Phase I study of lonafarnib (SCH66336) in combination with trastuzumab plus paclitaxel in Her2/neu overexpressing breast cancer: EORTC study 16023

• Published in: Cancer chemotherapy and pharmacology 2013, Vol.71 (1), p.53-62
• Main Authors: Kerklaan, Bojana Milojkovic, Diéras, Veronique, Le Tourneau, Christophe, Mergui-Roelvink, Marja, Huitema, Alwin D. R., Rosing, Hilde, Beijnen, Jos H., Marreaud, Sandrine, Govaerts, Anne-Sophie, Piccart-Gebhart, Martine J., Schellens, Jan H. M., Awada, Ahmad
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antibodies, Monoclonal, Humanized - administration & dosage; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cancer Research; Dose-Response Relationship, Drug; Female; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Maximum Tolerated Dose; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Original Article; Paclitaxel - administration & dosage; Pharmacology. Drug treatments; Pharmacology/Toxicology; Piperidines - administration & dosage; Pyridines - administration & dosage; Receptor, ErbB-2 - genetics; Trastuzumab; Treatment Outcome; Tumors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-1972-1

Purpose This phase I study was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, recommended dose for phase II studies, the pharmacokinetics, and antitumor activity of the combination of lonafarnib (farnesyl transferase inhibitor), trastuzumab, and paclitaxel in Her2-positive advanced breast cancer. Methods Twenty-three patients with Her2-overexpressing breast cancer received in the first cycle paclitaxel and trastuzumab and from cycle 2 onwards lonafarnib which was added to the combination. Dose-limiting toxicity (DLT) was determined during the second cycle. Results The MTD and the recommended dose for phase II trials are lonafarnib: 250 mg/day [125 mg/bi-daily (BID)] continuously, paclitaxel: 175 mg/m² 3-h infusion every 3 weeks, and trastuzumab: 4 mg/kg loading dose and 2 mg/kg/week thereafter. The most frequently observed adverse events starting from cycle 1 onwards were alopecia, myalgia, sensory neuropathy, fatigue, arthralgia, leukocytopenia, and neutropenia. From cycle 2 onwards, additional adverse events appeared, such as diarrhea, nausea, dyspepsia, vomiting, and allergy. The mean systemic exposures of both lonafarnib and paclitaxel through all dose levels were higher in the regimen with all three study medications but with no statistically significant difference. Preliminary antitumor activity (CR + PR) was observed in 58 % of all patients. Conclusion Lonafarnib can be safely combined and tolerated with full doses of paclitaxel and trastuzumab in Her2-positive advanced breast cancer patients. Promising preliminary antitumor activity warrants further evaluation of lonafarnib in combination with paclitaxel and trastuzumab in Her2-positive breast cancer.