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Blumenschein G.R.,University of Texas M. D. Anderson Cancer Center | Ciuleanu T.,Oncological Institute Ion Chiricuta | Robert F.,Central European Cooperative Oncology Group CECOG | Groen H.J.M.,University of Alabama at Birmingham | And 5 more authors.
Journal of Thoracic Oncology | Year: 2012

BACKGROUND:: This randomized, double-blind, multicenter study evaluated sunitinib plus erlotinib versus placebo plus erlotinib. Subjects with advanced non-small-cell lung cancer had received prior treatment with a platinum-based regimen. Here, we report safety, pharmacokinetics, and antitumor activity of the combination of sunitinib and erlotinib. METHODS:: Lead-in subjects in this phase II study received sunitinib 37.5 mg/d and erlotinib 150 mg/d. Safety, including dose-limiting toxicities (DLTs, cohort 1 only), pharmacokinetic profiles, and antitumor activity were investigated (cohorts 1 and 2). RESULTS:: Thirty patients were evaluated. The combination of sunitinib and erlotinib was tolerable. Diarrhea (76.9%), fatigue (61.5%), and decreased appetite (53.8%) were the most frequent adverse events in cohort 1; and diarrhea (52.9%) and rash (41.2%) were the most frequent adverse events in cohort 2. DLTs were observed (fatigue, n = 2 and paronychial inflammation, n = 1) in three of 13 patients evaluated for DLTs. Geometric mean ratios for the maximum plasma concentration (Cmax) and area under plasma concentration-time profile from time 0 to 24 hours of erlotinib with and without sunitinib were 1.05 and 1.03, respectively. Corresponding values for sunitinib with and without erlotinib were 0.62 and 0.62 for sunitinib, 2.13 and 2.07 for SU12662; and 0.81 and 0.79 for total drug. Three patients experienced partial response as per response evaluation criteria in solid tumor. CONCLUSION:: A dosage of sunitinib 37.5 mg/d concurrently with erlotinib 150 mg/d was tolerable and established the recommended combinatorial dose in subjects with platinum-refractory non-small-cell lung cancer. Coadministration of sunitinib with erlotinib does not affect the pharmacokinetics of erlotinib, but may result in decreased exposure to sunitinib. Copyright © 2012 by the International Association for the Study of Lung Cancer.

Zielinski C.,Medical University of Vienna | Zielinski C.,Central European Cooperative Oncology Group CECOG | Gralow J.,University of Washington | Martin M.,Hospital Clinico San Carlos
Annals of Oncology | Year: 2010

While 'targeted' drugs often take centre stage when considering developments in breast cancer, improved understanding, administration and use of chemotherapeutic agents also contribute to better outcomes for women with metastatic breast cancer. Moreover, these developments offer the potential for further improvements when chemotherapy and targeted agents are combined. In this article, we focus on capecitabine dosing in advanced breast cancer, review the available data and discuss the implications of this evidence on best treatment practice both for chemotherapy alone and for chemotherapy when combined with biological agents. It appears that a capecitabine starting dose of 1000mg/m2 twice daily enables treatment to be administered for longer periods, providing continuous exposure to cytotoxic therapy and thus prolonging the duration of disease control. Although no randomised data are available comparing different doses of capecitabine, the cumulative evidence supports this approach. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Miles D.,Mount Vernon Cancer Center | Zielinski C.,Medical University of Vienna | Zielinski C.,Central European Cooperative Oncology Group CECOG | Martin M.,Complutense University of Madrid | Robert N.,Virginia Cancer Specialists
European Journal of Cancer | Year: 2012

Both capecitabine and bevacizumab are established agents in the treatment of metastatic breast cancer, but until recently clinical data supporting their use in combination were limited. We review available data on the capecitabine-bevacizumab combination in breast cancer, particularly results from the RIBBON-1 trial in the first-line setting, and we discuss these findings in light of previous studies. We also examine ongoing trials investigating capecitabine-bevacizumab combination therapy. © 2011 Elsevier Ltd. All rights reserved.

Gridelli C.,S.G. Moscati Hospital | Brodowicz T.,Central European Cooperative Oncology Group CECOG | Brodowicz T.,Medical University of Vienna | Langer C.J.,University of Pennsylvania | And 6 more authors.
Clinical Lung Cancer | Year: 2012

A widely held misperception contends that all elderly patients, even those with good performance status (PS 0-1), are unable to tolerate aggressive chemotherapy. The objective of these analyses was to evaluate the survival and safety of treatment with pemetrexed in elderly patients with nonsquamous Non-Small-cell lung cancer (NSCLC) and PS 0-1. Two randomized studies, 1 reporting the activity of pemetrexed in combination with cisplatin vs. cisplatin and gemcitabine in chemotherapy-naive patients (N = 1725) and another comparing single-agent pemetrexed with placebo in the maintenance setting (N = 663) were retrospectively considered. Data from patients with nonsquamous advanced NSCLC with PS 0-1 in these studies were evaluated in 2 separate dichotomous analyses (< 65 years and < 65 years and < 70 years and < 70). Cox proportional hazard models were used to estimate covariate-adjusted between-arm hazard ratios (HRs) with 95% confidence intervals for each age group. In the first-line study, 32.7% of the 1252 patients with nonsquamous NSCLC were < 65 years and 12.8% were < 70 years old. In the maintenance study, 33.1% of the 481 patients with nonsquamous NSCLC were < 65 years and 16.0% were < 70 years old. In both studies, the adjusted HRs for overall survival (range, 0.62-0.89) favored pemetrexed and were similar between the older and younger age groups. Dose intensity delivered and toxicities observed for patients treated with pemetrexed were manageable and similar between the older and younger age groups. For elderly patients with nonsquamous advanced NSCLC and PS 0-1, pemetrexed therapy, with its favorable toxicity profile, is a viable option, either in combination with cisplatin in the first-line setting or as maintenance therapy after initial chemotherapy. © 2012 Elsevier Inc.

Thallinger C.,Vienna University Hospital | Lang I.,National Institute of Oncology | Kuhar C.G.,Institute of Oncology Ljubljana | Bartsch R.,Vienna University Hospital | And 6 more authors.
BMC Cancer | Year: 2016

Background: Vinorelbine constitutes effective chemotherapy for metastatic breast cancer (MBC) and acts synergistically with trastuzumab in HER-2/neu positive disease. The present study was set out to evaluate the efficacy and safety of vinorelbine when combined with lapatinib, an anti-HER2 tyrosine-kinase inhibitor, as late-line regimen administered beyond previous disease progression on prior lapatinib in patients with HER-2/neu- positive MBC. Methods: The CECOG LaVie study was designed as open-labeled, single-arm, multicenter phase II trial. Patients had to be pretreated with lapatinib plus chemotherapy, and received lapatinib at a daily dose of 1250 mg in combination with vinorelbine 20 mg/m2 i.v. on days 1 and 8 of a three-week cycle until disease progression, intolerable toxicity or withdrawal of consent. Progression-free survival (PFS) was defined as primary study endpoint; secondary endpoints included overall survival (OS), response rate according to RECIST 1.1, and safety. The study was terminated early due to poor accrual. Results: A total number of nine patients were included; lapatinib administered beyond disease progression combined with vinorelbine resulted in a median PFS of 7.7 months (95 % CI 0.56-14.91) and a median OS of 23.4 months (95 % CI 16.61-30.13), respectively. Partial remission was seen in one of nine patients, three patients had stable disease of > six months, whereas the remaining five patients had primary disease progression. In two patients, modification of vinorelbine dose due to toxicity became necessary; no dose modification was needed for lapatinib. The majority of reported adverse events (AE) were grade 1 and 2 in severity with diarrhea being the most commonly observed AE Conclusion: In this heavily pretreated patient population, combination of vinorelbine plus lapatinib showed encouraging activity and was characterized by an acceptable safety profile. Despite the low patient number, lapatinib plus vinorelbine may constitute a potential treatment option in heavily pretreated patients with HER-2/neu-positive MBC previously exposed to lapatinib. Trial registration: EudraCT number 2009-016826-15, (15. 10.2009) © 2016 Thallinger et al.

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