Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
1.
Breast J ; 25(2): 237-242, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30810258

RESUMO

The efficacy of anthracycline- and taxane-based chemotherapy for perioperative treatment of breast cancer (BC) has been established. No superiority of a cytotoxic regimen has been demonstrated, provided that administration of an anthracycline and a taxane is warranted. The ASTER study was designed to investigate the safety of 6 months of perioperative chemotherapy with Doxorubicin and Paclitaxel, followed by Cyclophosphamide, Methotrexate, and 5-Fluorouracil. ASTER enrolled patients with cT2-3 N0-1 or pT1-2 N1-3 BC, from November 2008 to August 2011. Treatment consisted of Doxorubicin 60 mg/sm, Paclitaxel 200 mg/sm q21 (AT) for three cycles followed by Cyclophosphamide 600 mg/sm, Methotrexate 40 mg/sm, 5-Fluorouracil 600 mg/sm d1,8 q28 (CMF) for three cycles, in either neo-adjuvant or adjuvant setting. All HER-positive patients received targeted therapy with Trastuzumab for 1 year. Disease-free and overall survival (DFS and OS, respectively) were estimated according to Kaplan-Meier method. Three hundred and thirty patients were enrolled, where 77.9% of cases were treated in an adjuvant setting; 65.5% received breast conservative surgery, 72.4% axillary dissection. 75.5% of cases presented estrogen receptor positivity, 66.7% progesterone receptor positivity; 18.5% of patients presented HER2-positive BC, 16.1% triple negative disease. Twenty-eight (8.5%) developed grade III-IV hematologic toxicity; nine patients (2.7%) developed grade III neurological toxicity. Loco-regional DFS was 99.6% at 1 year, 97.1% at 5 years, 95.9% at 7 years. Corresponding distant DFS was 98.4%, 90.2%, and 88.8%. One, 5, and 7-year OS was 99.6%, 94.9%, and 91.2%, respectively. Chemotherapy with ATx3→CMFx3 is confirmed safe and effective at 6.7 years follow-up. These results appear comparable to those reported in regulatory trials of most commonly prescribed anthracycline and taxane-based regimens.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Adulto , Idoso , Antraciclinas/administração & dosagem , Neoplasias da Mama/mortalidade , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Pessoa de Meia-Idade , Taxoides/administração & dosagem
2.
Breast Cancer Res ; 20(1): 109, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185228

RESUMO

BACKGROUND: This phase Ib study (NCT00960960) evaluated pictilisib (GDC-0941; pan-phosphatidylinositol 3-kinase inhibitor) plus paclitaxel, with and without bevacizumab or trastuzumab, or in combination with letrozole, in patients with locally recurrent or metastatic breast cancer. METHODS: This was a three-part multischedule study. Patients in parts 1 and 2, which comprised 3 + 3 dose escalation and cohort expansion stages, received pictilisib (60-330 mg) plus paclitaxel (90 mg/m2) with and without bevacizumab (10 mg/kg) or trastuzumab (2-4 mg/kg). In part 3, patients received pictilisib (260 mg) plus letrozole (2.5 mg). Primary objectives were evaluation of safety and tolerability, identification of dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of pictilisib, and recommendation of a phase II dosing regimen. Secondary endpoints included pharmacokinetics and preliminary antitumor activity. RESULTS: Sixty-nine patients were enrolled; all experienced at least one adverse event (AE). Grade ≥ 3 AEs, serious AEs, and AEs leading to death were reported in 50 (72.5%), 21 (30.4%), and 2 (2.9%) patients, respectively. Six (8.7%) patients reported a DLT, and the MTD and recommended phase II pictilisib doses were established where possible. There was no pictilisib-paclitaxel drug-drug interaction. Two (3.4%) patients experienced complete responses, and 17 (29.3%) patients had partial responses. CONCLUSIONS: Combining pictilisib with paclitaxel, with and without bevacizumab or trastuzumab, or letrozole, had a manageable safety profile in patients with locally recurrent or metastatic breast cancer. The combination had antitumor activity, and the additive effect of pictilisib supported further investigation in a randomized study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00960960 . Registered on August 13, 2009.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Neoplasias da Mama/patologia , Estudos de Coortes , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Letrozol/administração & dosagem , Letrozol/efeitos adversos , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos
3.
Sci Rep ; 14(1): 3379, 2024 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-38336861

RESUMO

In patients with advanced triple-negative breast cancer (TNBC), translational research efforts are needed to improve the clinical efficacy of immunotherapy with checkpoint inhibitors. Here, we report on the immunological characterization of an exceptional, long-lasting, tumor complete response in a patient with metastatic TNBC treated with dual PD-1 and LAG-3 blockade within the phase I/II study CLAG525X2101C (NCT02460224) The pre-treatment tumor biopsy revealed the presence of a CD3+ and CD8+ cell infiltrate, with few PD1+ cells, rare CD4+ cells, and an absence of both NK cells and LAG3 expression. Conversely, tumor cells exhibited positive staining for the three primary LAG-3 ligands (HLA-DR, FGL-1, and galectin-3), while being negative for PD-L1. In peripheral blood, baseline expression of LAG-3 and PD-1 was observed in circulating immune cells. Following treatment initiation, there was a rapid increase in proliferating granzyme-B+ NK and T cells, including CD4+ T cells, alongside a reduction in myeloid-derived suppressor cells. The role of LAG-3 expression on circulating NK cells, as well as the expression of LAG-3 ligands on tumor cells and the early modulation of circulating cytotoxic CD4+ T cells warrant further investigation as exploitable predictive biomarkers for dual PD-1 and LAG-3 blockade.Trial registration: NCT02460224. Registered 02/06/2015.


Assuntos
Antineoplásicos , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Receptor de Morte Celular Programada 1/metabolismo , Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos , Resultado do Tratamento , Antígeno B7-H1
4.
Tumori ; 110(5): 304-308, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38676437

RESUMO

The use of Digital Healthcare Products is leading to significant improvements in clinical practice. Herein, we discuss the development of PROACT 2.0 (Patient Reported Opinions About Clinical Tolerability v2.0), a novel open-source mobile and web application developed at Fondazione IRCCS Istituto Nazionale Tumori in Milan. It was developed in collaboration with The Christie, Manchester, in the context of work package 2 of the UpSMART Accelerator project, involving a consortium of referral cancer centers from the UK, Spain and Italy. PROACT 2.0 enhances communication between patients and healthcare providers in cancer clinical trials, allowing patients to report adverse events and side effects, and healthcare teams to collect valuable patient-reported outcome measures for treatment management. PROACT 2.0 supports text, audio, and video messaging, offering a secure, non-urgent communication channel that integrates with, or replaces, traditional methods. Its user-friendly and multilingual interface provides a new route for patient engagement and streamlines the handling of logistical information. Positive feedback from initial testing warrants future enhancements for broader applicability in cancer research and treatment.


Assuntos
Ensaios Clínicos como Assunto , Comunicação , Relações Médico-Paciente , Humanos , Neoplasias/terapia , Medidas de Resultados Relatados pelo Paciente , Aplicativos Móveis , Itália
5.
Clin Cancer Res ; 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39405343

RESUMO

PURPOSE: This multicenter phase Ib study investigated trastuzumab deruxtecan (T-DXd) plus nivolumab in patients with HER2-expressing metastatic breast cancer (mBC) and metastatic urothelial cancer (mUC). PATIENTS AND METHODS: Part 1 determined the recommended dose for expansion (RDE) of T-DXd plus nivolumab. Part 2 evaluated efficacy and safety; the primary endpoint was confirmed objective response rate (cORR) by independent central review. RESULTS: Seven patients with mBC were enrolled in part 1 and received T-DXd 3.2 mg/kg (4 patients) or 5.4 mg/kg (3 patients) plus nivolumab. The RDE for T-DXd was 5.4 mg/kg plus nivolumab 360 mg intravenously/3 weeks. In part 2, 32 patients with HER2-positive mBC (cohort 1; inclusive of 3 administered 5.4 mg/kg in part 1), 16 with HER2-low mBC (cohort 2), 30 with HER2-high mUC (cohort 3), and 4 with HER2-low mUC (cohort 4) were enrolled. At data cutoff (July 22, 2021), the cORR (95% CI) for cohorts 1-4 was 65.6% (46.8%-81.4%), 50.0% (24.7%-75.3%), 36.7% (19.9%-56.1%), and not assessed due to small sample size, respectively. Median treatment duration (range) with T-DXd in cohorts 1-4 was 8.9 (1-23), 6.9 (1-21), 3.9 (1-21) months, and not assessed; most common treatment-emergent adverse event was nausea (55.2%, 62.5%, 73.3%, 75.0%). Adjudicated drug-related ILD/pneumonitis rates (cohorts 1-3) were 20.7%, 0%, and 20.0% (1 grade 5 each, cohorts 1 and 3). CONCLUSION: T-DXd plus nivolumab demonstrated promising antitumor activity in HER2-expressing mBC or mUC and safety consistent with the known profile of T­DXd. ILD/pneumonitis is an important risk and requires careful monitoring and prompt intervention.

6.
Invest New Drugs ; 31(5): 1236-43, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23467812

RESUMO

The aim of this phase I study was to identify a feasible dose and schedule for the combination of cisplatin and trabectedin. The regimen evaluated consisted of cisplatin at a fixed dose of 75 mg/m(2) 1-hour intravenous (i.v.) infusion followed by escalating doses of trabectedin 3-hour i.v. infusion, both administered on day 1 every 3 weeks (q3wks). Two dose-limiting toxicities (DLTs), grade 4 neutropenia longer than 7 days duration and grade 3 vomiting despite standard antiemetic therapy, occurred at the starting dose of trabectedin (0.75 mg/m(2)). The immediately lower dose (trabectedin 0.60 mg/m(2)) was evaluated in a total of 8 patients; no DLTs occurred and this was declared the recommended dose (RD). The safety profile of the combination at this dose and schedule was consistent with the known side effects of each agent alone: nausea, fatigue, transient transaminase elevations and neutropenia. No new or unexpected adverse reactions were observed. Two partial responses were reported at the RD in patients with pretreated ovarian cancer. Comparison with population pharmacokinetic data suggests a PK interaction between trabectedin and cisplatin leading to increased plasma exposure of trabectedin in the first 48 h, lower platinum clearance and longer half-life. In conclusion, although the trabectedin dose achieved with this combination was low (50 % of single-agent when given q3wks), this day 1 q3wks trabectedin plus cisplatin combination showed a feasible administration, a tolerable safety profile and some antitumor activity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/farmacocinética , Dioxóis/administração & dosagem , Dioxóis/efeitos adversos , Dioxóis/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/efeitos adversos , Tetra-Hidroisoquinolinas/farmacocinética , Trabectedina , Resultado do Tratamento , Adulto Jovem
7.
Crit Rev Oncol Hematol ; 169: 103532, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34800655

RESUMO

In the era of precision medicine, monoclonal antibodies and small molecule inhibitors are the mainstays of the biological therapy in patients with solid tumors. However, resistance to treatment and the "undruggability" of certain key oncogenic proteins emerged as major limitations and jeopardize the clinical benefit of modern therapeutic approaches. Targeted protein degraders are novel molecules entering the early phase of clinical development that exploit the intracellular ubiquitine-proteasome system to promote a specific degradation of target proteins. Since the peculiar mechanism of action, targeted protein degraders have the potential to limit and overcome resistance to treatment and to allow a full actionability of certain cancer drivers that are actually elusive targets. Here, we discuss the state-of-the-art and the open issues in the development of these emerging biological agents from a clinical perspective and with a focus on solid tumors.


Assuntos
Neoplasias , Oncologistas , Humanos , Neoplasias/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas/metabolismo , Proteólise
8.
Target Oncol ; 16(1): 59-68, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33369704

RESUMO

BACKGROUND: Targeted agents, such as antiangiogenic drugs (e.g., bevacizumab) and poly(ADP-ribose) polymerase inhibitors (e.g., rucaparib), have been shown to improve outcomes in patients with newly diagnosed or recurrent ovarian cancer. Evidence suggests that combinations of these two classes of targeted agents may result in synergistic antitumor activity. OBJECTIVE: The phase I portion of MITO 25 was designed to determine the maximum tolerated dose, pharmacokinetics, and the safety profile of rucaparib when administered in combination with bevacizumab as maintenance treatment for patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. METHODS: This was a single-arm, phase I dose-escalation study. Cohorts of three patients were recruited to receive increasing rucaparib doses of 400 mg, 500 mg, or 600 mg twice daily for 28 days. Bevacizumab 15 mg/kg was administered at day 1 every 21 days. RESULTS: We enrolled nine patients. Two patients in the rucaparib 600-mg group had four grade 3 treatment-emergent adverse events: increased in alanine aminotransferase and aspartate aminotransferase levels, depression, and hallucinations. These were deemed to be dose-limiting toxicities related to rucaparib. Because these dose-limiting toxicities occurred in the 600-mg group and affected more than one in three patients, the maximum tolerated dose for rucaparib was considered 500 mg twice daily when combined with bevacizumab 15 mg/kg at day 1 every 21 days. There were no new safety concerns from using the combination. No substantial difference in pharmacokinetic parameters was found between the cohorts or in the pharmacokinetic profiles of rucaparib administered alone or with bevacizumab with respect to historical controls. CONCLUSIONS: The maximum tolerated dose of rucaparib is 500 mg twice daily when co-administered with bevacizumab. The plasma concentration-time profiles of rucaparib in combination with bevacizumab suggest no pharmacokinetic interactions between the drugs. The randomized phase II portion of MITO 25 will further investigate rucaparib maintenance treatment with or without bevacizumab in patients with newly diagnosed stage III-IV ovarian cancer who responded to carboplatin-paclitaxel chemotherapy with or without bevacizumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03462212; registered March 2018.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/farmacocinética , Bevacizumab/uso terapêutico , Indóis/farmacocinética , Indóis/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade
9.
Clin Cancer Res ; 27(21): 5760-5770, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34433648

RESUMO

PURPOSE: Data are sparse for oral selective estrogen receptor (ER) degraders (SERD) in cancer treatment. The investigational oral SERD LSZ102 was assessed in monotherapy and combination use in a phase I study. PATIENTS AND METHODS: A phase I, multicenter, open-label dose-escalation study (NCT02734615) of LSZ102 alone (arm A; n = 77) or with ribociclib (arm B; n = 78) or alpelisib (arm C; n = 43) in heavily pretreated adults with histologically confirmed ER-positive breast cancer and prior disease progression. Arm A received LSZ102 200-900 mg/day; arm B, LSZ102 200-600 mg/day plus ribociclib 300-600 mg/day; arm C, LSZ102 300-450 mg/day plus alpelisib 200-300 mg/day. Key outcomes were dose-limiting toxicities (DLT) in the first 28-day treatment cycle, adverse events (AE), laboratory parameters, pharmacokinetics, biopsy ER protein, and investigator-assessed clinical response (RECIST v1.1). RESULTS: The most common AEs were gastrointestinal. Treatment-related serious AEs occurred in 10% of participants (19/198), mostly in arm C [10/43 (23%)]. DLTs occurred in: arm A, 5% (4/77); arm B, 3% (2/78); and arm C, 19% (8/43). LSZ102 exposure was slightly greater than dose proportional. On-treatment biopsy ER reductions were observed, with a trend toward an LSZ102 dose response. Objective response rates (95% confidence interval) were: arm A, 1.3% (0.0-7.0); arm B, 16.9% (9.3-27.1); and arm C, 7.0% (1.5-19.1), and clinical benefit rates 7.8% (2.9-16.2), 35.1% (24.5-46.8), and 20.9% (10.0-36.0), respectively. CONCLUSIONS: LSZ102 was well tolerated alone and with ribociclib and had a manageable safety profile with alpelisib. Preliminary clinical activity was observed in combination use.


Assuntos
Neoplasias da Mama , Adulto , Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Purinas , Receptores de Estrogênio , Tiazóis , Tiofenos
10.
Cancers (Basel) ; 12(6)2020 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-32486385

RESUMO

This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5-300 mg/day; Arm A), BI 860585 (40-220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80-220 mg/day; Arm C) with 60-80 mg/m2/week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash (n = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash (n = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel.

11.
Cancers (Basel) ; 11(2)2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30769874

RESUMO

Predictive biomarkers of response to immune-checkpoint inhibitors (ICIs) are an urgent clinical need. The aim of this study is to identify manageable parameters to use in clinical practice to select patients with higher probability of response to ICIs. Two-hundred-and-seventy-one consecutive metastatic solid tumor patients, treated from 2013 until 2017 with anti- Programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) ICIs, were evaluated for baseline lactate dehydrogenase (LDH) serum level, performance status (PS), age, neutrophil-lymphocyte ratio, type of immunotherapy, number of metastatic sites, histology, and sex. A training and validation set were used to build and test models, respectively. The variables' effects were assessed through odds ratio estimates (OR) and area under the receive operating characteristic curves (AUC), from univariate and multivariate logistic regression models. A final multivariate model with LDH, age and PS showed significant ORs and an AUC of 0.771. Results were statistically validated and used to devise an Excel algorithm to calculate the patient's response probabilities. We implemented an interactive Excel algorithm based on three variables (baseline LDH serum level, age and PS) which is able to provide a higher performance in response prediction to ICIs compared with LDH alone. This tool could be used in a real-life setting to identify ICIs in responding patients.

12.
Clin Breast Cancer ; 19(2): e306-e318, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30635175

RESUMO

BACKGROUND: Single-agent gemcitabine is a moderately effective compound in metastatic breast cancer (mBC) treatment. Carboplatin is frequently used in addition to gemcitabine to improve tumor responses, but with an unclear effect on survival outcomes. In this study we evaluated the antitumor efficacy and safety profiles of gemcitabine and carboplatin-gemcitabine in mBC patients. PATIENTS AND METHODS: We retrospectively collected data on patients treated between April 2012 and February 2018 with gemcitabine 800 mg/m2or carboplatin at an area under the curve of 2 with gemcitabine 800 mg/m2, given on days 1 and 8 every 21 days. We compared progression-free survival (PFS), objective response rate (ORR), overall survival, and incidence of adverse events (AEs) in the 2 cohorts. RESULTS: Of 163 consecutive patients who met the inclusion criteria, 75 received gemcitabine and 88 carboplatin-gemcitabine. Patients in the combination cohort had received a lower number of previous chemotherapy lines (2 vs. 3), and were less likely to have received carboplatin (9 patients [10%] vs. 34 patients [45%]; P < .0001). We found no PFS differences in carboplatin-gemcitabine and gemcitabine cohorts (4.24 vs. 4.61 months; adjusted hazard ratio, 0.98; P = .92), whereas the combination was associated with a trend toward higher ORR (18 patients [20.4%] vs. 8 patients [10.6%]; P = .089) and with significantly higher incidence of Grade 3/4 neutropenia (30 patients [34%] vs. 5 patients [6.6%]; P < .0001). CONCLUSION: Using carboplatin in addition to gemcitabine is associated with more hematologic AEs but not with better PFS. Although single-agent gemcitabine remains a treatment option for heavily pretreated mBC patients, finding biomarkers of response to platinum salts might help to identify patients more likely to benefit from carboplatin-gemcitabine.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carboplatina/administração & dosagem , Desoxicitidina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias da Mama/patologia , Carboplatina/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento , Gencitabina
13.
Breast ; 42: 68-73, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30189381

RESUMO

OBJECTIVES: Cancer Testis Antigens are immunogenic tumor-specific proteins. We investigated NY-ESO-1, MAGE-A3 and PRAME, in addition to WT1 expression in different Breast Cancer (BC) subtypes. We then evaluated the expression rate of NY-ESO-1 in early Triple Negative breast cancer (TNBC), and investigated whether its expression would be maintained or lost in the metastatic setting to explore possible immunotherapy indication. MATERIALS AND METHODS: Three subgroups of BC patients were selected by the expression of ER, PgR and Her2. Tissue microarray was performed on a total of 92 Invasive BC. Sections were stained for NY-ESO-1, MAGE-A3, PRAME and WT1. The second cohort was composed by 26 metastatic TNBC patients from whom both the primary and secondary lesion tissues were available. Sections were stained for NY-ESO-1. RESULTS: NY-ESO-1 was the only differentially expressed antigen and was absent in ER+ and ER-PgR + tumors, as for an exclusive expression of either NY-ESO-1 or at least one hormonal receptor (HR+). NY-ESO-1 was particularly represented in TNBC. No correlation has been found between MAGE-A3 and PRAME expression and subtype WT1 had low expression, except in the Her2+ group. In the second cohort, NY-ESO-1 was expressed in 12 and 24% of primary and metastatic lesions respectively. CONCLUSIONS: This study defines a distinction between HR+ and HR-tumors through NY-ESO-1 expression. TNBC subgroup has the highest frequency of NY-ESO-1+ cases, and it could be the candidate population for the development of anti-NY-ESO-1 vaccine, both in the adjuvant or metastatic setting, and for the selection of cases suitable for immunotherapy.


Assuntos
Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Antígenos Específicos de Melanoma/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas WT1/metabolismo , Adulto , Neoplasias da Mama/terapia , Estudos de Coortes , Feminino , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Estadiamento de Neoplasias
14.
ESMO Open ; 3(2): e000303, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29464112

RESUMO

BACKGROUND: Changes in glycosylation of the constant domain (Fc) of monoclonal antibodies (mAbs) enhance antibody-dependent cell-mediated cytotoxicity independently of downstream effects following receptor blockade by the antibody, thus extending their indication. We investigated the safety, pharmacokinetics, pharmacodynamics and antitumour activity of tomuzotuximab, an IgG1 glycoengineered mAb against the epidermal growth factor receptor with enhanced tumour cytotoxicity in a phase I dose-escalation study (NTC01222637). PATIENTS AND METHODS: Forty-one patients with advanced solid tumours refractory to standard therapies received tomuzotuximab weekly (12-1370 mg) or two-weekly (990 mg) on a three-plus-three dose escalation design. RESULTS: A maximum tolerated dose was not reached. The most frequent treatment-related adverse events were infusion-related reactions in 31 (76%) patients (grade 3, 12%), mainly confined to the first dose, and skin toxicities (grade 1 or 2) in 30 (73%) patients. Hypomagnesaemia was observed in 9 out of 23 evaluable patients (39%). Similar to cetuximab, tomuzotuximab concentrations increased proportionally to dose from doses≥480 mg with a median terminal half life (t½) of 82 hours, range 55-113 hours. Antitumour activity included one complete response ongoing since more than 4.5 years in a patient with non-small-cell lung cancer and one partial response lasting 353 days in a patient with colorectal cancer. Twelve patients achieved stable disease (median, 166 days, range, 71-414 days) and two patients had prolonged control (>1 year) of their non-measurable disease. CONCLUSION: Tomuzotuximab was safe and showed promising antitumour activity in heavily pretreated patients with advanced metastatic disease. A phase IIb trial of chemotherapy and weekly tomuzotuximab or cetuximab followed with maintenance therapy with the corresponding mAb in patients with recurrent or metastatic head and neck squamous cell carcinoma is ongoing.

15.
Cancer Discov ; 7(4): 400-409, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28183697

RESUMO

Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.Significance: Gene fusions of NTRK1/2/3, ROS1, and ALK (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. Cancer Discov; 7(4); 400-9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 339.


Assuntos
Benzamidas/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Indazóis/administração & dosagem , Carcinoma Secretor Análogo ao Mamário/tratamento farmacológico , Melanoma/tratamento farmacológico , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Crizotinibe , Relação Dose-Resposta a Droga , Feminino , Humanos , Indazóis/efeitos adversos , Indazóis/farmacocinética , Masculino , Carcinoma Secretor Análogo ao Mamário/genética , Melanoma/genética , Melanoma/patologia , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Receptor trkA/antagonistas & inibidores , Receptor trkA/genética , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Receptor trkC/antagonistas & inibidores , Receptor trkC/genética , Proteína Sequestossoma-1/genética
16.
Cancer Res ; 76(18): 5562-72, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27402080

RESUMO

Organization of cancer cells into endothelial-like cell-lined structures to support neovascularization and to fuel solid tumors is a hallmark of progression and poor outcome. In triple-negative breast cancer (TNBC), PDGFRß has been identified as a key player of this process and is considered a promising target for breast cancer therapy. Thus, we aimed at investigating the role of miRNAs as a therapeutic approach to inhibit PDGFRß-mediated vasculogenic properties of TNBC, focusing on miR-9 and miR-200. In MDA-MB-231 and MDA-MB-157 TNBC cell lines, miR-9 and miR-200 promoted and inhibited, respectively, the formation of vascular-like structures in vitro Induction of endogenous miR-9 expression, upon ligand-dependent stimulation of PDGFRß signaling, promoted significant vascular sprouting of TNBC cells, in part, by direct repression of STARD13. Conversely, ectopic expression of miR-200 inhibited this sprouting by indirectly reducing the protein levels of PDGFRß through the direct suppression of ZEB1. Notably, in vivo miR-9 inhibition or miR-200c restoration, through either the generation of MDA-MB-231-stable clones or peritumoral delivery in MDA-MB-231 xenografted mice, strongly decreased the number of vascular lacunae. Finally, IHC and immunofluorescence analyses in TNBC specimens indicated that PDGFRß expression marked tumor cells engaged in vascular lacunae. In conclusion, our results demonstrate that miR-9 and miR-200 play opposite roles in the regulation of the vasculogenic ability of TNBC, acting as facilitator and suppressor of PDGFRß, respectively. Moreover, our data support the possibility to therapeutically exploit miR-9 and miR-200 to inhibit the process of vascular lacunae formation in TNBC. Cancer Res; 76(18); 5562-72. ©2016 AACR.


Assuntos
MicroRNAs/genética , Neovascularização Patológica/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/biossíntese , Neoplasias de Mama Triplo Negativas/patologia , Animais , Western Blotting , Diferenciação Celular , Células Endoteliais/patologia , Feminino , Imunofluorescência , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Camundongos SCID , Neovascularização Patológica/patologia , Reação em Cadeia da Polimerase , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Neoplasias de Mama Triplo Negativas/genética
17.
Expert Opin Drug Saf ; 2(1): 59-71, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12904125

RESUMO

The association of doxorubicin (DOX) and paclitaxel (PTX) is very active in breast cancer. Unfortunately, PTX may potentiate the cardiotoxic effects of anthracyclines: it causes nonlinear disposition of DOX and its metabolites, leading to persistant of elevated plasma concentrations of the anthracyclines. However, this pharmacokinetic interference is not sufficient to explain the enhanced cardiotoxicity of the combination. Recent data suggest that PTX stimulates the conversion of DOX to cardiotoxic metabolites (namely doxorubicinol) inside cardiomyocytes. Docetaxel (DTX) does not have a major influence on DOX plasma concentration because it does not interfere with its elimination. Clinical data suggest that DTX may not enhance anthracycline cardiotoxicity, but patients seldom received a total anthracycline dose compatible with increased risk. Furthermore, there are experimental data indicating that DTX can also stimulate the metabolism of DOX to toxic species in human heart.


Assuntos
Antraciclinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Cardiopatias/induzido quimicamente , Taxoides , Antraciclinas/metabolismo , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Doxorrubicina , Esquema de Medicação , Feminino , Humanos , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Risco
18.
Eur J Cancer ; 48(16): 3036-44, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22749255

RESUMO

AIMS: Approximately 20% of soft tissue sarcomas (STS) have subtype-specific chromosomal translocations; these generate chimeric oncoproteins which can act as abnormal transcription factors. Since trabectedin can bind to DNA and displace transcription factors, antitumour activity was explored in translocation-related sarcoma (TRS) subtypes. METHODS: The current retrospective pooled analysis includes data from 81 patients with TRS treated in 8 phase II trials. RESULTS: TRS subtypes were: synovial sarcoma (SS, n=45), myxoid-round cell liposarcoma (MRC-L-sarcoma, n=27), alveolar soft part sarcoma (ASPS, n=4), endometrial stromal sarcoma (ESS, n=3) and clear cell sarcoma (CCS, n=2). All but one patient had received prior chemotherapy (median of 2 lines). Patients received a median of 4 trabectedin cycles (range, 1-48; median dose intensity=0.40 mg/m(2)/week). Partial responses according to Response Evaluation Criteria in Solid Tumours (RECIST) occurred in 8 patients (ORR=10%; 95% CI, 4-19%): four in MRC-L-sarcoma; three in SS and one in ESS. Tumour control rate (ORR plus stable disease) was 59% (95% CI, 48-70%). Median PFS was 4.1 months (6-month PFS rate=40%). Median overall survival was 17.4 months (survival rate at 12 months=60%). Trabectedin had a manageable safety profile. CONCLUSION: Trabectedin demonstrates encouraging disease control in TRS. Since these promising results were generally noted in patients following chemotherapy, a phase III randomised trial in first-line is ongoing to compare trabectedin with doxorubicin-based chemotherapy in patients with TRS.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Dioxóis/uso terapêutico , Sarcoma/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Translocação Genética , Adolescente , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Ensaios Clínicos Fase II como Assunto , Dioxóis/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sarcoma/genética , Sarcoma/mortalidade , Sarcoma/patologia , Tetra-Hidroisoquinolinas/efeitos adversos , Fatores de Tempo , Trabectedina , Resultado do Tratamento , Adulto Jovem
19.
J Clin Oncol ; 28(30): 4554-61, 2010 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-20855840

RESUMO

PURPOSE: Synergistic/additive cytotoxicity in tumor models and widespread applicability of fluoropyrimidines in solid tumors prompted the study of the combination of the mammalian target of rapamycin (mTOR) inhibitor, non-prodrug rapamycin analog ridaforolimus, with capecitabine. PATIENTS AND METHODS: Thirty-two adult patients were treated. Intravenous ridaforolimus was given once weekly for 3 weeks and capecitabine was given from days 1 to 14 every 4 weeks. Ridaforolimus was given at 25, 37.5, 50, or 75 mg with capecitabine at 1,650 mg/m(2) or 1,800 mg/m(2) divided into two daily doses. Pharmacokinetics of both drugs were determined during cycles 1 and 2. Pharmacodynamic studies in peripheral blood mononuclear cells (PBMCs) and wound tissue of the skin characterized pathways associated with the metabolism or disposition of fluoropyrimidines and mTOR and ERK signaling. RESULTS: Two recommended doses (RDs) were defined: 75 mg ridaforolimus/1,650 mg/m(2) capecitabine and 50 mg ridaforolimus/1,800 mg/m(2) capecitabine. Dose-limiting toxicities were stomatitis and skin rash. One patient achieved a partial response lasting 10 months and 10 of 29 evaluable patients had stable disease for ≥ 6 months. The only pharmacokinetic interaction was a ridaforolimus-induced increase in plasma exposure to fluorouracil. PBMC data suggested that prolonged exposure to capecitabine reduced the ridaforolimus inhibition of mTOR. Ridaforolimus influenced the metabolism of fluoropyrimidines and inhibited dihydropyrimidine dehydrogenase, behavior similar to that of rapamycin. Inhibition of the target thymidylate synthase by capecitabine was unaffected. mTOR and ERK signaling was inhibited in proliferating endothelial cells and was more pronounced at the RD with the larger amount of ridaforolimus. CONCLUSION: Good tolerability, feasibility of prolonged treatment, antitumor activity, and favorable pharmacologic profile support further investigation of this combination.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biópsia , Capecitabina , Proteínas de Ciclo Celular , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Esquema de Medicação , Europa (Continente) , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Tecido de Granulação/enzimologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/enzimologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/patologia , Fosfoproteínas/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Serina-Treonina Quinases/metabolismo , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Pele/efeitos dos fármacos , Pele/enzimologia , Serina-Treonina Quinases TOR , Timidina Fosforilase/metabolismo , Timidilato Sintase/metabolismo , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA