Erlotinib in combination with capecitabine and docetaxel in patients with metastatic breast cancer: A dose-escalation study

Twelves, Chris; Trigo, José; Jones, Rob; Rosa, Flavio De; Rakhit, Ashok; Fettner, Scott; Wright, Tonya; Baselga, José

doi:10.1016/j.ejca.2007.12.011

Cited by 48 publications

(30 citation statements)

References 25 publications

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“…Pharmacokinetic analyses were performed in multiple studies of erlotinib combined with chemotherapy revealing no significant interactions, supporting the hypothesis that the study drug combination would be safe and tolerable [17, 21]. While significant lymphopenia and low CD4 counts have been observed with bendamustine, serious or opportunistic infections are uncommon [5, 22].…”

Section: Introductionmentioning

confidence: 88%

“…Although EGFR over-expression is present in approximately 13 % of all breast cancers [1], the majority of TNBCs express EGFR [3, 12, 13] and many also have EGFR gene amplification [3, 13]. Several early phase clinical trials of EGFR inhibitors combined with chemotherapy in metastatic TNBC patients have been conducted with varying results [14–17]. …”

Section: Introductionmentioning

confidence: 99%

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Severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer

Layman

Ruppert

Lynn

et al. 2013

Cancer Chemother Pharmacol

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Purpose Triple negative breast cancers (TNBC) frequently have high epidermal growth factor receptor (EGFR) expression and are sensitive to DNA-damaging agents. Improved therapies are needed for this aggressive malignancy. Patients and methods We performed a phase I trial of bendamustine and erlotinib, an EGFR tyrosine kinase inhibitor, in patients with metastatic TNBC, ECOG performance status ≤2, and ≤1 prior chemotherapy for metastatic disease. Each 28-day cycle included intravenous bendamustine on days 1, 2 and oral erlotinib on days 5–21 with dose escalation according to a 3 + 3 phase I study design. Dose-limiting toxicity (DLT) was determined by toxicities related to study therapy observed during cycle 1. Results Eleven patients were treated, 5 on dose level 1 and 6 on dose level 2. One patient had DLT on dose level 2. However, cumulative toxicities were observed, including grade 3/4 lymphopenia in 91 % (95 % CI 0.59–0.998) with progressively decreased CD4 counts and grade ≥3 infections in 36 % (95 % CI 0.11–0.69) of patients. Conclusions Combination therapy with bendamustine and erlotinib causes excessive toxicity with severe, prolonged lymphopenia, depressed CD4 counts, and opportunistic infections and should not be pursued further. Future trials of bendamustine combinations in TNBC patients should account for potential cumulative lymphocyte toxicity necessitating patient monitoring during and after treatment.

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Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer

Layman

Ruppert

Lynn

et al. 2013

Cancer Chemother Pharmacol

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“…They also noted reduced levels of 5 0 -deoxy-5-fluorouridine when erlotinib and capecitabine were administered together. In a study of erlotinib with capecitabine in patients with breast cancer (33), the C max (ng/mL) of capecitabine when administered with docetaxel was 6,274 ng/mL but when combined with erlotinib was only 3,934 ng/mL, thus suggesting an effect of erlotinib on pharmacokinetics of capecitabine in plasma. Such interaction may also result in lower clearance of nucleoside drugs-for example, Goss and colleagues showed that gemcitabine clearance was significantly reduced in the presence of cediranib (P > 0.02; ref.…”

Section: Discussionmentioning

confidence: 99%

Erlotinib, Gefitinib, and Vandetanib Inhibit Human Nucleoside Transporters and Protect Cancer Cells from Gemcitabine Cytotoxicity

Damaraju

Scriver

Mowles

et al. 2014

Clinical Cancer Research

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Purpose: Combinations of tyrosine kinase inhibitors (TKI) with gemcitabine have been attempted with little added benefit to patients. We hypothesized that TKIs designed to bind to ATP-binding pockets of growth factor receptors also bind to transporter proteins that recognize nucleosides.Experimental Design: TKI inhibition of uridine transport was studied with recombinant human (h) equilibrative (E) and concentrative (C) nucleoside transporters (hENT, hCNT) produced individually in yeast. TKIs effects on uridine transport, gemcitabine accumulation, regulation of hENT1 activity, and cell viability in the presence or absence of gemcitabine were evaluated in human pancreatic and lung cancer cell lines.Results for 24 hours reduced hENT1 activity which was reversed by subsequent incubation in drug-free media for 24 hours. Greater cytotoxicity was observed when gemcitabine was administered before erlotinib, gefitinib, or vandetanib than when administered together and synergy, evaluated using the CalcuSyn Software, was observed in three cell lines resulting in combination indices under 0.6 at 50% reduction of cell growth.Conclusions: Vandetanib inhibited hENT1, hENT2, hCNT1, hCNT2, and hCNT3, whereas erlotinib inhibited hENT1 and hCNT3 and gefitinib inhibited hENT1 and hCNT1. The potential for reduced accumulation of nucleoside chemotherapy drugs in tumor tissues due to inhibition of hENTs and/or hCNTs by TKIs indicates that pharmacokinetic properties of these agents must be considered when scheduling TKIs and nucleoside chemotherapy in combination.

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“…The cetuximab/carboplatin regimen was well tolerated, with grade 3 toxicity consisting of rash, fatigue, nausea, and vomiting, each occurring in 6% of the patients. The EGFR tyrosine kinase inhibitor erlotinib also has shown activity when combined with capecitabine/docetaxel chemotherapy [71]. It remains to be seen whether this agent will be more effective in a selected population of patients with TNBC.…”

Section: Future Directionsmentioning

confidence: 99%

Triple negative breast cancer: unmet medical needs

Pal

Childs

Pegram

2010

Breast Cancer Res Treat

282

249

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Triple negative breast cancer (TNBC) is an aggressive clinical phenotype characterized by lack of expression (or minimal expression) of estrogen receptor (ER) and progesterone receptor (PR) as well as an absence of human epidermal growth factor receptor–2 (HER2) overexpression. It shows substantial overlap with basal-type and BRCA1-related breast cancers, both of which also have aggressive clinical courses. However, this overlap is not complete, and the expression of ER, PR, and HER2 has been noted in basal-like tumors. TNBC also includes the normal-like subtype, and not all patients with TNBC harbor BRCA1 mutations. Because of its expression profile, TNBC is not amenable to treatment with hormone therapy or the anti-HER2 monoclonal antibody trastuzumab, and systemic treatment options are currently limited to cytotoxic chemotherapy. Overall survival, whether in early-stage or advanced disease, is poor compared with that in patients who have other phenotypes. A number of targeted approaches to TNBC are undergoing clinical evaluation, including the use of agents with poly(ADP-ribose) polymerase inhibitory properties such as iniparib (the United States Adopted Name for the investigational agent BSI-201), olaparib (AZD2281), and veliparib (ABT-888), antiangiogenic agents such as bevacizumab and sunitinib, and epidermal growth factor receptor blockers such as cetuximab and erlotinib. Encouraging results with some of these agents have been reported, thereby offering the promise for improved outcomes in patients with TNBC. The clinical characteristics of TNBC and clinical experience to date with novel targeted agents under development for this aggressive phenotype is reviewed.

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Erlotinib in combination with capecitabine and docetaxel in patients with metastatic breast cancer: A dose-escalation study

Cited by 48 publications

References 25 publications

Severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer

Severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer

Erlotinib, Gefitinib, and Vandetanib Inhibit Human Nucleoside Transporters and Protect Cancer Cells from Gemcitabine Cytotoxicity

Triple negative breast cancer: unmet medical needs

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