Phase I and pharmacological trial of lapatinib in combination with gemcitabine in patients with advanced breast cancer

Abstract

SummaryBackground Lapatinib has proven efficacy as monotherapy and in combination with capecitabine in patients with metastatic breast cancer (MBC) overexpressing HER2 and/or EGFR. Gemcitabine also has anti-tumor activity in MBC and a favourable toxicity profile. In this phase I study lapatinib and gemcitabine were combined. Methods Female patients with advanced BC were given lapatinib once daily (QD) in 28-day cycles with gemcitabine administered on day 1, 8 and 15. Physical examinations, vital signs and blood sampling for hematology, clinical chemistry and pharmacokinetics (PK) and radiological assessments of disease were performed at regular intervals. Results In total, 33 patients were included. Six dose-limiting toxicities were observed, mostly grade 3 increases in liver function tests. Most common toxicities were fatigue (73 %), nausea (70 %), diarrhea (58 %), increases in ALAT and ASAT (55 and 52 %, respectively) and rash (46 %). The maximum tolerated dose was lapatinib 1250 mg QD with gemcitabine 1000 mg/m2. Lapatinib and gemcitabine PK did not appear to be influenced by each other. Anti-tumor activity was observed with one patient (4 %) showing complete response and six (23 %) partial response. Conclusion Despite a slightly increased toxicity profile compared to their respective monotherapies, lapatinib and gemcitabine can be safely combined while showing signs of anti-tumor activity.

MicroRNA-7 suppresses the homing and migration potential of human endothelial cells to highly metastatic human breast cancer cells

“…We observed that transfection with mimic miR-7 suppressed expression of EGFR, IGF-1R and WAVE3 in MDA-MB-231 cells but did not change expression of these proteins in MCF-7 cells. The tyrosine kinase receptors, EGFR and IGF-1R are oncogenes frequently observed to be mutated or amplified in a wide range of solid tumours and have been considered as an important therapeutic target for clinical studies partly because of their involvement in human cancer progression and metastasis ( van der Noll et al , 2015 ). In cancers including breast, lung, colorectal and glioblastoma it has been reported that miR-7 inhibits EGFR and its downstream signalling pathways [31–33].…”

Intracellular pharmacokinetics of gemcitabine, its deaminated metabolite 2′,2′‐difluorodeoxyuridine and their nucleotides

“…One possibility was that the comedication had had some influence. However, previous combination studies with lapatinib [22,32], sorafenib [33] and carboplatin [34] showed no clinically relevant influence of concomitant use of these drugs on the plasma PK of gemcitabine.…”

“…The intracellular PK of gemcitabine, dFdU and their nucleotides was examined in two patient cohorts. Cohort A consisted of 12 female patients who were participating in a phase I study in advanced breast cancer [22], exploring the safety, PK profile and the preliminary antitumour activity of the combination of gemcitabine and lapatinib. Gemcitabine was given as a 30-min intravenous infusion at a dose of 1000 mg m -2 on days 1, 8 and 15 of a 28-day treatment cycle.…”

Dynamic ordering design for dose finding in drug‐combination trials

“…The target toxicity rate was 33%. The second example is a phase I trial designed to identify the MTD of combination drugs, gemcitabine and lapatinib, for patients with advanced breast cancer 5 . In the trial, gemcitabine was experimented with two doses: 750 and 1000 mg/m 2 , and lapatinib with four doses: 750, 1000, 1250, and 1500 mg. A total of 33 patients were recruited and treated at various dose combinations in cohorts of size three.…”