, Antony,
`France.
`Submitted March 13, 1995; accepted August 3, 1995.
`C.A.H. and J.P.A.C. are recipients of American Cancer Society
`Career Development Awards; A.D.S. and J.B. are recipients of
`American Society of Clinical Oncology Career Development
`Awards.
`Address reprint requests to Clifford A. Hudis, MD, Memorial
`Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY
`10021.
`© 1996 by American Society of Clinical Oncology.
`0732-183X/96/1401-0009$3.00/0
`
`first-cycle plasma area under the concentration-time
`curve (AUC) did not correlate with toxicity, although an
`ineligible patient with hepatic metastases (pretreatment
`bilirubin level 1.8 mg/dL) had an elevated AUC and died
`of toxicity. Responses were seen at all sites. On an intent-
`to-treat basis, there were two (5%) complete responses
`(CRs) and 18 (49%) partial responses (PRs). The overall
`response proportion (CRs plus PRs) was 54% (95% con-
`fidence interval, 37% to 71%). The median time to re-
`sponse was 12 weeks (range, 3 to 15) and the median
`duration was 26 weeks (range, 10 to 58+).
`Conclusion: Docetaxel is active for metastatic breast
`cancer. Neutropenia and fluid retention are dose-lim-
`iting. The AUC did not predict toxicity, but caution is war-
`ranted when treating patients with liver dysfunction. An
`understanding of the pathophysiology of the fluid reten-
`tion may facilitate prevention. Frequent HSR may war-
`rant prophylactic premedication.
`J Clin Oncol 14:58-65. © 1996 by American So-
`ciety of Clinical Oncology.
`
`tine or vinblastine, taxanes promote the formation of tu-
`bulin dimers and stabilize microtubules against depoly-
`merization.4 Through various mechanisms, this results in
`growth inhibition and loss of cell viability. In recent phase
`II trials, the overall response rate for paclitaxel following
`little or no prior therapy for metastatic breast cancer was
`as high as 56% to 62%, but lower in those with more
`extensive prior treatment.2,3,5
`Partly because of earlier concerns regarding the long-
`term availability of paclitaxel, which has been historically
`derived from the bark of mature yew trees, there has been
`extensive effort directed at identifying taxane analogs de-
`rived from renewable resources. Several years ago, re-
`searchers were able to prepare a semisynthetic taxane
`using a precursor extracted from a renewable resource:
`the needles of the European yew, Taxus baccata. This
`drug, docetaxel, has been shown to have in vivo activity
`against a variety of tumors and to have an acceptable
`toxicity profile in animals.' Its mechanism of action is
`similar or identical to that of paclitaxel in that it enhances
`microtubule assembly and inhibits the depolymerization
`of tubulin, which leads to intracellular bundling of micro-
`tubules and M-phase cell-cycle blockade. 7' 8
`Five human phase I studies have been performed. The
`highest maximum-tolerated dose (MTD) was seen using
`a 1-hour infusion schedule and the greatest dose-intensity
`was achieved using an every-3-week administration
`
`58
`
`Journal of Clinical Oncology, Vol 14, No 1 (January), 1996: pp 58-65
`
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`
`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`MYLAN - EXHIBIT 1048
`Mylan Laboratories Limited v. Aventis Pharma S.A.
`IPR2016-00712
`
`

`

`DOCETAXEL IN METASTATIC BREAST CANCER
`
`schedule. A dose of 100 mg/m 2 over I hour every 3
`weeks, one level below the highest dose reached using
`this schedule, was recommended for phase II testing.9
`Because testing new agents in extensively pretreated
`patients can make the demonstration of efficacy more
`difficult, and because there is no initial therapy for meta-
`static breast cancer with high likelihood of complete re-
`sponse (CR), we chose to study minimally pretreated pa-
`tients who had not yet received chemotherapy
`for
`metastatic disease.
`This phase II study was designed primarily to estimate
`the major objective response proportion and duration of
`response to intravenous (IV) docetaxel 100 mg/m2 every
`21 days as first chemotherapy for patients with metastatic
`breast cancer. We also sought to determine the qualitative
`and quantitative toxicities associated with the administra-
`tion of this agent, as well as their reversibility, and to
`correlate the pharmacologic profile of docetaxel with cy-
`cle 1 toxicity.
`
`PATIENTS AND METHODS
`
`Eligibility Criteria
`Eligibility criteria included the following: nonlactating female pa-
`tients, age > 18 years; nonchildbearing potential or using adequate
`contraception with a negative pregnancy test at study entry; histolog-
`ically confirmed metastatic breast cancer; metastatic or locally ad-
`vanced and inoperable disease; bidimensionally measurable and non-
`irradiated indicator lesions; life expectancy Ž 12 weeks; Karnofsky
`performance status - 60%; WBC count > 3,500 cells/pL, absolute
`neutrophil count (ANC) - 2,000 cells/pL, platelet count Ž 100,000
`cells/pL, creatinine concentration - 2.0 mg/dL, and bilirubin level
`- 1.5 mg/dL; and stable heart rhythm, no unstable angina, no clinical
`evidence of congestive heart failure. Previous therapy was allowed
`only as follows: prior hormone therapy as adjuvant treatment and/
`or as treatment for metastatic disease must have been stopped at
`least 1 month before protocol entry; adjuvant chemotherapy had to
`have been completed at least 12 months before protocol entry and
`could not have required bone marrow or peripheral-blood stem cell
`transfusion; and radiotherapy that involved up to 10% of the bone
`marrow was allowed, but not to a site used to assess response unless
`a new lesion had subsequently developed in the field. Exclusion
`criteria included the following: clinically evident brain metastases;
`history of prior malignancy except completely excised in situ carci-
`noma of the cervix or nonmelanoma skin cancer; other serious ill-
`ness; current symptomatic grade II or greater peripheral neuropathy;
`or concomitant biphosphonate use, use of scalp-cooling device, or
`use of corticosteroids within 30 days of beginning protocol therapy.
`The protocol was approved by the institutional review board at Me-
`morial Hospital, and written informed consent was required before
`protocol therapy was begun.
`Measurable disease was defined as tumor masses with identifiable
`diameters measurable in two dimensions on physical examination,
`radiograph, or ultrasound. To be considered measurable, computed
`tomography (CT) and ultrasound-measured lesions had to be at least
`2.0 X 2.0 cm, and chest x-ray and skin or lymph node lesions
`measured by physical examination had to be at least 1.0 x 1.0
`
`59
`
`cm. Pulmonary lymphangitic metastases, bone lesions, malignant
`effusions, tumor markers, and abnormal liver function tests did not
`constitute measurable disease. Any other nonmeasurable lesions
`were recorded as assessable or nonassessable and monitored. All
`responses were reviewed and confirmed by a panel of outside physi-
`cians, including medical oncologists and radiologists.
`
`Treatment Plan
`
`Study drug. Docetaxel (Taxotere, RP 56976) was supplied by
`Rhone-Poulenc Rorer (Antony, France) as a concentrated sterile so-
`lution that contained a 40-mg/m2 dose in polysorbate 80 in a 15-
`mL clear-glass vial with a stopper and an aluminum cap. Each vial
`contained 2 mL of injectable solution. Vials were packed in boxes
`of 50, labeled in an open manner, and stored protected from light
`at 41C.
`The initial dosage of docetaxel was 100 mg/m2, administered as
`an IV infusion over 1 hour repeated at 21-day intervals. There was
`no dose escalation; however, dose reductions for all subsequent treat-
`ment cycles were made based on hematologic and nonhematologic
`toxicities using the National Cancer Institute common toxicity crite-
`ria. Treatment could also be delayed up to 1 week to allow recovery
`from acute toxicity. A maximum of two dose reductions was allowed
`per patient (100 to 75 mg/m2 to 55 mg/m2). Patients were taken off
`study if they did not recover sufficiently to receive treatment within
`35 days from their prior dosage.
`Premedication. Initially, premedications were not used. How-
`ever, after we observed acute hypersensitivity reactions (HSRs) in
`two of the first six patients, a variety of pretreatment regimens that
`incorporated diphenhydramine, corticosteroids, and cimetidine were
`used. In case of acute HSR, diphenhydramine 50 mg IV could be
`administered and it could also be repeated as prophylaxis if the
`docetaxel infusion was interrupted and then restarted. In such cases,
`the recommended treatment also included dexamethasone 10 mg IV
`at least 30 minutes before resumption of the docetaxel infusion.
`During the first 15 to 30 minutes of docetaxel infusion, a physician
`or a chemotherapy nurse remained at the bedside. Blood pressure
`was monitored every 15 minutes during the hour of the infusion.
`Duration of therapy. After the initial dose of docetaxel, we
`planned to administer at least one additional treatment unless disease
`progression (PD) or intolerable (grade 3 to 4) nonhematologic toxic-
`ity precluded further treatment. We planned to continue treatment
`until dose-limiting toxicity or PD occurred.
`
`Pretreatment Evaluation
`
`A complete history and physical examination were performed
`before the first cycle of therapy. These included height, weight,
`vital signs, performance status, tumor measurements, and detailed
`neurologic examination with quantitative vibration and thermal sen-
`sory testing. Laboratory studies included a complete blood cell
`(CBC) count with differential and platelet count, prothrombin time
`(PT)/partial thromboplastin time (PTT), and measurements of serum
`chemistry (AST, alkaline phosphate, total bilirubin, and lactate dehy-
`[LDH]), serum creatinine, carcinoembryonic antigen
`drogenase
`(CEA) and CA 15-3, and serum beta-human chorionic gonadotropin
`(P-HCG; if indicated to rule out pregnancy). An ECG and postero-
`anterior and lateral chest radiograph were required. If needed to
`evaluate bidimensionally measurable disease, CT scan, magnetic
`resonance imaging (MRI), and/or ultrasound were performed. Bone
`scans were performed if clinically warranted, but were not used to
`monitor measurable disease.
`
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`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`

`

`60
`
`Evaluation During Treatment
`At the end of every cycle, on day 1 (before beginning the infusion
`for the next cycle), a repeat history and physical examination, which
`included weight, vital signs, performance status, and tumor measure-
`ments, was performed. Neurologic evaluation that included a symp-
`tom-evaluation questionnaire and detailed neurologic examination
`with quantitative vibration and thermal sensory testing was per-
`formed again during the first cycle, and a full neurologic examination
`was performed every other cycle. The chest x-ray, toxicity assess-
`ment, and laboratory studies listed earlier (excluding 6-HCG) were
`repeated. During the first two cycles only, a CBC count with differ-
`ential was performed twice per week; for subsequent cycles, it was
`performed weekly. If tumor measurements were only obtainable by
`imaging study (CT, MRI, ultrasound, or radiograph), these studies
`were performed every 6 weeks (two cycles). Patients with cutaneous
`lesions were to have serial photographic documentation, along with
`physical examination measurements, whenever possible. Three
`weeks after the final treatment cycle, the history and physical exami-
`nation and all laboratory testing except for the 3-HCG were repeated.
`
`Criteria for Response
`CR was defined as the disappearance of all clinical evidence of
`tumor by physical examination or imaging studies for a minimum
`of 4 weeks. Partial response (PR) was defined as a -- 50% reduction
`in the sum of the products of the biperpendicular diameters of all
`measurable lesions, without the appearance of new lesions, for at
`least 4 weeks. When there were multiple sites of metastases, the
`largest masses (up to five) were considered as the index lesions.
`Stable disease included regression that did not meet the criteria for
`CR or PR. PD was defined as the appearance of any new lesions,
`an increase by
`- 25% of an indicator lesion or the sum of the
`product of the biperpendicular diameters of the measured lesions,
`or any increase in the estimated size of a nonmeasurable lesion.
`
`Pharmacokinetic Studies
`
`During the first cycle, a limited-sampling strategy was used to
`allow us to relate interpatient pharmacokinetic variability to various
`pathophysiologic covariates, to generate individual estimates of sys-
`temic exposure to docetaxel (determine the areas under the plasma
`concentration versus time curve [AUC]), and to use these estimates
`as prognostic factors for toxicity. The design was based on popula-
`tion pharmacokinetic parameter estimates obtained from phase I
`data.' 4 Four 3-mL heparinized samples were obtained on the first
`day of the first cycle of docetaxel administration for each patient.
`Subsequent sampling was performed according to one of four ran-
`domly assigned pharmacokinetic protocols. Each sample was centri-
`fuged within 30 minutes of collection at 3,000 rpm for 15 minutes
`and the plasma was removed to a plastic tube, labeled, flash-frozen,
`-20 0C for shipment to Rhone-Poulenc Rorer for
`and stored at -
`analysis. Docetaxel was assayed using high-performance liquid chro-
`matography and UV detection after solid-phase extraction."- Individ-
`ual estimates of docetaxel clearance were obtained using bayesian
`estimation implemented in the NONMEM program.' These esti-
`mates allowed computation of the plasma AUC.
`
`HUDIS ET AL
`
`Because therapeutic responses were seen, accrual was extended to
`estimate the response rate better. Response and survival determina-
`tions were measured from the date of initiation of docetaxel. All
`responses were reviewed by a panel of outside experts.
`Pharmacology/toxicity. The estimate of the Pearson correlation
`coefficient was used to examine relationships between toxicity and
`the AUC.
`
`RESULTS
`
`Demographic Data
`
`Between July 14, 1992 and October 31, 1993, 37 fe-
`male patients were accrued. Visceral disease was present
`in 76% of patients and nearly half of the patients had
`three or more involved organ systems. Patient characteris-
`tics are listed in Table 1. All patients were assessable
`for toxicity. Response was evaluated on an intent-to-treat
`basis and includes two patients (5%) who only received
`one cycle of therapy.
`
`Response
`
`There were two (5%) CRs and 18 (49%) PRs, for an
`objective response proportion (CRs plus PRs) of 54%
`(95% confidence interval, 37% to 71%). Responses were
`observed at all sites of metastatic disease. The median
`time to detection of response was 12 weeks (range, 3 to
`15). Four patients (11%) withdrew from study while in
`PR or CR to receive high-dose chemotherapy. Excluding
`these four patients, the median response duration was 26
`weeks (range, 10 to 58+). Response data and reasons for
`discontinuation of therapy are listed in Table 2.
`
`Hematologic Toxicity
`
`Leukopenia and neutropenia were both observed in 35
`patients (95%) (Table 3). The median number of days to
`neutrophil nadir was 8 (range, 5 to 22). The median nadir
`counts and days to nadir were similar across multiple
`cycles and by dose level.
`There were 19 episodes of febrile neutropenia compli-
`cating 9% of all treatment cycles. Fifteen episodes were
`seen at the first dose level (100 mg/m2), three at the
`second level (75 mg/m2), and one at the third level (55
`mg/m2). Six patients (16%) developed neutropenic fever
`during the first treatment cycle, six (16%) during cycle
`2, two (5%) during cycle 3, and five (14%) during subse-
`quent cycles. Infection was documented in six patients
`(16%) and 13 cycles (6%).
`
`Statistical Analysis
`Responses. If no responses were observed among the first 14
`patients, the predicted true response rate would have been less than
`20% with 95% confidence and the trial would have been terminated.
`
`Nonhematologic Toxicities
`
`HSRs. After two of the first six patients (33%) treated
`developed some form of possible HSR, a variety of pre-
`medications were administered to new patients (Table 4).
`
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`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`

`

`DOCETAXEL IN METASTATIC BREAST CANCER
`
`61
`
`Table 1. Patient Characteristics
`
`Table 2. Response and Outcome (intent-to-treat basis)
`
`Patients
`
`Variable
`
`Total no. assessable
`CRs
`PRs
`CRs + PRs
`Reason for withdrawal from study:
`PD
`Toxicity*
`Consent withdrawn
`Lost to follow-up
`
`No.
`
`37
`2
`18
`20
`
`16
`14
`6
`1
`
`%
`
`95% Confidence Limits
`
`1-18
`32-66
`37-71
`
`5
`49
`54
`
`43
`38
`16
`3
`
`*Includes 1 (2.7%) toxic death.
`"tlncludes 4 (10.8%) treated with high-dose therapy.
`
`lowing: flushing, hypertension, complaints of throat and/
`or chest tightness, pain, dyspnea, pruritus, bronchospasm,
`complaints of feeling warm, nausea, crampy abdominal
`pain, upper respiratory tract angioedema, and lacrimation.
`An additional three reactions occurred during rechallenge,
`so that a total of 50 reactions were seen. One patient (3%)
`withdrew consent subsequent to developing an HSR.
`However, it is not certain that she actually experienced
`an HSR, as within several seconds of the initiation of
`the first docetaxel infusion, and following prophylactic
`premedication with IV diphenhydramine (50 mg), she
`developed hypotension, bradycardia, and loss of con-
`sciousness. The infusion was stopped and the patient was
`treated with additional IV diphenhydramine, IV cortico-
`steroids, and supplemental nasal oxygen with complete
`recovery. The etiology of this patient's reaction remains
`unclear and may instead be attributable to a cardiac con-
`duction disturbance.
`Treatment for HSR was not undertaken for 16 episodes
`(32%). In three episodes (6%), the infusions were not
`interrupted, in six (12%) the infusions were stopped and
`restarted without additional medication, and in 24 (48%)
`
`No.
`
`37
`
`%
`
`100
`
`50
`
`28-71
`
`5
`62
`16
`16
`
`11
`
`68
`
`62
`49
`41
`35
`22
`19
`8
`27
`3
`
`35
`22
`19
`14
`
`5 5
`
`27
`8
`27
`35
`49
`14
`
`23.3
`1-95.1
`
`2
`23
`
`6 6
`
`12
`25
`
`23
`18
`15
`13
`
`8 7 3
`
`10
`1
`
`13
`
`8 7 5 2 2
`
`10
`3
`10
`13
`18
`5
`
`Characteristic
`
`Patients entered
`Age, years
`Median
`Range
`Performance status'
`
`0 1 2 U
`
`nknown
`Menopausal status
`Pre-
`Post-
`Specific sites involved
`Lymph nodes
`Lung
`Bone
`Liver
`Pleura
`Breast
`Skin
`Other soft tissue
`Other viscera
`Distribution of sites
`Soft tissue + viscera
`Soft tissue + viscera + bone
`Only soft tissue
`Viscera + bone
`Soft tissue + bone
`Only viscera
`Extent of prior systemic therapy
`None
`Prior hormone therapy only
`Prior adjuvant chemotherapy only
`Both
`Prior anthracycline
`No prior anthracycline
`Time from prior chemotherapy to
`study entry, months
`Median
`Range
`
`*World Health Organization.
`
`In 24 patients (65%), this included diphenhydramine 50
`mg IV within 1 hour of commencing docetaxel. In two
`patients (5%), dexamethasone 20 mg IV was added, and
`in one patient (3%) each Decadron (dexamethasone;
`Merck & Co, West Point, PA) and cimetidine 300 mg IV,
`or cimetidine alone, were added to the diphenhydramine.
`Because of the small sample sizes and the fact that these
`interventions were not implemented in a randomized fash-
`ion, it is not possible to analyze the impact of specific
`pretreatment regimens on the incidence of HSR.
`In total, 47 (HSRs) occurred in 20 patients (54%). As
`listed in Table 4, the signs and symptoms felt possibly
`related to HSR included (in order of frequency) the fol-
`
`Table 3. Hematologic Toxicity: All Cycles
`
`Variable
`
`Median
`
`Range
`
`No.
`
`%
`
`No.
`
`%
`
`Nadir
`
`Grade 3
`
`Grade 4
`
`Toxicity
`WBC count (x10 3/gL)
`ANC (x10 3 /p/L)
`Platelet count (xl 103/pL)
`Hemoglobin level (g/dL)
`
`1.4
`0.2
`183
`9.0
`
`0.3-28.0
`0-25.5
`33-353
`5-31
`
`25
`2
`1
`5
`
`68
`5
`3
`14
`
`Patients
`
`No.
`
`%
`
`38
`14
`Febrile neutropenia*
`8
`3
`Packed RBC transfusions
`*Grade 3 or 4 neutropenia with fever > 38 0C.
`
`No.
`
`19
`
`4
`32
`0
`0
`
`Cycles
`
`11
`87
`0
`0
`
`%
`
`9
`
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`
`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`

`

`62
`
`Table 4. HSRs
`
`Patients
`
`Cycles
`
`Variable
`
`Overall incidence
`Cycle no. for first HSR
`1
`2
`4
`6
`Maximum grade of HSR
`+1
`+2
`+3
`+4
`Ungraded
`Signs and symptoms*
`Flushing
`Hypertension
`Chest tightness
`Pain
`Dyspnea
`Pruritus
`Bronchospasm
`Throat tightness
`Warm feeling
`Nausea
`Crampy abdominal pain
`Upper respiratory tract angioedema
`Lacrimation
`Cycle no. 1 premedications
`None
`Diphenhydramine
`"+ Decadron
`"+ Decadron + cimetidine
`Cimetidine + diphenhydramine
`
`No.
`
`20
`
`13
`4
`2
`1
`
`8
`9
`0
`1
`2
`
`16
`6
`6
`6
`5
`4
`4
`3
`3
`2
`2
`1
`1
`
`9
`24
`2
`1
`1
`
`%
`
`54
`
`65
`20
`10
`5
`
`22
`24
`0
`3
`5
`
`80
`30
`30
`30
`25
`20
`20
`15
`15
`10
`10
`5
`5
`
`24
`65
`5
`3
`3
`
`No.
`
`47
`
`%
`
`22
`
`14
`1
`25
`1
`
`33
`8
`11
`9
`10
`7
`5
`4
`4
`9
`2
`3
`2
`
`30
`2
`53
`2
`
`70
`17
`23
`19
`21
`15
`11
`9
`9
`19
`4
`6
`4
`
`*The following signs or symptoms occurred in 1 patient (5%) and 1 cycle
`(2.1%) only: rash, dysesthesia, drug fever, hypotension, anxiety, arrhyth-
`mia, cold feeling, loss of consciousness, pressure in head, sneezing, tachy-
`cardia, urticaria, and unspecified.
`
`the infusions were stopped and resumed following medi-
`cation. As earlier, one patient (2%) did not resume therapy
`following a possible HSR.
`Subsequent to experiencing an HSR, antihistamines
`alone were given to 10 patients (50% of those with
`HSRs), corticosteroids alone to two patients (10%), and
`both to 13 (65%).
`Other acute toxicities. Two patients (5%) had local
`reactions. One (3%) had a grade 2 mild local cutaneous
`erythema at the injection site during cycle 1 that lasted
`4 days. This was later diagnosed as an extravasation and
`did not recur in subsequent cycles. A second patient (3%)
`had an extravasation reaction with cycle 2.
`Twelve patients (32%) experienced nausea (including
`the two patients who noted this as part of an HSR). It
`occurred in 13 of 124 cycles (11%) given at 100 mg/m2
`
`HUDIS ET AL
`
`and eight (13%) of 61 given at 75 mg/m 2. Vomiting was
`observed in seven patients (19%). Seven emetic episodes
`occurred in 124 cycles (6%) at 100 mg/m2 and two more
`among the 61 cycles (3%) at 75 mg/m2.
`At the 100-mg/m 2 dose level, stomatitis occurred in 11
`of 124 cycles (9%), and at the 75-mg/m2 dose level in
`four of 61 cycles (7%). One ineligible patient (3%) with
`an elevated pretreatment bilirubin level of 1.8 mg/dL was
`treated at her request and the request of her primary oncol-
`ogist and with institutional review board and sponsor
`(Rhone-Poulenc Rorer) approval. She developed grade 4
`neutropenia and grade 4 mucositis with massive gastroin-
`testinal hemorrhage and died on day 12 following the first
`cycle of therapy. The steady-state docetaxel level (AUC)
`for this patient was 11.58 pg/mL, which was well above
`the median for the 34 patients studied (median, 4.59 Ig/
`mL; range, 2.86 to 11.74). Autopsy showed diffuse hem-
`orrhagic enterocolitis.
`Except for the signs associated with acute HSR, there
`was no cardiac toxicity. One patient (3%) was noted to
`develop an elevated creatinine concentration (grade 2).
`The total bilirubin level increased in two patients (5%),
`both with known liver metastases. Mild hypoalbuminemia
`developed in 33 patients (89%), but in only two (5%)
`was it severe (< 2 g/dL).
`Cutaneous toxicity included erythema in 14 patients
`(38%), pruritus in 11 (30%), papulae in eight (22%), rash
`in seven (19%), and desquamation in six (16%). The
`median cumulative dose received at the onset of cutane-
`ous toxicity was 502 mg/m 2 (range, 96.9 to 588.6). In
`addition, nail changes, including onycholysis that was
`considered moderate in two (5%), occurred in eight pa-
`tients (22%), of whom seven (19%) had additional cutane-
`ous toxicity. Two patients (5%) developed subungual su-
`perinfection with Pseudomonas that required antibiotic
`treatment.
`Neurologic. Thirty-four patients (92%) underwent
`baseline testing and, of these, 31 (84%) had at least one
`follow-up neurologic evaluation. Neurologic toxicity was
`common (Table 5). Among 34 patients with detailed base-
`line evaluations, seven (21%) had mild neuropathic symp-
`in five
`toms, which were attributed to radiculopathy
`(15%), carpal tunnel syndrome in one (3%), and pure
`sensory neuropathy in one (3%). Of 31 assessable pa-
`tients, 29 (94%) developed new or worsened signs or
`symptoms of peripheral neuropathy. Thirteen (42%) de-
`veloped both signs and symptoms, 12 (39%) symptoms
`only, and four (13%) signs only. The symptoms were
`paresthesias only in 10 (32%), numbness only in six
`(19%), and both in nine (29%). Symptoms involved both
`fingers and toes in 18 (58%), toes only in three (10%), and
`
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`
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`
`

`

`DOCETAXEL IN METASTATIC BREAST CANCER
`
`63
`
`Table 5. Nonhematologic Toxicity
`
`Toxicity
`
`Alopecia
`Gastrointestinal
`Nausea
`Vomiting
`Diarrhea
`Stomatitis
`AST
`No liver metastases
`Liver metastases
`Alkaline phosphatase
`Cutaneous
`Neurosensory
`Neuromotor
`
`Patients
`
`+1
`
`+2
`
`No.
`
`27
`
`12
`7
`8
`13
`
`10/24
`7/13
`10
`22
`29/31
`5/31
`
`%
`
`73
`
`32
`19
`22
`35
`
`42
`54
`42
`60
`94
`16
`
`No.
`
`0
`
`6
`1
`2
`5
`
`8
`4
`4
`6
`13
`2
`
`%
`
`0
`
`16
`3
`5
`14
`
`80
`57
`11
`16
`42
`40
`
`No.
`
`27
`
`4
`5
`4
`6
`
`1
`1
`4
`8
`11
`2
`
`%
`
`73
`
`11
`14
`11
`16
`
`10
`14
`11
`22
`35
`40
`
`*Patient with baseline abnormal liver function tests: died during cycle 1.
`
`Maximal Grade
`
`+3
`
`+4
`
`Unknown
`
`No.
`
`%
`
`No.
`
`%
`
`No.
`
`%
`
`2
`1
`1
`1
`
`1
`1
`2
`5
`5
`1
`
`5
`3
`3
`3
`
`10
`14
`5
`14
`16
`20
`
`0
`0
`0
`1
`
`1
`0
`1
`0
`0
`
`0
`0
`0
`3*
`
`14
`0
`3
`0
`0
`
`1
`
`2
`
`3
`
`5
`
`fingers only in four (13%). By National Cancer Institute
`toxicity criteria, 13 of 29 (45%) were grade 1, 11 of 29
`(38%) grade 2, and five of 29 (17%) grade 3. The median
`number of cycles at which the maximum severity of
`symptoms developed was five (range, three to 10).
`Among 16 patients monitored after discontinuation of
`docetaxel treatment, 13 (81%) experienced stabilization
`or improvement of these symptoms and signs.
`Weakness, mostly proximal and in the legs, developed
`in five patients (16%). It was grade 1 in two patients,
`grade 2 in two, and grade 3 in one.
`Fluid retention. Fluid retention was noted in 30 pa-
`tients (81%). Figure 1 shows the distribution of the major
`signs and symptoms of fluid retention. Nine patients
`(24%) had only peripheral edema, six (16%) had periph-
`eral edema plus weight gain, four (11%) had peripheral
`edema plus pleural effusion, and 11 (30%) had all three
`manifestations (peripheral edema plus pleural effusion
`plus weight gain). The weight gain experienced by 16
`patients (43%) was grade 1 in nine (25%), grade 2 in
`four (11%), and grade 3 in three (8%).
`In seven patients (19%), this syndrome of fluid reten-
`tion was considered severe and caused six patients (16%)
`to withdraw from study. An additional five patients (14%)
`were removed from treatment by the investigators be-
`cause of fluid retention, so that a total of 11 (30%) stopped
`treatment because of this toxicity and did not resume
`therapy with docetaxel. The nature and timing of subse-
`quent therapy was left to the physician's discretion.
`Timing of onset offluid retention. Among 30 patients
`with this toxicity, it was noted after only one cycle of
`therapy in eight (22%), after two cycles in four (11%),
`after three cycles in six (16%), after four cycles in 10
`
`(27%), and after seven and eight cycles in one patient
`(3%) each. A median cumulative docetaxel dose of 297
`mg/m2 (range, 99.6 to 424.5) was delivered at the time
`of onset of this toxicity. For the 11 patients who subse-
`quently discontinued treatment because of fluid retention,
`the median cumulative dose was 662 mg/m2 (range, 298.8
`to 877.5).
`
`Dose Delivery and Reductions
`
`Doses were reduced in 27 cycles and 19 patients (51%).
`Overall, 84 of 215 cycles (39%) were given at less than
`100 mg/m 2.
`
`Fig 1. Signs and symptoms of fluid retention. (0) None; (0)
`edema; (0) edema and weight gain; (E) edema and weight gain and
`pleural effusion; (B) edema and pleural effusion.
`
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`
`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`

`

`64
`
`Pharmacokinetic/Pharmacodynamic Results
`
`For the 35 assessable patients, the median clearance
`and AUC were, respectively, 37.32 L/h (range, 14.85 to
`60.75) and 4.59 /tg -h/mL (range, 2.86 to 11.7), which
`are consistent with estimates from phase I patients.14 Us-
`ing the estimate of the Pearson correlation coefficient, we
`looked for associations between first-cycle toxicity and
`the AUC. We found only that there was a negative rela-
`tionship between AUC and hemoglobin level (-57%, P
`= .0006, no adjustment for multiple comparisons). One
`patient with a decreased clearance and increased AUC
`did have extensive hematologic and nonhematologic tox-
`icity and died with massive gastrointestinal hemorrhage.
`Among the other 34 assessable patients, one other had an
`AUC in this range, but she did not experience excessive
`toxicity.
`
`DISCUSSION
`
`This trial confirms the previous report that docetaxel is
`highly active in the treatment of metastatic breast cancer."
`Indeed, docetaxel activity is comparable to that of single-
`agent doxorubicin or paclitaxel or to the cyclophospha-
`mide, methotrexate, and fluorouracil (CMF)-type combina-
`tions that are usually considered most active and are most
`widely used in this setting.' Preliminary reports from a
`third trial also demonstrate this high level of activity.' 8
`In general, the toxicities associated with docetaxel ther-
`apy are similar to the toxicities of other highly active
`cytotoxic agents. In particular, neurotoxicity is moderate
`and frequent, and myelosuppression and alopecia are
`usual, while nausea and vomiting are rare. Dermatologic
`toxicity, including onycholysis, is also common.'" Of
`note, in our series, one ineligible patient with delayed
`clearance, probably attributable to preexisting liver dis-
`ease, died following the administration of one dose of
`docetaxel. Only one other patient had an AUC in this
`range, and although she did not experience unusual toxic-
`ity, caution appears warranted in treat