Capecitabine For Advanced Breast Cancer Research Articles

A Pilot Study of the Combination of Entinostat with Capecitabine in Advanced Breast Cancer.

Breast cancer has an unacceptably high recurrence rate when any residual disease is found following neoadjuvant treatment of high-risk disease. Based on clinical data suggesting an adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open-label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial. A multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2-negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3 mg to 5 mg and capecitabine 800 mg/m2 to 1000 mg/m2. Thirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar-plantar dysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a prespecified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase, due to drug supply limitations. The tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer. This study's clinical investigation of entinostat in breast cancer was halted, but drug development of this agent continues outside the US. There remains a need for postoperative adjuvant drug therapy for the subpopulation of breast cancer patients with high-risk residual cancer after curative therapy. This trial is registered with NCT03473639.

Efficacy of capecitabine in patients with locally advanced or metastatic breast cancer with or without prior treatment with fluoropyrimidine: a retrospective study

PurposeWe conducted a retrospective study to assess the outcomes of capecitabine for advanced breast cancer (ABC) after perioperative fluoropyrimidines (FPs).MethodsThe charts of patients with ABC who received capecitabine between 2008 and 2016 at the National Cancer Center Hospital (Tokyo, Japan) were reviewed. Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were compared between two groups: an FP group (prior perioperative FP use) and a non-FP group (no prior FP use).ResultsOverall, 288 patients (FP n = 105; non-FP n = 183) were analyzed. The two groups had similar patient characteristics. The FP group had significantly poorer PFS than the non-FP group (multivariate hazard ratio [HR] 1.33; 95% confidence interval [CI] 1.02–1.73; p = 0.036), although the OS did not differ significantly between the groups (multivariate HR 1.00; 95% CI 0.67–1.50; p = 0.994). With different cut-off values (relapse-free interval [RFI] = 3, 4, and 5 years), multivariate HRs for PFS were 1.32–1.67 (short RFI), and 1.00–1.25 (long RFI). A trend for a larger HR in the FP group compared to the non-FP group with short RFI than in that with long RFI was also seen for OS. Response rate (RR) and disease control rate (DCR) did not differ significantly between the groups (RR in FP vs non-FP 13.8 vs 21.0%; p = 0.173; DCR 54.0 vs 59.9%; p = 0.418). No significant difference in AEs existed between the groups.ConclusionsExtra caution is needed when capecitabine is considered for patients with ABC who used perioperative FP, especially those who had early recurrence.

Complete response in advanced breast cancer patient treated with a combination of capecitabine, oral vinorelbine and dasatinib

BackgroundCurrently, there are no data available on the best choice of treatment in heavily pretreated patients with advanced breast cancer. However, the combination of oral vinorelbine and capecitabine has been demonstrated to be effective and safe in patients with advanced breast cancer pretreated with anthracycline. Furthermore, some studies assessed the activity of dasatinib, an oral tyrosine kinase inhibitor that inhibits five oncogenic tyrosine kinase families, alone or in combination with different chemotherapy in patients affected with advanced breast cancer.Case presentationA patient with metastatic breast cancer, hormone receptor positive and human epidermal grow factor receptor 2 negative, pretreated with epirubicine, taxanes and nab-paclitaxel, was submitted to third line chemotherapy with vinorelbine 60 mg/m2 on day 1, 8 plus capecitabine 1000 mg/m2 twice daily from day 1 to day 14 every 21 days. The patient was taking also dasatinib 100 mg once daily for chronic myeloid leukemia. The treatment was well tolerated and, after 15 months, computed tomography scan showed a complete response of liver metastases and bone stable disease. After another 28 months, a 18-fluorodeoxyglucose positron emission tomography scan showed a metabolic response of bone metastases without other site of disease.ConclusionsThis is the first case in literature about activity of dasatinib in combination with a chemotherapy schedule of oral vinorelbine and capecitabine in advanced breast cancer. This treatment showed both good tolerability and great activity with a long progression free survival of 54 months.

Long-term disease control with capecitabine in advanced breast cancer.

e12566 Background: Capecitabine is an active agent in the treatment of advanced breast cancer (ABC). It is commonly administered at the approved dosage of 1250 mg/m2 twice daily for 2 weeks followed by 1 week rest period. Methods: The study population included 162 pts retrospectively analyzed with ABC treated with capecitabine between 2006 and 2015 at our Institute. Capecitabine was given 14 day on,7 day off cycle at a daily dose of 1900 mg/m2, a modified schedule used to minimize side effects. The objective were overall response rate (ORR), median duration of treatment (MDT) progression-free survival (PFS), overall survival (OS). Results: The median age was 64 years (range 33-89). Pts with hormone receptor positive ABC were 133 (82%), 6 (4%) had HER-2 positive disease and 29 (18%) a triple negative profile. One hundred and thirty eight (85%) had already received chemotherapy in adjuvant and/or metastatic setting; anthracycline and taxanes were given in 64 pts (40%), anthracycline in 60 pts (37%) and taxane in 4 pts (2%), 9 pts (6%) received other regimens of chemotherapy. Twenty-five pts (15%) were chemo-naive. One hundred and thirty-three pts (82%) received endocrine therapy. Sixty-four pts (38%) had predominantly non-visceral metastases, 26 pts (16%) exclusive visceral involvement, 72 (44%) exhibited both characteristics. ORR was 58% (CR = 2%, PR = 16% SD = 40%) and MDT was 6.9 months. The median PFS and OS were 6.9 months and 21 months, respectively. We defined as “long responders” 19 pts (12%) with disease control interval > 24 months and, among them, as “very long responders”, 9 pts (6%) who exceeded 36 months. Efficacy was unrelated to biological profiles, sites of metastasis or previous therapies. No grade 3 and 4 adverse events occurred. Conclusions: Our results show that in pts with ABC a lower dose of capecitabine has a good toxicity profile and similar overall response rate and survival data in comparison to the approved dose. In addition, we identified a subset of long and very long responders but further studies are warranted to evaluate clinical/biological predictors of a long-term response.

Toxicity profile of lapatinib plus capecitabine in advanced breast cancer – a single-centre follow-up study

Breast cancer is the most prevalent female neoplasm in Poland as well as in the rest of the world, accounting for 25% of all cancers. Lapatinib is a reversible inhibitor of the HER-1 and HER-2 tyrosine kinase receptors. Combined with capecitabine, it is administered in patients suffering from advanced breast cancer with HER-2 receptor overexpression. The present article analyses data obtained from medical records of 24 breast cancer patients treated with lapatinib and capecitabine in the years 2010–2015, in order to examine the treatment-related toxicity. The major adverse effects observed under treatment included diarrhoea, nausea, emesis, skin toxicity, and elevated transaminases. In 3 patients, grade 3 adverse events were reported, as assessed in accordance with CTCAE. The most frequent cause behind the cessation of treatment was disease progression. The analysis has indicated that lapatinib plus capecitabine is a well-tolerated treatment regimen.

Vinflunine plus capecitabine for advanced breast cancer previously treated with or resistant to anthracycline and resistant to taxane: A phase III study versus capecitabine.

1013^ Background: Vinflunine (VFL) is a microtubule inhibitor with single-agent activity in advanced breast cancer (ABC) pretreated with anthracycline (A) and resistant to taxane (T). Synergy with capecitabine (CAPE) was demonstrated in this setting. This phase 3 study compared VFL plus CAPE with CAPE alone in A pretreated or resistant and T-resistant ABC. Methods: Open-label, multicenter study, in which 770 ABC patients with up to 3 prior chemotherapy (CT) regimens were randomised to VFL 280 mg/m² on day 1 plus CAPE 1,650 mg/m² (N = 384) or to CAPE alone at 2,500 mg/m² (N = 386) on days 1 to 14 every 3 weeks. Randomization was stratified by resistance to anthracycline, performance status, disease measurability and number of prior lines of CT for ABC. Primary endpoint was PFS assessed by a blinded independent review committee (IRC) in the ITT population. Results: Patients had a median age of 54 years (range: 27 - 81); metastatic disease for 97%; anthracycline resistance for 63%; received study treatment a...

Dasatinib plus Capecitabine for Advanced Breast Cancer: Safety and Efficacy in Phase I Study CA180004

Dasatinib is an Src family kinase inhibitor with modest activity in advanced breast cancer. We aimed to assess toxicity and maximum tolerated dose (MTD) for dasatinib plus capecitabine, estimate efficacy, and explore effects on angiogenesis. Dose levels (DL) were dasatinib 50 mg twice daily (DL1), 70 mg twice daily (DL2 and DL3), or 100 mg daily (DL3a); plus capecitabine on days 1 to 14 of a 21-day cycle, at 825 mg/m(2) twice daily (DL1 and DL2) or 1,000 mg/m(2) twice daily [DL3 and DL3a (MTD)]. DL3a was expanded to evaluate safety/efficacy. Plasma samples were collected for biomarker analysis. Thirty-one and 21 patients were treated in the escalation and expansion phases. Sixty percent of tumors were hormone receptor-positive. Most common adverse events (AE) were any grade nausea (58%), hand-foot syndrome (44%), diarrhea (33%), fatigue (33%), vomiting (31%), and asthenia (31%). Most common grade 3/4 AEs were hand-foot syndrome (12%), diarrhea (8%), fatigue (8%), pleural effusion (8%), and vomiting (6%). The MTD was defined at DL3a (capecitabine 1,000 mg/m(2) twice daily and dasatinib 100 mg daily). Of 25 response-evaluable patients treated at DL3a, confirmed partial response was noted in 24% and stable disease in an additional 32%; median progression-free survival was 14.4 weeks. Significant decreases in plasma VEGF-A and increases in VEGFR-2 and collagen-IV were observed. Dasatinib 100 mg once daily plus capecitabine 1,000 mg/m(2) twice daily were tolerable and were associated with clinical benefit in 56% of response-evaluable patients. Biomarker changes were consistent with an antiangiogenic effect.

Design of RESILIENCE: a phase 3 trial comparing capecitabine in combination with sorafenib or placebo for treatment of locally advanced or metastatic HER2-negative breast cancer

A double-blind, randomized, phase 2b screening trial (SOLTI-0701) of sorafenib, an oral multikinase inhibitor, in patients with HER2-negative advanced breast cancer (BC), showed a statistically significant improvement in progression-free survival (PFS) in the sorafenib + capecitabine arm versus the placebo + capecitabine arm: 6.4 versus 4.1 months (hazard ratio = 0.58; one-sided P = 0.0006). Grade 3/4 toxicities were comparable except G3 hand-foot skin reaction/syndrome (HFSR/HFS) (44% vs. 14%). These results support a phase 3 trial of sorafenib + capecitabine in advanced BC.

Capecitabine in Breast Cancer: The Issue of Cardiotoxicity During Fluoropyrimidine Treatment

Capecitabine is an orally available fluoropyrimidine carbamate that selectively delivers fluorouracil (5-FU) to tissues expressing high levels of thymidine phosphorylase (TP) such as tumors. The drug has demonstrated efficacy in metastatic breast cancer, colorectal, and pancreatic cancer. Although these are considered safe drugs, a growing body of literature reports adverse cardiac effects. Clinical trials indicate that capecitabine has a cardiac toxicity similar to that of infused fluoropyrimidines such as 5-FU. Here, we review cardiotoxicity in the use of fluoropyrimidines, with particular attention toward capecitabine. We also describe a severe, reversible cardiac event that occurred in a 39-year-old woman, with no cardiac risk factors, treated with capecitabine for advanced breast cancer. This review and our experience confirm that fluoropyrimidine cardiotoxicity is an infrequent but documented side effect. Oncology patients under treatment should be closely observed and monitored for cardiac symptoms with particular attention in case of signs or symptoms of cardiovascular complications. The implementation of cardio-oncology interdisciplinary teams should, in the future, reduce the impact of cancer treatment-associated cardiotoxicity syndromes.

Management of hand-foot skin reaction (HFSR)/hand-foot syndrome (HFS) in SOLTI-0701: A double-blind, randomized phase IIb study comparing sorafenib (SOR) versus placebo (PL) in combination with capecitabine (CAP) in patients (pts) with advanced breast cancer (BC).

1083 Background: We reported data from SOLTI-0701 demonstrating a clinical benefit with the oral regimen of SOR+CAP vs. PL+CAP in pts with advanced BC for progression-free survival (median, 6.4 vs. 4.1 mo; hazard ratio 0.58; 1-sided p=0.0006). Toxicities were comparable between treatment arms except for HFSR/HFS, which was not unexpected as HFSR and HFS are associated with SOR and CAP, respectively. Here we describe HFSR/HFS toxicity during this study. Methods: SOLTI-0701 is a multinational (Brazil, France, Spain) phase 2b study in HER2-negative pts with locally advanced or metastatic BC and ≤1 prior chemo regimen for advanced BC (n=229). Pts were randomized (1:1) to receive CAP (1,000 mg/m2 po, twice daily [BID], 14 of every 21 days) with PL or SOR (400 mg po, BID). The protocol recommended managing HFSR/HFS with symptomatic therapy, study drug (SOR, PL, CAP) interruption for grade (G) 2 toxicity, study drug interruption and dose reduction for recurrent G2 or G3 toxicity, and discontinuation for persistent G2/G3 toxicity. Results: Incidence of HFSR/HFS for SOR+CAP vs. PL+CAP was 89% vs. 63% for any grade and 45% vs. 13% for G3; Kaplan-Meier estimate of median time to onset for first incidence of any grade was 14 and 64 days, respectively. In the SOR+CAP arm, 48% and 78% of pts required SOR and CAP dose reductions, resulting in mean daily doses of 603 mg and 1485 mg/m2, respectively; mean number of cycles was 7.7 and 7.5, respectively. In the PL+CAP arm, 11% and 32% of pts required PL and CAP dose reductions, resulting in mean daily doses of 749 mg and 1,850 mg/m2, respectively; mean number of cycles was 6.5 and 6.6, respectively. HFSR/HFS led to treatment discontinuation in 8 pts (7.0%) for SOR+CAP and 2 pts (1.8%) for PL+CAP. Conclusions: Despite high incidence of HFSR/HFS, few pts discontinued treatment due to HFSR/HFS. Dose attenuation for both treatment agents was effective. More proactive management may reduce event duration and severity. In view of the PFS benefit, a phase 3 registration trial will commence in 2010 evaluating the combination of SOR+ CAP for advanced BC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx Pharmaceuticals

Dasatinib Plus Capecitabine for Advanced Breast Cancer: Safety and Efficacy Data from Phase 1 Study CA180-004.

Abstract Background: SRC is a potential therapeutic target in breast cancer and has a central role in hormone therapy resistance and in osteoclast activity. Dasatinib is a potent SRC inhibitor that inhibits breast cancer cell proliferation and migration in vitro, including synergy with 5FU in some cell lines, and inhibits osteoclast activity in clinical trials. CA180-004 is a phase 1 study designed to identify dose-limiting toxicities (DLT) and recommended phase 2 doses of dasatinib plus capecitabine in women with advanced breast cancer (ABC). Safety and efficacy data are now reported with additional follow-up.Methods: Cohorts of pts with ABC were treated at four dose levels (DL) with capecitabine (mg/m2 twice daily [BID] on D1-14 of 21-day cycles) and dasatinib (mg daily): DL1: capecitabine 825 + dasatinib 50 BID; DL2: capecitabine 825 + dasatinib 70 BID; DL3: capecitabine 1000 + dasatinib 70 BID; DL3a: capecitabine 1000 + dasatinib 100 once daily (QD). All pts had performance status 0-1, prior taxane and/or anthracycline and ≤2 prior chemotherapy-containing regimens for advanced disease. Disease assessments were performed every 6 weeks. DL3a was expanded for further safety and efficacy estimate using best objective response and progression-free survival (PFS) rates.Results: To date, 47 pts with ABC have been treated, 31 in escalation phase plus 16 in expansion (5 too early). Median age was 52 years (range 35-77). Tumor subtypes: 14% were Her2-amplified, 57% ER+ or PR+, 29% triple-negative. Safety was previously reported (ASCO 2009) for escalation phase; no MTD was defined based on DLTs. Of 20 evaluable pts in DL3a, 2 DLTs have been observed: 1 pneumonia, pain and pleural effusion plus 1 diarrhea, neutropenia, vomiting, mucositis and anemia. The most common drug-related adverse events (AEs, any grade) were headache, fatigue/asthenia, nausea/vomiting, diarrhea, hand-foot syndrome (HFS) and pleural effusion. The most common grade 3/4 AEs were fatigue/asthenia, HFS, vomiting and diarrhea. To date, 19 have remained on treatment ≥4 months, including 3 for >1 year. Median duration of treatment (n=42) was 13 weeks; 23 pts have discontinued for progression and 7 for toxicity. Of 38 pts with on-study assessment, 6 had confirmed partial response (treatment durations 17+, 23, 25, 36+, 71, 73 wks), 6 had unconfirmed partial or clinical response (5, 11, 13, 18, 23+, 24 wks), and 9 had prolonged stable disease (16+, 17, 23+, 24+, 25+, 29, 39+, 48+, 63+ wks). Updated efficacy data, including PFS by hormone receptor status, will be presented.Conclusions: Dasatinib and capecitabine combination treatment was well tolerated and encouraging efficacy was observed. Further assessment of this combination is warranted. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3092.

Capecitabine in advanced breast cancer: Predictive factors for response

1126 Background: Capecitabine is increasingly used in the treatment of metastatic breast cancer (MBC). We evaluated the use of capecitabine therapy (XT) in MBC at our centre, to determine factors t...

Lapatinib Approved in Combination with Capecitabine for Advanced Breast Cancer

Lapatinib Approved in Combination with Capecitabine for Advanced Breast Cancer

Oral vinorelbine in combination with capecitabine in advanced breast cancer

10586 Background: the availability of chemotherapeutic drugs given by oral route represents a step forward in the management of cancer patients (pts). Vinorelbine and capecitabine have demonstrated established efficacy in metastatic breast cancer (MBC) with distinct mechanism of action. Oral vinorelbine (OVRL) interacts with tubulin and capecitabine (XLD) acts through antimetabolite properties of 5FU. OVRL is rapidly absorbed (1.5- 3h) with elimination half-life around of 40h. No pharmacokinetic interaction was found between these two compounds and its metabolites according to a recent phase I trial. Methods: The treatment schedule was 60 mg/m2 of OVRL on day 1 and 8; XLD 1000 mg/ m2 bid from day 1 to 14 every 3 weeks. Cycles were repeated if ≥1000/mm3 neutrophils and ≥100000 platelets. In case of ≥ Grade (G) 3 haematological and non haematological toxicity dose adjustments were planned: OVRL from 60 mg/ m2 50 or 40 mg/ m2 and XLD from 1000 mg/ m2 to 900 mg/m2 or 750 mg/ m2 b.i.d. Results: Between June 2003 to December 2005, 29 advanced breast cancer pts were included in this trial. Median age: 64 years [range (42–85)]. PS0: 60, PS1: 40. Eight pts, 9 pts and 12 pts received the combination as 1st line, 2nd line and ≥3rd line treatment respectively. A median of 5 cycles [1–30] was given. No G 3/4 haematological toxicity was observed. One pt. suffered from G3 diarrhoea, G2 mild diarrhoea and abdominal pain was reported after ORVRL lasting 24 hours. No hand-foot syndrome has been observed.Out of 18 evaluable pts, 17 had clinical benefit: 1 CR, 4 PR and 12 SD (90% of tumour control). Conclusion: Oral vinorelbine and capecitabine combination is well tolerated and active in MCB pts allowing long-term treatment in ambulatory setting avoiding central venous line and infusions; therefore, this combination should be investigated in early lines of treatment. Final results will be presented during the meeting. [Table: see text]

Actinic keratosis and capecitabine therapy

Topical application of 5-fluorouracil (5-FU) is one of the most effective clinical strategies available to treat actinic keratosis (AK). During treatment, an apparent toxic skin reaction occurs before dermal quiescence ensues. We report a case of a typical flare of AK in a woman treated with capecitabine for advanced breast cancer.

Phase II Study of Pemetrexed in Patients Pretreated with an Anthracycline, a Taxane, and Capecitabine for Advanced Breast Cancer

Background This phase II study evaluated the efficacy, safety, and health outcomes of pemetrexed treatment in heavily pretreated patients with advanced breast cancer. Patients and Methods Women with metastatic breast cancer, Karnofsky performance status ≥ 70, and previous treatment with ≥ 3 regimens containing anthracyclines, taxanes, and capecitabine were eligible. Pemetrexed 500 mg/m 2 intravenous infusion was administered on day 1 of a 21-day treatment cycle. Results Eighty patients were enrolled, and 60 received concurrent folic acid and vitamin B₁₂ supplements per protocol amendment to minimize possible pemetrexed-related toxicity. The median numbers of cycles delivered were 3 for vitamin-supplemented patients and 2 for non—vitamin-supplemented patients. Regardless of vitamin supplementation, the overall response rate was 8% (95% CI, 3%–16.6%), stable disease was exhibited in 36% of patients, median time to disease progression was 2.9 months, and median survival was 8.2 months. Improvements in patient-reported symptoms ranged from 16.2% for pain intensity to 32.1% for nausea. Major grade 3/4 toxicities were hematologic, with grade 4 neutropenia in 10% of patients and grade 3 toxicities consisting primarily of neutropenia (29%) and leukopenia (21%). There were no clear trends of the effect of supplementation on toxicity. Conclusion Pemetrexed has modest antitumor activity and is well tolerated in heavily pretreated patients with breast cancer. Further evaluation of this multitargeted antifolate in advanced breast cancer is warranted.