368 research outputs found
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Bosutinib plus capecitabine for selected advanced solid tumours: results of a phase 1 dose-escalation study
Background: This phase 1 study evaluated the maximum tolerated dose (MTD), safety, and efficacy of bosutinib (competitive Src/Abl tyrosine kinase inhibitor) plus capecitabine. Methods: Patients with locally advanced/metastatic breast, pancreatic, or colorectal cancers; cholangiocarcinoma; or glioblastoma received bosutinib plus capecitabine at eight of nine possible dose combinations using an ‘up-down' design to determine the toxicity contour of the combination. Results: Among 32 enrolled patients, none of the 9 patients receiving MTD (bosutinib 300 mg once daily plus capecitabine 1000 mg m−2 twice daily) experienced dose-limiting toxicities (DLTs). Overall, 2 out of 31 (6%) evaluable patients experienced DLTs (grade 3 neurologic pain (n=1); grade 3 pruritus/rash and increased alanine aminotransferase (n=1)). Most common treatment-related adverse events (AEs) were diarrhoea, nausea, vomiting, palmar-plantar erythrodysesthesia (PPE), fatigue; most frequent grade 3/4 AEs: PPE, fatigue, and increased alanine/aspartate aminotransferase. Although diarrhoea was common, 91% of affected patients experienced maximum grade 1/2 events that resolved. Best overall confirmed partial response or stable disease >24 weeks (all tumour types) was observed in 6 and 13% of patients. Conclusions: In this population of patients with advanced solid tumours, bosutinib plus capecitabine demonstrated a safety profile similar to that previously reported for bosutinib or capecitabine monotherapy; limited efficacy was observed
Novel self-assembling cyclic peptides with reversible supramolecular nanostructures
Self-assembly peptides (SAPs) are an important class of hydrogels used in nanomedicine for tissue repair and neural regeneration. Due to their unique properties, SAPs may be used in a wide range of applications but some limitations, such as low bioavailability and rapid hydrolysis degradation, need to be overcome. Here, we describe the synthesis and characterization of two novel cyclic SAPs without the use of d/l-alternating amino acids, showing a reversible transition of their supramolecular nanostructures, from nanotubes/nanofibers into nanovesicles/nanospheres. The investigation, characterization and optimization are performed using atomic force microscopy (AFM), attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, Raman analysis, circular dichroism (CD), and rheology measurements. Also, in vitro cell viability assays show negligible toxicity of the representative optimized cyclic SAP towards human neural stem cells (hNSCs). Our results suggest that linear SAP theoretical background can be applied to develop cyclic SAPs, with important implications in the scalable fabrication of inter-changeable nanostructures, as well as for biomedical applications, including tissue regeneration, drug-delivery, drug-design, sensing, imaging, and size selectivity
Feasibility and Cardiac Safety of Trastuzumab Emtansine After Anthracycline-Based Chemotherapy As (neo) Adjuvant Therapy for Human Epidermal Growth Factor Receptor 2-Positive Early-Stage Breast Cancer
Purpose Trastuzumab emtansine (T-DM1), an antibody-drug conjugate comprising the cytotoxic agent DM1, a stable linker, and trastuzumab, has demonstrated substantial activity in human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer, raising interest in evaluating the feasibility and cardiac safety of T-DM1 in early-stage breast cancer (EBC). Patients and Methods Patients (N = 153) with HER2-positive EBC and prechemotherapy left ventricular ejection fraction (LVEF) \u3e= 55% received (neo) adjuvant doxorubicin plus cyclophosphamide or fluorouracil plus epirubicin plus cyclophosphamide followed by T-DM1 for four cycles. Patients could then receive three to four cycles of optional docetaxel with or without trastuzumab. T-DM1 was then resumed with optional radiotherapy (sequential or concurrent) for 1 year (planned) of HER2-directed therapy. The coprimary end points were rate of prespecified cardiac events and safety. Results Median follow-up was 24.6 months. No prespecified cardiac events or symptomatic congestive heart failures were reported. Four patients (2.7%) had asymptomatic LVEF declines (\u3e= 10 percentage points from baseline to LVEF\u3c 50%), leading to T-DM1 discontinuation in one patient. Of 148 patients who received \u3e= one cycle of T-DM1, 82.4% completed the planned 1-year duration of HER2-directed therapy. During T-DM1 treatment, 38.5% and 2.7% of patients experienced grade 3 and 4 adverse events, respectively. Approximately 95% of patients receiving T-DM1 plus radiotherapy completed \u3e= 95% of the planned radiation dose with dela
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Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study.
PurposeThe KRISTINE study compared neoadjuvant trastuzumab emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, trastuzumab plus P (TCH+P) for the treatment human epidermal growth factor receptor 2-positive stage II to III breast cancer. T-DM1+P led to a lower pathologic complete response rate (44.4% v 55.7%; P = .016), but fewer grade 3 or greater and serious adverse events (AEs). Here, we present 3-year outcomes from KRISTINE.MethodsPatients were randomly assigned to neoadjuvant T-DM1+P or TCH+P every 3 weeks for six cycles. Patients who received T-DM1+P continued adjuvant T-DM1+P, and patients who received TCH+P received adjuvant trastuzumab plus pertuzumab. Secondary end points included event-free survival (EFS), overall survival, patient-reported outcomes (measured from random assignment), and invasive disease-free survival (IDFS; measured from surgery).ResultsOf patients, 444 were randomly assigned (T-DM1+P, n = 223; TCH+P, n = 221). Median follow-up was 37 months. Risk of an EFS event was higher with TDM-1+P (hazard ratio [HR], 2.61 [95% CI, 1.36 to 4.98]) with more locoregional progression events before surgery (15 [6.7%] v 0). Risk of an IDFS event after surgery was similar between arms (HR, 1.11 [95% CI, 0.52 to 2.40]). Pathologic complete response was associated with a reduced risk of an IDFS event (HR, 0.24 [95% CI, 0.09 to 0.60]) regardless of treatment arm. Overall, grade 3 or greater AEs (31.8% v 67.7%) were less common with T-DM1+P. During adjuvant treatment, grade 3 or greater AEs (24.5% v 9.9%) and AEs leading to treatment discontinuation (18.4% v 3.8%) were more common with T-DM1+P. Patient-reported outcomes favored T-DM1+P during neoadjuvant treatment and were similar to trastuzumab plus pertuzumab during adjuvant treatment.ConclusionCompared with TCH+P, T-DM1+P resulted in a higher risk of an EFS event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadjuvant treatment, and more AEs leading to treatment discontinuation during adjuvant treatment
A randomized, phase II, three-arm study of two schedules of ixabepilone or paclitaxel plus bevacizumab as first-line therapy for metastatic breast cancer
The aim of this phase II trial was to estimate the objective response rate (ORR) of two different schedules of ixabepilone [weekly or every 3 weeks (Q3W)] combined with bevacizumab, relative to a reference arm of weekly paclitaxel and bevacizumab. Patients with human epidermal growth factor receptor 2-normal, chemotherapy-naïve metastatic breast cancer (MBC) were randomized 3:3:2 to ixabepilone 16 mg/m(2) weekly plus bevacizumab 10 mg/kg Q2W (Arm A: n = 46); ixabepilone 40 mg/m(2) Q3W (reduced to 32 mg/m(2) after four cycles of treatment) plus bevacizumab 15 mg/kg Q3W (Arm B: n = 45); or paclitaxel 90 mg/m(2) weekly plus bevacizumab 10 mg/kg intravenous infusion Q2W (Arm C: n = 32). Of 123 randomized patients, 122 were treated. All were followed for ≥19 months; 5 % of patients remained on study treatment at the time of this analysis. Grade 3 or 4 neutropenia was more common in Arm B (60 %) than Arms A (16 %) or C (22 %); other adverse events were similar. The investigator-assessed ORR was 48, 71, and 63 % for Arms A, B, and C, respectively. Median progression-free survival (randomized patients) was 9.6 months in Arm A, 11.9 months in Arm B, and 13.5 months in Arm C. In conclusion, ixabepilone Q3W plus bevacizumab has clinical activity as first-line therapy for MBC relative to paclitaxel plus bevacizumab, but with significantly greater risk of grade 3 or 4 neutropenia. In addition, these data suggest that weekly dosing of ixabepilone may be less active than Q3W dosing, but with less neutropenia
Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial
Background: To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial. Methods: We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment. Results: The incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy. Conclusions: Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patient
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