Elsevier

European Journal of Cancer

Volume 47, Issue 14, September 2011, Pages 2091-2098
European Journal of Cancer

A phase I/II trial of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab as first-line treatment in HER-2-positive locally advanced or metastatic breast cancer

https://doi.org/10.1016/j.ejca.2011.05.005Get rights and content

Abstract

Aim

To assess the activity and safety of non-pegylated liposomal doxorubicin (Myocet®) in combination with docetaxel and trastuzumab as first-line treatment of patients with HER-2/neu-positive metastatic breast cancer (MBC).

Patients and methods

The maximum tolerated dose of the combination was defined in the phase I part of the study. In the phase II part, 45 HER-2/neu-positive MBC patients were enrolled to receive 6–8 cycles of Myocet® 50 mg/m2 (day 1), docetaxel 30 mg/m2 (days 2 and 9) plus trastuzumab (day 2, 4 mg/kg followed by 2 mg/kg/week) every 21 d until unacceptable toxicity or progression occurred. Objective response (primary end-point) and treatment tolerability were assessed according to World Health Organisation criteria. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure and/or a decrease in left ventricular ejection fraction (LVEF).

Results

The overall response rate was 55.6% (complete response 8.9%, partial response 46.7%), with a median time-to-progression of 10.9 months (C.I. 8.7–15.0). Median overall survival was not reached. The most frequent grade 3–4 adverse events were granulocytopaenia (60.0%), leukocytopenia (43.2%) and alopecia (35.6%). Grade 3–4 diarrhoea, pain, oral and skin toxicity (4.4%, each) and nausea/vomiting, thrombocytopenia and elevated alkaline phosphatase (2.2%, each) were also reported. In 2 patients LVEF fell to <50%, with a decrease from baseline >15%. LVEF median values remained stable from baseline to the end of the study (60%).

Conclusions

The combination of Myocet®, docetaxel and trastuzumab is safe and shows promising activity as first-line treatment of HER-2-positive MBC.

Introduction

Combination chemotherapy has been shown to be more effective than monotherapy in metastatic breast cancer (MBC) in terms of response rate, time-to-progression (TTP) and overall survival (OS). In turn, anthracycline-containing regimens generally obtain better results than those without anthracyclines.1 Anthracycline and taxane combinations are accepted as one of the most effective treatments in metastatic breast cancer. Trastuzumab in combination with taxanes significantly improves therapeutic results compared to taxane monotherapy2, 3 in HER-2-positive MBC. Therefore, regimens combining anthracyclines, taxanes and trastuzumab would be expected to represent the best option for this patient population. However, the use of anthracyclines is limited by cardiotoxicity, especially late irreversible cardiomyopathy which is strongly dose-related and can be either clinically silent or lead to congestive heart failure.4

Early studies combining anthracyclines and taxanes in metastatic breast cancer showed an increased risk of cardiotoxicity compared to that observed when taxanes or anthracyclines were used alone.5 Moreover, adjuvant studies of trastuzumab in HER-2 early breast cancer revealed a higher risk of cardiotoxicity, especially when trastuzumab was administered concomitantly with rather than sequentially to taxanes.6 Assuming that the combination of these drugs for this population of patients would represent the best therapeutic regimen, the challenge we are faced with is how to avoid the unacceptable risk of severe cardiac toxicity.

Liposomal anthracycline formulations have been developed to reduce the risk of cardiotoxicity and have proven to be equally as effective as conventional anthracyclines,7, 8 obtaining a significantly higher objective response rate compared to doxorubicin in anthracycline pre-treated patients. Recent studies have investigated the use of non-pegylated liposomal doxorubicin in HER-2-positive MBC patients receiving concomitant treatment with taxanes and/or trastuzumab as first-line chemotherapy.9, 10, 11

On the basis of this strategy, we designed a phase I/II study where non-pegylated doxorubicin (Myocet®) was combined with trastuzumab and docetaxel as first-line combination therapy in patients with HER-2 positive MBC. In the present study, docetaxel was administered on days 2 and 9 in combination with Myocet® administered every 21 d. The administration of docetaxel was timed in order to achieve a more favourable safety profile. This schedule would seem to have an anti-angiogenic effect.12, 13, 14, 15, 16, 17, 18, 19 In addition, docetaxel was administered 16 h after Myocet® on the basis of our preclinical and clinical data highlighting a synergic effect between anthracyclines and paclitaxel without clinically relevant cardiotoxicity.20, 21

Section snippets

Study design

This was an open, single arm, non-randomised multicentric phase I/II study, divided into two steps (steps 1 and 2). Step 1 was designed as a dose-escalation phase I study aimed at assessing the maximum tolerated dose (MTD) of Myocet® and docetaxel in a three-drug combination regimen containing Myocet, docetaxel and trastuzumab (Herceptin®) as first-line treatment of patients with HER-2-positive locally advanced or metastatic breast cancer. The recommended dose for the phase II part was defined

Patient characteristics

From November 2003 to November 2006, 52 patients (7 in phase I and 45 in phase II) were enrolled. Their main characteristics are reported in Table 1. Among patients recruited in the phase I study, one had locally advanced disease and 3 had received previous adjuvant chemotherapy. The median baseline LVEF of these patients was 66% (range 60–82%). One of the patients recruited in the phase II part had locally advanced disease. Ductal infiltrating carcinoma was the most frequent histological type.

Discussion

Anthracycline based-regimens remain a milestone of first-line treatment for metastatic breast cancer and are at least as effective as taxanes in terms of response rate, TTP and OS.22, 23 Anthracycline–taxane combinations are widely used in this setting of patients with better results than single drug therapy.20, 24 Moreover, HER-2-positive breast cancer patients seem to be more sensitive to anthracyclines than to non-anthracycline based regimens and significantly benefit from trastuzumab–taxane

Role of the study sponsor

The sponsor supplied the drugs used and was involved in the study design and drafting/final revision of the manuscript.

Conflict of interest statement

Alfredo Barbato and Bruno Baconnet are both employees of Cephalon s.r.l., the company that sponsored the study.

Acknowledgements

The following co-authors are acknowledged: G. Bisagni, Oncology Unit, Santa Maria Nuova Hospital, Reggio Emilia; S. Cascinu, Clinica di Oncologia Medica, Ospedali Riuniti Umberto I-GM Lancisi-G Salesi di Ancona; F. Artioli, Oncology Department, Ramazzini Hospital, Carpi; G.Lelli, Oncologia Clinica, Azienda Ospedaliera Universitaria di Ferrara Arcispedale S.Anna, Ferrara; R. Mattioli, Medical Oncology Unit, Fano; A.M. D’Arco, Internal Medicine and Oncohematology Unit, Nocera Inferiore; L.

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