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


CONCLUSIONS
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.
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Bojana
B
Milojkovic Kerklaan
Bojana Milojkovic
BM
Kerklaan
Veronique
V
Diéras
Christophe
C
Le Tourneau
Marja
M
Mergui-Roelvink
Alwin D R
AD
Huitema
Hilde
H
Rosing
Jos H
JH
Beijnen
Sandrine
S
Marreaud
Anne-Sophie
AS
Govaerts
Martine J
MJ
Piccart-Gebhart
Jan H M
JH
Schellens
Ahmad
A
Awada
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D000068878:Trastuzumab; D016896:Treatment Outcome; D003986:Dibenzocycloheptenes
D061067:Antibodies, Monoclonal, Humanized; D017239:Paclitaxel; D010880:Piperidines; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C115354:lonafarnib; D003986:Dibenzocycloheptenes