Phase Ib dose-finding trial of lapatinib plus pegylated liposomal doxorubicin in advanced HER2-positive breast cancer

Andrea Rocca, Lorenzo Cecconetto, Alessandro Passardi, Elisabetta Melegari, Daniele Andreis, Manuela Monti, Roberta Maltoni, Samanta Sarti, Elisabetta Pietri, Alessio Schirone, Francesco Fabbri, Caterina Donati, Oriana Nanni, Anna Fedeli, Marina Faedi, Dino Amadori, Andrea Rocca, Lorenzo Cecconetto, Alessandro Passardi, Elisabetta Melegari, Daniele Andreis, Manuela Monti, Roberta Maltoni, Samanta Sarti, Elisabetta Pietri, Alessio Schirone, Francesco Fabbri, Caterina Donati, Oriana Nanni, Anna Fedeli, Marina Faedi, Dino Amadori

Abstract

Purpose: Combination of anthracyclines with trastuzumab is hampered by cardiotoxicity. Pegylated liposomal doxorubicin and lapatinib could represent a safer alternative to combination therapy.

Methods: In this phase Ib study with 3 + 3 dose escalation design, patients with HER2-positive advanced breast cancer received pegylated liposomal doxorubicin 30 mg/m2 intravenously on day 1 plus lapatinib 1250 (level 1) or 1500 (level 2) mg/day orally on days 1-21 of each 21-day cycle. The aims were to establish the maximum tolerated dose at first cycle, and the activity and safety of multiple cycles.

Results: Nine patients out of 11 enrolled were evaluable: 3 at level 1 and 6 at level 2. No dose-limiting toxicities occurred at dose level 1, while 1 (grade 3 diarrhea) occurred at dose level 2, leading to the expansion of this cohort to 6 patients, with no further dose-limiting toxicities. Main grade 1-2 toxicities at first cycle were leucopenia, diarrhea, elevated transaminases, mucositis. Three patients had grade 3 toxicities at subsequent cycles, including colitis, anorexia, stomatitis plus hand-foot syndrome. One partial response, 5 disease stabilizations, and 3 disease progressions were reported.

Conclusions: Combination of pegylated liposomal doxorubicin and lapatinib is feasible and potentially active in pretreated HER2-positive advanced breast cancer patients.

Trial registration: NCT02131506 (ClinicalTrials.gov identifier).

Keywords: Breast cancer; HER2; Lapatinib; Pegylated liposomal doxorubicin; Phase Ib; Targeted therapy.

Conflict of interest statement

Conflict of interest

Andrea Rocca received honoraria for speaker lectures from Novartis Pharmaceuticals Corporation. Lorenzo Cecconetto declares that he has no conflict of interest. Alessandro Passardi declares that he has no conflict of interest. Elisabetta Melegari declares that she has no conflict of interest. Daniele Andreis declares that he has no conflict of interest. Manuela Monti declares that she has no conflict of interest. Roberta Maltoni declares that she has no conflict of interest. Samanta Sarti declares that she has no conflict of interest. Elisabetta Pietri declares that she has no conflict of interest. Alessio Schirone declares that he has no conflict of interest. Francesco Fabbri declares that he has no conflict of interest. Caterina Donati declares that she has no conflict of interest. Oriana Nanni declares that she has no conflict of interest. Anna Fedeli declares that she has no conflict of interest. Marina Faedi declares that she has no conflict of interest. Dino Amadori declares that he has no conflict of interest.

Funding

This study was partially funded by GlaxoSmithKline PLC and by Novartis Pharmaceutical Corporation (from March 02 2015), with a research contribution and lapatinib drug provision.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1
Fig. 1
Temporal trends of cardiac parameters and biomarkers: a left ventricular ejection fraction (LVEF, normal value ≥55%); b high-sensitivity troponin T (TnT-hs, normal value <10 ng/L; rule-in value for myocardial damage >50 ng/L); c N-terminal pro b-type Natriuretic Peptide (NT-proBNP, normal value <450 pg/ml)

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