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Originally published as JCO Early Release 10.1200/JCO.2003.12.109 on September 24 2003 © 2003 American Society for Clinical Oncology Pharmacokinetics, Safety, and Efficacy of Trastuzumab Administered Every Three Weeks in Combination With PaclitaxelFrom McGill University, Montreal, Quebec; British Columbia Cancer Agency, Vancouver, British Columbia; Hamilton Regional Cancer Center, Hamilton; Ottawa Regional Cancer Centre, Ottawa; F. Hoffmann-La Roche Ltd, Mississauga, Ontario, Canada; and F. Hoffmann-La Roche Ltd, Welwyn Garden City, United Kingdom. Address reprint requests to Brian Leyland-Jones, Department of Oncology, McGill University, 546 Pine Avenue West, Montreal QC H2W, Canada; e-mail: brian.leyland-jones{at}mcgill.ca.
Purpose: This phase II study evaluated the pharmacokinetics and safety of trastuzumab and paclitaxel given every 3 weeks to women with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer. Patients and Methods: Thirty-two patients received a loading dose of trastuzumab 8 mg/kg intravenously (day 1) and paclitaxel 175 mg/m2 (day 0). Thereafter, trastuzumab 6 mg/kg was administered on the same day as paclitaxel 175 mg/m2 every 3 weeks for seven cycles. In responding patients, trastuzumab monotherapy every 3 weeks was then continued until disease progression or patient withdrawal.
Results: Trastuzumab trough levels were more than 20 µg/mL by the end of cycle 1. The half-life of trastuzumab was estimated to be 18 to 27 days, although this may be an underestimate. The combination of paclitaxel and trastuzumab was generally well tolerated, with no unexpected toxicities and no pharmacokinetic interaction. The most common adverse events were myalgia, paresthesias, alopecia, arthralgia, and fatigue. Events associated with trastuzumab included infusion-related reactions and cardiac dysfunction. Ten patients had a Conclusion: Additional investigation of trastuzumab administered every 3 weeks is warranted. In combination with paclitaxel, it is generally well tolerated. Plasma trastuzumab trough levels and clinical response rates compare favorably with those achieved with the standard weekly trastuzumab regimen plus chemotherapy. The presence of trastuzumab does not alter exposure to paclitaxel.
HUMAN EPIDERMAL growth factor receptor 2 (HER2) overexpression or amplification occurs in approximately 20% to 25% of patients with breast cancer and is associated with aggressive disease and decreased survival.1,2 This finding, together with preclinical studies showing that transfection of HER2 genes into human breast cancer cells causes malignant transformation,3 identified HER2 as a therapeutic target. Murine monoclonal antibodies to the HER2 extracellular domain had been shown to inhibit proliferation of HER2-overexpressing tumors. The most potent of these, designated 4D5, was studied further and humanized to produce trastuzumab (Herceptin; F. Hoffmann-LaRoche Ltd, Basel, Switzerland), which inhibits the growth of such tumors in vitro and in vivo.4–6 Murine antibody 4D5 causes maximal tumor growth inhibition at concentrations of 1 to 23 µg/mL (data on file). At least comparable results were expected with trastuzumab because it has greater affinity for HER2.4 Thus, a minimum serum trough concentration (Cmin) of 10 to 20 µg/mL was targeted in early clinical studies. This was shown to be achievable using a weekly dose regimen, and evidence of clinical activity justified progression to phase II and III clinical trials.5,6 In the initial phase II and III studies in women with HER2-positive metastatic breast cancer (MBC), trastuzumab was administered weekly (4 mg/kg loading dose intravenously [IV], followed by 2 mg/kg IV weekly).7–9 This regimen produced durable objective responses as a single agent7,9 and improved survival when combined with chemotherapy (paclitaxel or doxorubicin + cyclophosphamide).8 Second- and third-line weekly trastuzumab monotherapy and first-line weekly trastuzumab plus paclitaxel are currently recommended for treatment of women with HER2-positive MBC in the United States and many other countries. Pharmacokinetic and safety data suggest that less frequent administration of a larger dose of trastuzumab also might be feasible.10 The elimination half-life of trastuzumab at the doses used in clinical trials was initially estimated to be 8.3 days, on the basis of the erroneous assumption that the drug had dose-related nonlinear pharmacokinetics, with the elimination half-life increasing with increasing dosage.11 This assumption was the rationale for studying a higher trastuzumab dose at a longer dosing interval in this study, and simulation of a regimen of trastuzumab 6 mg/kg every 3 weeks suggested that this would produce Cmin of 40 to 50 µg/mL, similar to Cmin levels observed in earlier trials of 2 mg/kg weekly (data on file, Roche). This regimen was predicted to be well tolerated on the basis of a study in which trastuzumab 8 mg/kg followed by 4 mg/kg weekly was administered without undue toxicity.9 Subsequent to the initiation of this study, trastuzumab has been found not to exhibit dose-related nonlinear pharmacokinetics. Data from a recent reanalysis of population pharmacokinetic data, which was based on a two-compartment model, indicate that the drug has a half-life of 28.5 days.12 These data offer additional support to the rationale for this study. Preclinical studies indicate that trastuzumab shows additive or synergistic antitumor activity with taxanes, platinum analogs, vinorelbine, and other agents.5,13,14 The widespread use of taxanes in MBC, combined with the proven efficacy and tolerability profile of trastuzumab, provide a rationale for the development of a well-tolerated regimen that includes both agents. A large randomized phase III trial has demonstrated that adding weekly trastuzumab to paclitaxel every 3 weeks improves response rate, response duration, and survival compared with chemotherapy alone in women with HER2-positive MBC.8 However, patient convenience would be improved if both drugs were administered using a similar schedule. Weekly trastuzumab plus weekly paclitaxel appears to be well tolerated and is associated with a high response rate.15 Alternatively, both drugs could be administered every 3 weeks. The ability to administer trastuzumab every 3 weeks may be particularly important for patients receiving adjuvant therapy. The phase II study reported here had the primary objectives of evaluating the pharmacokinetics and safety of trastuzumab and paclitaxel administered every 3 weeks to patients with HER2-positive MBC. This study also aimed to make a preliminary assessment of any pharmacokinetic interaction between paclitaxel and trastuzumab. Observations on the efficacy of this regimen are also reported.
Study Design This open-label study was conducted at four Canadian centers. After analysis of safety and pharmacokinetic data in an initial cohort of 16 patients, a second cohort of 16 patients was to be enrolled. The additional 16 patients would be treated at the same dose as the initial cohort if exposure was adequate (serum trough concentrations > 20 µg/mL) and there were no new safety concerns compared with previous trials. Inadequate exposure but acceptable tolerability would result in the second cohort receiving a higher dose of trastuzumab every 3 weeks. Safety assessment was performed on an ongoing basis; pharmacokinetic assessment was performed on batches of samples. A decision to modify the trastuzumab dose could be made before all patients reached the pharmacokinetic assessment points.
Patients Patients of reproductive potential were not to be pregnant or lactating, had to have a negative pregnancy test, and had to be using effective contraception. Patients receiving any investigational drug within 30 days before starting trastuzumab treatment or prior anti-HER2 therapy at any time were excluded, as were patients with any of the following conditions: uncontrolled serious illness; uncontrolled CNS metastases or invasive malignancy other than breast cancer (unless free of disease for > 5 years); prior chemotherapy with taxanes for MBC (prior taxane adjuvant therapy was allowed); prior chemotherapy or radiotherapy of any type within the preceding 3 weeks; severe dyspnea at rest caused by complications of advanced malignancy or requiring supplementary oxygen therapy; or New York Heart Association (NYHA) class III or IV congestive heart failure, or a left ventricular ejection fraction (LVEF) less than 50% assessed by multigated radionuclide angiography scan or echocardiography. In addition, patients demonstrating the following hematologic and laboratory abnormalities at baseline were excluded: hemoglobin less than 10 g/dL, neutrophils less than 1.5 x 109/L, platelets less than 100 x 109/L, serum total bilirubin more than 1.5x upper limit of normal (ULN; except for patients with clearly documented Gilbert’s syndrome), ALT or AST more than 2.5x ULN (> 5.0x ULN if liver metastases were present), alkaline phosphatase more than 2.5x ULN (> 4.0x ULN if liver or bone metastases were present), and/or serum creatinine more than 1.5x ULN. Patients underwent screening and baseline assessments on days -28 to -1. This included medical history, physical examination, vital signs, performance status, body weight, hematology, blood chemistry, LVEF, and tumor assessment.
Study Treatment Any medication that was necessary for the management of the patient was permitted, other than chemotherapy or immunotherapy. Growth factors could be used as clinically indicated. The recommended paclitaxel premedication regimen was to be used. Patients experiencing mild or moderate infusion-related symptoms could be treated with antipyretics and antihistamines. Premedication with corticosteroids, antihistamines, and antipyretics could be used before subsequent trastuzumab infusions.
Pharmacokinetics For trastuzumab, serum samples were taken at 0, 1.5 (end of infusion), 3, 4, 6, 8, 24, 96, 168, and 336 hours after the first infusion. Peak and trough serum samples were taken at all subsequent cycles up to cycle 13. For paclitaxel, serum samples were taken at 0, 1.5, 3 (end of infusion), 3.25, 4, 6, 8, and 24 hours after the first infusion. More frequent samples were taken at cycles 1 (paclitaxel only), 4 (trastuzumab and paclitaxel), and 12 (trastuzumab only) to allow assessment of any pharmacokinetic interaction. For three patients, the trastuzumab-only profile was taken at cycle 10, before implementing a protocol amendment that specified sampling at cycle 12. For paclitaxel, sampling was based on an optimal design of eight samples in 24 hours. In addition, in selected consenting patients who discontinued trastuzumab treatment, up to six samples were collected during the 6-month period after discontinuation of trastuzumab to determine terminal pharmacokinetics.
Noncompartmental pharmacokinetic analysis on the basis of the per-protocol data set was performed, and the following pharmacokinetic parameters were calculated: maximum serum concentration (Cmax), time to Cmax (tmax), Cmin, terminal half-life (t1/2), area under the serum concentration-time curve up to the last sampling (AUClast), and clearance (Cl). t1/2 was estimated from (ln 2)/ Actual times for duration of infusion were used for estimation of pharmacokinetic parameters at cycles 4, 10, and 12. Deviation from the scheduled duration of infusion (90 minutes for trastuzumab and 180 minutes for paclitaxel) was less than 5 minutes in all patients.
Safety Assessments
Patients whose LVEF decreased by
Efficacy Assessment
Statistical Hypothesis and Analytic Plan
Demographics Table 1  lists patient baseline characteristics. Overall, the population was relatively heavily pretreated and had widespread disease. Most patients received trastuzumab and paclitaxel as first- or second-line therapy for MBC. Of the 32 patients entered onto the study, 13 completed all 16 cycles of treatment for pharmacokinetic assessments; 25 patients completed at least four cycles of treatment and yielded data to compare paclitaxel pharmacokinetics with and without trastuzumab. The median numbers of cycles of trastuzumab and paclitaxel received were 12 (range, one to 32) and eight (range, one to eight), respectively. The disposition of patients is summarized in Figure 1.
Pharmacokinetics Mean trastuzumab serum concentration profiles at cycles 4, 10, and 12 are presented in Figure 2 . Estimates of pharmacokinetic parameters are listed in Table 2. Mean t1/2 was approximately 19, 27, and 18 days at cycles 4, 10, and 12, respectively. Cmax values occurred on average 4.4 hours (range, 1.5 to 9.6 hours) after infusion start at cycle 4, and on average 2.5 hours (range, 1.6 to 6.0 hours) after infusion start at cycle 12. Predose (trough) values indicated a degree of accumulation: average values increased by 45% over eight cycles (cycle 4, 50.1 µg/mL [coefficient of variation {CV}, 4%]; cycle 12, 72.3 µg/mL [CV, 9%]; Table 2). Steady-state was reached at about cycle 8.
Figure 3 compares serum trough trastuzumab concentrations for the every-3-weeks regimen and the approved weekly regimen.7 Serum trough levels appeared to be comparable over the study period, although trough concentrations were slightly lower with the every-3-weeks regimen. Trough levels exceeded the targeted minimum of 20 µg/mL before administration of the second cycle and therefore both cohorts of 16 patients were treated at 6 mg/kg every 3 weeks. Trough concentrations also were analyzed using a nonlinear saturable model (Hill equation), revealing that trough concentrations are within 20% of the plateau by cycle 8 (ie, week 24). At cycle 4 and thereafter, average trough concentrations exceeded 50 µg/mL. End of infusion values (Fig 4) showed an approximate 25% increase across eight cycles (cycle 4, 169 µg/mL [CV, 24%]; cycle 12, 215 µg/mL [CV, 21%]).
Figure 5 and Table 3 show average paclitaxel serum profiles and pharmacokinetic parameters for paclitaxel in the absence (cycle 1) and presence (cycle 4) of trastuzumab. The tmax of paclitaxel for both cycles corresponded to the end of infusion. The mean percentage of total AUC under the terminal phase was 26 (CV%, 165). Exposure (Cmax or AUC), Cl, and t1/2 were similar for cycles 1 and 4 (Table 3), indicating that the presence of trastuzumab did not affect paclitaxel pharmacokinetics.
Safety The combination regimen was generally well tolerated and no unexpected toxicities were identified. The most common adverse events were myalgia, paresthesia, alopecia, arthralgia, and fatigue (Table 4 ). Most adverse events were mild to moderate in intensity. Ten patients experienced a total of 13 serious adverse events (Table 5). Three of these were considered related to trastuzumab treatment: two infusion-related reactions were resolved after the first trastuzumab infusion was stopped early, with both patients able to receive additional trastuzumab infusions without recurrence; and one decrease in LVEF to 32%, leading to symptomatic heart failure (NYHA class III). The latter patient, who had received doxorubicin 2 months before trastuzumab therapy, improved after trastuzumab was stopped early and the patient was treated for heart failure (LVEF 44% to 50% at follow-up).
Overall, nine patients had an absolute decrease in LVEF of  15% at some time during the study. Two patients had an LVEF value less than 40%, one of whom also had a decrease of 15%. Of these 10 patients, one withdrew as a result of NYHA grade 3 heart failure as described above. Two other patients withdrew as a result of decreased LVEF during paclitaxel plus trastuzumab therapy; one patient withdrew as a result of mild dyspnea, palpitations, and chest heaviness, and a decrease in LVEF of 17%; and one patient experienced a decrease in LVEF to 45% 9 weeks after therapy was stopped as a result of progressive disease. The remaining five patients continued therapy despite the decrease in LVEF: LVEF improved in one patient and was unchanged in three patients; no additional data were available for the remaining patient. Four of these five patients were responding to therapy, and one had stable disease. In addition, two other patients withdrew because of an asymptomatic LVEF decrease of 14%. Both improved after withdrawal of treatment. No clear association with prior anthracycline treatment was observed in these patients. Nine of 12 patients had received anthracyclines between 1 and 196 months previously. The proportion of patients exposed to anthracyclines (22 of 32 patients) and the interval between exposure and trastuzumab therapy (1 to 196 months) were similar in the total population. Overall, four patients withdrew for safety reasons during the first year of therapy: one for chest tightness and hoarseness on day 1 after the first paclitaxel infusion but before receiving trastuzumab, and three for asymptomatic decreases in LVEF. Three additional patients withdrew during the extension phase and before data cutoff (two for LVEF decreases and one with symptoms of heart failure). One patient developed grade 4 febrile neutropenia, six developed grade 3 neutropenia, and four developed grade 3 lymphopenia. Hematologic toxicity led to paclitaxel dose reduction in one patient and delay in receiving one paclitaxel cycle in another patient. Three patients died, all as a result of progressive disease.
Efficacy
We have evaluated trastuzumab administered every 3 weeks plus paclitaxel, hypothesizing that this schedule (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) was likely to result in trastuzumab exposure similar to that of the standard weekly regimen, and also was likely to be well tolerated and more convenient than the weekly schedule. This trial was designed to test this hypothesis and ensure that altering trastuzumab dose does not cause greater toxicity or pharmacokinetic changes and interactions that might affect efficacy. Drug interactions involving paclitaxel are common because the drug is metabolized via cytochrome P450 isozymes.17 However, there is no evidence that trastuzumab is metabolized by this enzyme system and interactions would not be expected. Our data show that paclitaxel pharmacokinetics were not altered in the presence of trastuzumab, as has been observed previously and in support of this finding.18 Similarly, trastuzumab pharmacokinetics were not altered in the presence of paclitaxel. Thus, there is no pharmacokinetic need for dose adjustment when these drugs are coadministered.
The pharmacokinetic data indicate that trastuzumab administered every 3 weeks has pharmacokinetics similar to the standard weekly regimen. Importantly, in trials in which trastuzumab has demonstrated efficacy, mean serum trough concentrations of
It also is interesting to consider time to steady-state. As expected, this is similar with the regimens administered weekly and every 3 weeks because it is dependent on half-life rather than dose and can be reduced only by using loading dose schedules. It is perhaps surprising that steady-state was not reached for eight cycles. However, recent population pharmacokinetic analysis of data from four phase I, II, and III studies indicates that trastuzumab has a half-life of 28.5 days rather than 8.3 days.12 This trial produced estimates of 18 to 27 days (Table 2
The combination regimen was generally well tolerated. The most common adverse events were myalgia, paresthesias, alopecia, arthralgia, and fatigue, as seen in other studies evaluating this combination.8,15,21 No new or unexpected toxicities were identified. Two patients had severe infusion-associated symptoms during administration of the first dose of trastuzumab requiring interruption of the infusion. However, they were able to receive subsequent infusions without problems. This supports previous experience indicating that such reactions occur predominantly with the first infusion and do not recur with subsequent infusions.22 One patient developed symptoms of heart failure (NYHA class III). The patient had received prior anthracycline therapy, which is a known risk factor for cardiotoxicity in patients receiving trastuzumab. Nine other patients experienced an asymptomatic decrease in LVEF ( The incidence of cardiac dysfunction in this study is consistent with that observed in other trials.8,22 Retrospective review of data from the phase III trial by an independent cardiac review and evaluation committee indicated that cardiac dysfunction occurred in 13% of patients receiving trastuzumab plus paclitaxel, including NYHA class III or IV heart failure in 2% of patients; 91% of these patients had received prior anthracyclines.23 Age, anthracycline exposure, and presence of cardiac risk factors were found to predict cardiac adverse events in trastuzumab recipients. The majority of patients who develop adverse events improve with standard conservative treatment, including angiotensin-converting enzyme inhibitors, diuretics, and cardiac glycosides.24 Similarly, in this study asymptomatic decreases in LVEF proved generally to be reversible, either with continuing trastuzumab therapy or without therapy, and the one patient who developed heart failure improved with standard cardiac therapy.
It should be noted that patients in this study represent a poor prognostic group, on the basis of tumor characteristics, presence of metastases, and the number of prior therapies received (Table 1 In conclusion, these pharmacokinetic, safety, and efficacy data support the feasibility of a regimen of trastuzumab administered every 3 weeks. A recently completed trial of first-line trastuzumab monotherapy administered every 3 weeks will provide additional data regarding the feasibility of the regimen, which is being used in several major trials of trastuzumab as adjuvant breast cancer therapy. Patient convenience, quality of life, and cost considerations are important when therapy for patients with cancer is being selected.27 These factors provide additional support to the continued evaluation of this regimen in patients with primary breast cancer and MBC.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock: Reg Dias, Roche; Parviz Ghahramani, Roche. Acted as a consultant within the last 2 years: Brian Leyland-Jones, Roche, Genentech. Performed contract work within the last 2 years: Brian Leyland-Jones, Roche, Genentech. Received more than $2,000 a year from a company for either of the last 2 years: Reg Dias, Roche; Parviz Ghahramani, Roche; Brian Leyland-Jones, Roche, Genentech.
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15. Seidman AD, Fornier MN, Esteva FJ, et al: Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 19:2587–2595, 2001 16. World Health Organization: WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland, World Health Organization, 1979
17. Cresteil T, Monserrat B, Alvinerie P, et al: Taxol metabolism by human liver microsomes: Identification of cytochrome P450 isozymes involved in its biotransformation. Cancer Res 54:386–392, 1994 18. Gianni L, Albanell J, Eiermann W, et al: Feasibility, pharmacology, and antitumour activity of Herceptin (H) with doxorubicin and Taxol followed by weekly Taxol (AT & T) in women with HER2-positive advanced breast cancer (ABC). Proc Am Soc Clin Oncol 20:44a, 2001 (abstr 174) 19. Carbonell Castellon X, Castaneda-Soto NJ, Clemens M, et al: Efficacy and safety of 3-weekly Herceptin (H) monotherapy in women with HER2-positive metastatic breast cancer (MBC): Preliminary data from a phase II study. Proc Am Soc Clin Oncol 21:19a, 2002 (abstr 73) 20. Ghahramani P, Barton C, Leyland-Jones B. Pharmacokinetics of Herceptin administered three-weekly compared to weekly: A simulation based on data from the clinical studies. Breast 12:S40, 2003 (suppl 1, abstr P89) 21. Gianni L, Eiermann W, Albanell J, et al: Cardiac safety and antitumour activity of doxorubicin and Taxol followed by weekly Taxol (AT & T) when Herceptin is initiated with AT or with T alone in women with HER2-positive advanced breast cancer. Eur J Cancer 37:S191, 2001 (suppl 6, abstr 698) 22. Cook-Bruns N: Retrospective analysis of the safety of Herceptin immunotherapy in metastatic breast cancer. Oncology 61:58–66, 2001 (suppl 2)
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
. The terminal rate constant of elimination, 
, present study) and the standard weekly regimen (
, previous study H0649g7).
