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2.
PLoS One ; 13(10): e0204973, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30304013

RESUMO

INTRODUCTION: Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker. METHODS: An open-label, multicenter, randomized, parallel-group, phase 1 study (target n = 60; NCT02052128) included female patients ≥18 years with PRpos tumors. APR analysis was performed on archival tumor tissue. Patients were randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint was to identify the recommended phase 2 dose. Secondary endpoints included safety, clinical benefit and pharmacokinetics. RESULTS: The phase 1 dose escalation component of the study is complete (n = 52). Tumor diagnosis included: endometrial carcinoma 12; breast cancer 20; ovarian cancer 13; other 7. Median age was 64 (36-84). No dose limiting toxicity was observed with reported liver function test elevation related only to liver metastases. The RP2D was 50 mg ER BID. Median therapy duration was 8 weeks (range 2-44), and 9 patients had clinical benefit ≥24 weeks, including 2 patients with APRpos endometrial carcinoma. CONCLUSION: Clinical benefit with excellent tolerance was seen in heavily pretreated patients with endometrial, ovarian and breast cancer. The data support the development of Onapristone in endometrial endometrioid cancer. Onapristone should also be evaluated in ovarian and breast cancers along with APR immunohistochemistry validation.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Gonanos/uso terapêutico , Receptores de Progesterona/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Preparações de Ação Retardada , Feminino , Gonanos/efeitos adversos , Gonanos/farmacocinética , Meia-Vida , Humanos , Pessoa de Meia-Idade , Náusea/etiologia , Metástase Neoplásica , Recidiva Local de Neoplasia
3.
J Nucl Med Technol ; 2017 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-29127252

RESUMO

The main objective of the present work was to ensure quality of radiopharmaceuticals syringes withdrawn with a "Spinal needle/obturator In-Stopper" system. Methods: Visual examinations and physicochemical tests are performed at T0 and T+4h for [99mTc]albumin nanocolloid and T+7h for [99mTc]eluate, [99mTc] HydroxyMethylene DiPhosphonate and [99mTc]Human Serum Albumin. Microbiological validation was performed according to European pharmacopoeia. Fingertip radiation exposure was evaluated to confirm the safety of the system. Results: Results show stable visual and physicochemical properties. The integrity of the connector was not affected after 30 punctures (no cores). No microbiological contamination was found on tested syringes. Conclusion: The system could be used 30 times. The stability of syringes drawing with this method is guaranteed up to 4 hours for [99mTc]albumin nanocolloid and 7 hours for [99mTc]eluate, [99mTc]HydroxyMethylene DisPhosphonate and [99mTc]Human serum albumin.

4.
Eur J Cancer ; 86: 28-36, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28950146

RESUMO

BACKGROUND: Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms. PATIENTS AND METHODS: PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments. RESULTS: A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug-drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57-92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12-51%]). CONCLUSION: Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population. TRIAL REGISTRATION ID: NCT01589861.


Assuntos
Aminopiridinas/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Morfolinas/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/administração & dosagem , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/administração & dosagem , Administração Oral , Adulto , Idoso , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Esquema de Medicação , Cálculos da Dosagem de Medicamento , Resistencia a Medicamentos Antineoplásicos , Feminino , França , Humanos , Lapatinib , Dose Máxima Tolerável , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinas/efeitos adversos , Quinazolinas/farmacocinética , Receptor ErbB-2/metabolismo , Trastuzumab/efeitos adversos , Resultado do Tratamento
5.
Int J Cancer ; 139(9): 2047-55, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-27388964

RESUMO

Bromodomain and extraterminal (BET) bromodomain (BRD) proteins are epigenetic readers that bind to acetylated lysine residues on chromatin, acting as co-activators or co-repressors of gene expression. BRD2 and BRD4, members of the BET family, are significantly increased in glioblastoma multiforme (GBM), the most common primary adult brain cancer. OTX015 (MK-8628), a novel BRD2/3/4 inhibitor, is under evaluation in dose-finding studies in solid tumors, including GBM. We investigated the pharmacologic characteristics of OTX015 as a single agent and combined with targeted therapy or conventional chemotherapies in glioblastoma cell lines. OTX015 displayed higher antiproliferative effects compared to its analog JQ1, with GI50 values of approximately 0.2 µM. In addition, C-MYC and CDKN1A mRNA levels increased transiently after 4 h-exposure to OTX015, while BRD2, SESN3, HEXIM-1, HIST2H2BE, and HIST1H2BK were rapidly upregulated and sustained after 24 h. Studies in three additional GBM cell lines supported the antiproliferative effects of OTX015. In U87MG cells, OTX015 showed synergistic to additive activity when administered concomitant to or before SN38, temozolomide or everolimus. Single agent oral OTX015 significantly increased survival in mice bearing orthotopic or heterotopic U87MG xenografts. OTX015 combined simultaneously with temozolomide improved mice survival over either single agent. The passage of OTX015 across the blood-brain barrier was demonstrated with OTX015 tumor levels 7 to 15-fold higher than in normal tissues, along with preferential binding of OTX015 to tumor tissue. The significant antitumor effects seen with OTX015 in GBM xenograft models highlight its therapeutic potential in GBM patients, alone or combined with conventional chemotherapies.


Assuntos
Acetanilidas/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Acetanilidas/farmacologia , Animais , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Sinergismo Farmacológico , Everolimo/administração & dosagem , Everolimo/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Irinotecano , Camundongos , Temozolomida , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Lancet Haematol ; 3(4): e186-95, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27063977

RESUMO

BACKGROUND: Bromodomain and extraterminal (BET) proteins are chromatin readers that preferentially affect the transcription of genes with super-enhancers, including oncogenes. BET proteins bind acetylated histone tails via their bromodomain, bringing the elongation complex to the promoter region. OTX015 (MK-8628) specifically binds to BRD2, BRD3, and BRD4, preventing BET proteins from binding to the chromatin, thus inhibiting gene transcription. OTX015 inhibits proliferation in many haematological malignancy cell lines and patient cells, in vitro and in vivo. We aimed to establish the recommended dose of OTX015 in patients with haematological malignancies. We report the results of patients with acute leukaemia (leukaemia cohort). METHODS: In this dose-escalation, phase 1 study we recruited patients from seven university hospital centres (in France [five], UK [one], and Canada [one]). Adults with acute leukaemia who had failed or had a contraindication to standard therapies were eligible to participate. OTX015 was given orally at increasing doses from 10 mg/day to 160 mg/day (14 of 21 days), using a conventional 3 + 3 design. In this open-label trial, OTX015 was initially administered once a day, with allowance for exploration of other schedules. The primary endpoint was dose-limiting toxicity (DLT), assessed during the first treatment cycle (21 days). The study is ongoing and is registered with ClinicalTrials.gov, NCT01713582. FINDINGS: Between Jan 18, 2013, and Sept 9, 2014, 41 patients, 36 with acute myeloid leukaemia, a median age of 70 years (IQR 60-75) and two lines of previous therapy, were recruited and treated across six dose levels of OTX015. No DLT was recorded until 160 mg/day, when one patient had grade 3 diarrhoea and another had grade 3 fatigue. However, concomitant grade 1-2 non-DLT toxic effects (ie, gastrointestinal, fatigue, or cutaneous) from 120 mg doses hampered patient compliance and 80 mg once a day was judged the recommended dose with a 14 days on, 7 days off schedule. Common toxic effects for all OTX015 doses were fatigue (including grade 3 in three patients) and bilirubin concentration increases (including grade 3-4 in two patients). OTX015 plasma exposure increased proportionally up to 120 mg/day with trough concentrations in the in-vitro active range from 80 mg/day (274 nmol/L). Three patients (receiving 40 mg/day, 80 mg/day, and 160 mg/day) achieved complete remission or complete remission with incomplete recovery of platelets lasting 2-5 months, and two additional patients had partial blast clearance. No predictive biomarkers for response have been identified so far. INTERPRETATION: The once-daily recommended dose for oral, single agent oral OTX015 use in patients with acute leukaemia for further phase 2 studies is 80 mg on a 14 days on, 7 days off schedule. FUNDING: Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme Corp.


Assuntos
Acetanilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Acetanilidas/administração & dosagem , Idoso , Antineoplásicos/administração & dosagem , Canadá , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , França , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Reino Unido
7.
Lancet Haematol ; 3(4): e196-204, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27063978

RESUMO

BACKGROUND: The first-in-class small molecule inhibitor OTX015 (MK-8628) specifically binds to bromodomain motifs BRD2, BRD3, and BRD4 of bromodomain and extraterminal (BET) proteins, inhibiting them from binding to acetylated histones, which occurs preferentially at super-enhancer regions that control oncogene expression. OTX015 is active in haematological preclinical entities including leukaemia, lymphoma, and myeloma. We aimed to establish the recommended dose of OTX015 in patients with haematological malignancies. We report the results from a cohort of patients with lymphoma or multiple myeloma (non-leukaemia cohort). METHODS: In this dose-escalation, open-label, phase 1 study, we recruited patients from seven university hospital centres (in France [four], Switzerland [one], UK [one], and Italy [one]). Adult patients with non-leukaemia haematological malignancies who had disease progression on standard therapies were eligible to participate. Patients were treated with oral OTX015 once a day continuously over five doses (10 mg, 20 mg, 40 mg, 80 mg, and 120 mg), using a conventional 3 + 3 design, with allowance for evaluation of alternative administration schedules. The primary endpoint was dose-limiting toxicity (DLT) in the first treatment cycle (21 days). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity of OTX015. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01713582. FINDINGS: Between Feb 4, 2013, and Sept 5, 2014, 45 patients (33 with lymphoma and 12 with myeloma), with a median age of 66 years (IQR 55-72) and a median of four lines of prior therapy (IQR 3-5), were enrolled and treated. No DLTs were observed in the doses up to and including 80 mg once a day (first three patients). We then explored a schedule of 40 mg twice a day (21 of 21 days). DLTs were reported in five of six patients receiving OTX015 at this dose and schedule (all five patients had grade 4 thrombocytopenia). We explored various schedules at 120 mg once a day but none was tolerable, with DLTs of thrombocytopenia, gastrointestinal events (diarrhoea, vomiting, dysgeusia, mucositis), fatigue, and hyponatraemia in 11 of 18 evaluable patients. At this point, the Safety Monitoring Committee decided to establish the feasibility of 80 mg once a day on a continuous basis, and four additional patients were enrolled at this dose. DLTs (grade 4 thrombocytopenia) was noted in two of the patients. In light of these DLTs and other toxicities noted at 120 mg, the dose of 80 mg once a day was selected, although on a schedule of 14 days on, 7 days off. Common toxic effects reported in the study were thrombocytopenia (43 [96%] patients), anaemia (41 [91%]), neutropenia (23 [51%]), diarrhoea (21 [47%]), fatigue (12 [27%]), and nausea (11 [24%]). Grade 3-4 adverse events were infrequent other than thrombocytopenia (26 [58%]). OTX015 plasma peak concentrations and areas under the concentration versus time curve increased proportionally with dose. Trough concentrations increased less than proportionally at lower doses, but reached or exceeded the in-vitro active range at 40 mg twice a day and 120 mg once a day. Three patients with diffuse large B-cell lymphoma achieved durable objective responses (two complete responses at 120 mg once a day, and one partial response at 80 mg once a day), and six additional patients (two with diffuse large B-cell lymphoma, four with indolent lymphomas) had evidence of clinical activity, albeit not meeting objective response criteria. INTERPRETATION: The once-daily recommended dose for oral, single agent oral OTX015 in patients with lymphoma is 80 mg on a 14 days on, 7 days off schedule, for phase 2 studies. OTX015 is under evaluation in expansion cohorts using this intermittent administration (14 days every 3 weeks) to allow for recovery from toxic effects. FUNDING: Oncoethix GmbH (a wholly owned subsidiary of Merck Sharp & Dohme Corp).


Assuntos
Acetanilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Linfoma/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Acetanilidas/administração & dosagem , Idoso , Antineoplásicos/administração & dosagem , Esquema de Medicação , Feminino , França , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Itália , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Suíça , Reino Unido
8.
Chemotherapy ; 61(1): 15-22, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26528705

RESUMO

BACKGROUND: Dose-intensive chemotherapy with hematopoietic stem cell transplantation has been evaluated as a salvage treatment for recurrent ovarian cancer, but its benefit has not yet been demonstrated. In a previous phase I trial, we reported the feasibility of administering topotecan as a salvage regimen. METHODS: Twenty-one patients were treated with escalating doses of topotecan associated with a fixed dose of cyclophosphamide. RESULTS: The maximum tolerated dose was established at 9.0 mg/m2 on a 5-day regimen, analogously to what was reported for topotecan monotherapy. One toxic death from septic shock and multiorgan failure occurred. Although hematopoietic toxicities were overcome by peripheral blood stem cell transplantation, superior nonhematological toxicities were observed as compared to the initial trial. CONCLUSION: Response rates were generally short and survival rates were poor. Results of the ITOV 01bis study demonstrate that, in the setting of recurrent ovarian cancer, intensive chemotherapy based on topotecan-cyclophosphamide association is not currently clinically indicated.


Assuntos
Adenocarcinoma de Células Claras/terapia , Adenocarcinoma Mucinoso/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cistadenocarcinoma Seroso/terapia , Neoplasias do Endométrio/terapia , Transplante de Células-Tronco Hematopoéticas , Neoplasias Ovarianas/terapia , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Adolescente , Adulto , Idoso , Estudos de Coortes , Terapia Combinada , Ciclofosfamida/administração & dosagem , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Feminino , Seguimentos , Humanos , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Terapia de Salvação , Taxa de Sobrevida , Topotecan/administração & dosagem , Adulto Jovem
9.
Clin Pharmacokinet ; 55(3): 397-405, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26341814

RESUMO

BACKGROUND AND OBJECTIVES: OTX015 (MK-8628) is a novel inhibitor of the bromodomain and extraterminal (BET)-bromodomain (BRD) protein family, binding specifically to bromodomains BRD2/3/4 and impacting the epigenetic regulation of several oncogenes. We characterized the pharmacokinetics of this first-in-class BET-BRD inhibitor administered as a single agent, including population pharmacokinetic modelling. METHODS: A dose-escalation, phase Ib study was performed with oral OTX015 in patients with haematologic malignancies, at doses starting from 10 mg once daily (QD) with continuous or discontinuous schedules. Five or eight blood samples were collected per patient for pharmacokinetic analysis. OTX015 plasma concentrations were determined using validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and analysed using a nonlinear mixed-effects modelling software program. A population pharmacokinetic model was fitted to the data, and patient demographics and clinical chemistry parameters were tested as predictive covariates on the model parameters. RESULTS: Blood samples were analysed from 81 patients treated with OTX015 at doses ranging from 10 to 160 mg QD or 40 mg twice daily (BID), and 633 time-plasma concentrations were available for analysis. A one-compartment open model with linear elimination adequately described OTX015 pharmacokinetics. The most significant covariate was lean body mass (LBM), which decreased the between-subject variability in apparent total body clearance (CL) and the volume of distribution (V). The estimated pharmacokinetic parameters were the absorption rate constant (k a) = 0.731 h(-1), V = 71.4 L and CL = 8.47 L·h(-1). CONCLUSION: The pharmacokinetics of oral OTX015 in patients with haematologic malignancies can be described with a one-compartment model. Population pharmacokinetic modelling of OTX015 plasma concentrations showed that LBM influences V and CL. These findings do not suggest the need for dose adjustment.


Assuntos
Acetanilidas/farmacocinética , Antineoplásicos/farmacocinética , Neoplasias Hematológicas/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Modelos Biológicos , Acetanilidas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/sangue , Proteínas de Ciclo Celular , Feminino , Compostos Heterocíclicos com 3 Anéis/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas de Ligação a RNA/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Adulto Jovem
10.
Br J Clin Pharmacol ; 81(5): 941-8, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26714164

RESUMO

AIMS: Trastuzumab, an antibody binding to epidermal growth factor receptor-2 (HER2), has been approved to treat HER2-positive breast cancer in different settings. This study aimed at evaluating the influence of tumour size on trastuzumab pharmacokinetics (PK) in non-metastatic breast cancer patients treated with short term pre-operative trastuzumab. METHODS: Trastuzumab PK data were obtained from a multicentre, randomized and comparative study. This antibody was administered pre-operatively to patients with localized HER2-positive breast cancer as a single 4 mg kg(-1) loading dose followed by 5 weekly 2 mg kg(-1) doses. Trastuzumab concentrations were measured repeatedly using an ELISA technique. Tumour size was evaluated at baseline using breast echography. Trastuzumab pharmacokinetics were studied using a population approach and a two compartment model. The influence of tumour burden on trastuzumab pharmacokinetics was quantified as a covariate. RESULTS: A total of 784 trastuzumab concentrations were available from the 79 eligible patients. Estimated parameters (interindiviual standard deviation) were central volume of distribution =2.1 l (23%), peripheral volume of distribution =1.3 l (38%), intercompartment clearance =0.36 l day(-1) , with an elimination half-life of 11.8 days. Typical clearance was 0.22 l day(-1) (19%) and its value was increased with tumour size. In patients with the highest tumour size, trastuzumab clearance was 50% [18%-92%] higher than in patients with the lowest tumour size. CONCLUSIONS: In non-metastatic breast cancer patients, trastuzumab clearance increases with tumour size. The elimination half-life of trastuzumab was shorter in the present population of patients than in metastatic breast cancer patients previously studied.


Assuntos
Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Everolimo/farmacocinética , Trastuzumab/farmacocinética , Carga Tumoral , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/metabolismo , Everolimo/administração & dosagem , Everolimo/uso terapêutico , Feminino , Meia-Vida , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Trastuzumab/administração & dosagem , Trastuzumab/uso terapêutico , Ultrassonografia Mamária
11.
Cancer Chemother Pharmacol ; 76(1): 171-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26006702

RESUMO

PURPOSE: Onapristone is an antiprogestin with activity in breast cancer and is under investigation for use in endometrial, ovarian and prostate cancers. Megestrol acetate and abiraterone generally show variability in absorption and, depending on the formulation, food effect. This study was conducted to determine the effect of food on 10 mg oral immediate-release (IR) onapristone and to help identify a formulation to minimize variability. METHODS: This is an open-label, randomized, crossover study to determine the pharmacokinetic profile of onapristone and its main metabolite, N-mono-desmethyl onapristone. Twelve healthy female subjects received 10 mg of oral IR onapristone after an overnight fast, or within 30 min of a high-fat, high-calorie meal with a 2-week washout between dosing periods. RESULTS: Onapristone plasma t1/2 (mean ± SD) was 4.36 ± 0.81 h for the fasted state and 3.76 ± 0.36 h for the fed state. Following food, onapristone tmax was delayed from 1 to 4 h. Food intake was also associated with a small increase in AUC0-∞ of approximately 13 % and a statistically significant decrease in Cmax of approximately 18 %. One subject experienced a 23-day delay in menses after one 10 mg onapristone dose, while another subject experienced transient grade 2 NCI-CTCAE liver enzyme elevation 3 weeks post dose. CONCLUSION: The results are consistent with previous observations, indicating that there is a small increase in onapristone exposure and a significant decrease in Cmax when taken with food. These changes are within acceptable limits set out by the FDA. Thus, our findings indicate that onapristone could be administered without regard to food.


Assuntos
Antineoplásicos/farmacocinética , Interações Alimento-Droga , Gonanos/farmacocinética , Adulto , Antineoplásicos/sangue , Estudos Cross-Over , Jejum/sangue , Jejum/metabolismo , Feminino , Gonanos/sangue , Humanos , Absorção Intestinal , Estrutura Molecular , Adulto Jovem
12.
Eur J Cardiothorac Surg ; 48(2): 228-35, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25414426

RESUMO

OBJECTIVES: Colorectal cancer is the third most commonly diagnosed cancer worldwide, with up to 25% of patients presenting with metastases at the time of diagnosis. Despite pulmonary metastasectomy many patients go on to develop pulmonary recurrence, which might be linked to the presence of lung micrometastases. In this setting, the adjuvant administration of high-dose chemotherapy by isolated lung perfusion (ILP) has shown encouraging results. However, the tolerance to and efficacy of modern gemcitabine (GEM)-based chemotherapy regimens during adjuvant ILP remain unknown. We conducted a dose-escalating preclinical study to evaluate the immediate and delayed toxicity of GEM in a pig model to define dose-limiting toxicity (DLT) and maximum tolerated concentration. METHODS: Twenty-three pigs were given increasing concentrations of GEM during ILP, and were awakened at the end of the procedure. The concentrations of GEM were 40, 80, 160, 320, 640 and 1280 µg/ml. Serum and lung samples were taken to measure GEM concentrations. Pulmonary damage was evaluated by histological examination and cleaved caspase-3 detection. Immediate and delayed (1 month) toxicity were recorded. RESULTS: All of the animals underwent successful ILP with GEM. No systemic leak was observed. The three pigs that received a concentration of GEM of 1280 µg/ml died of hypoxia after lung recirculation at the end of the procedure. Eleven pigs survived for 1 month. Major lung toxicity was observed for the concentration of GEM of 640 µg/ml, both at the end of the procedure and after 1 month. DLT was defined at the concentration of 640 µg/ml and the maximum tolerated dose (MTD) was defined at the concentration of 320 µg/ml. CONCLUSIONS: ILP with GEM is a safe and reproducible technique in this large-animal model, which includes 1 month of survival. The MTD in this pig model was a concentration of GEM of 320 µg/ml.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Antimetabólitos Antineoplásicos/toxicidade , Quimioterapia do Câncer por Perfusão Regional/efeitos adversos , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/secundário , Doença Aguda , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Anestesia Geral/métodos , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Quimioterapia do Câncer por Perfusão Regional/métodos , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Desoxicitidina/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Pulmão/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Sus scrofa , Gencitabina
13.
Breast ; 23(5): 663-9, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25065668

RESUMO

OBJECTIVE: This phase I study assessed the pharmacokinetic (PK), tolerability, safety and preliminary clinical activity of tamoxifen (T) and lapatinib (L) in patients with metastatic breast cancer (MBC). METHODS: Patients (pts) with hormone receptor positive MBC, irrespective of HER-2 status, were randomly assigned to T → T + L group, tamoxifen in cycle 1 for 28 days then adding lapatinib on day 1 of cycle 2; or L → T + L group, lapatinib in cycle 1 for 14 days, then adding tamoxifen on day 1 of cycle 2 to evaluate the potential drug-drug PK interaction at steady-state. The dose of tamoxifen was 20 mg/day and lapatinib 1500 mg/day. RESULTS: Twenty-five pts were enrolled of which 23 started treatment, five (22%) of them were HER-2 positive. Median age was 59 years and 96% had PS ≤1. Eleven (91.7%) pts in the T → T + L group and 10 (76.9%) in L → T + L group received at least 2 cycles of treatment. The most frequently reported drug-related adverse events (>25% of patients) were diarrhoea (62%), anaemia (56%), rash (52%), fatigue (52%), dermatology other (34%) and leukopenia (28%). Grade 3-4 drug-related toxicities were infrequent (<10%). No cardiotoxicity was observed. T plasma concentrations did not appeared to be affected by the presence of lapatinib. L steady-state plasma concentrations were 20% lower after 28 days of co-administration with T. Eight (36.4%) patients experienced stable disease and median progression free survival was 2.7 months. CONCLUSIONS: The combination of L and T was safe and clinically active. T affected L plasma concentrations, which remained within the therapeutic index.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/sangue , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Lapatinib , Pessoa de Meia-Idade , Metástase Neoplásica , Quinazolinas/administração & dosagem , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Tamoxifeno/administração & dosagem , Resultado do Tratamento
14.
J Infect Dis ; 210(5): 824-33, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24604822

RESUMO

Granulomas are the hallmark of Mycobacterium tuberculosis infection. As the host fails to control the bacteria, the center of the granuloma exhibits necrosis resulting from the dying of infected macrophages. The release of the intracellular pool of nucleotides into the surrounding medium may modulate the response of newly infected macrophages, although this has never been investigated. Here, we show that extracellular adenosine triphosphate (ATP) indirectly modulates the expression of 272 genes in human macrophages infected with M. tuberculosis and that it induces their alternative activation. ATP is rapidly hydrolyzed by the ecto-ATPase CD39 into adenosine monophosphate (AMP), and it is AMP that regulates the macrophage response through the adenosine A2A receptor. Our findings reveal a previously unrecognized role for the purinergic pathway in the host response to M. tuberculosis. Dampening inflammation through signaling via the adenosine A2A receptor may limit tissue damage but may also favor bacterial immune escape.


Assuntos
Trifosfato de Adenosina/metabolismo , Macrófagos/imunologia , Macrófagos/microbiologia , Mycobacterium tuberculosis/imunologia , Monofosfato de Adenosina/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Receptores Purinérgicos P1/metabolismo , Transdução de Sinais
15.
Breast Cancer Res Treat ; 139(2): 421-8, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23666532

RESUMO

We have previously reported an association between ABCB1 C3435T polymorphism and docetaxel pharmacokinetics in breast cancer patients. We therefore investigated whether these parameters could account for variations in pathological response. Five ABCB1 polymorphisms including C3435T polymorphism were analyzed in breast cancer patients receiving neoadjuvant chemotherapy with doxorubicin and docetaxel (n = 101). Pathological response was assessed using the Sataloff classification. Pharmacokinetic analysis was performed for the first course of docetaxel (n = 84). No significant association was found between ABCB1 polymorphisms or docetaxel pharmacokinetics and pathological complete response. C3435T genotype was an independent predictive factor of good response in breast (response >50 %, i.e., Sataloff T-A and T-B): OR: 4.6 (95 % CI: 1.3-16.1), p = 0.015, for TT patients versus CT and CC patients. Area under the plasma concentration-time curve (AUC) of docetaxel was the only independent predictive factor of the total absence of response in breast (Sataloff T-D): OR: 14.3, (95 % CI: 1.7-118), p = 0.015, for AUC of docetaxel <3,500 µg h/L versus ≥3,500 µg h/L. These results suggest that C3435T polymorphism and docetaxel exposure are involved in the response to neoadjuvant chemotherapy in breast cancer patients and may be useful to optimize individualized therapy.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Polimorfismo Genético , Taxoides/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP , Antineoplásicos/farmacocinética , Neoplasias da Mama/patologia , Docetaxel , Feminino , Genótipo , Humanos , Terapia Neoadjuvante , Estadiamento de Neoplasias , Prognóstico , Taxoides/farmacocinética , Resultado do Tratamento
16.
Cancer Chemother Pharmacol ; 71(6): 1499-506, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23543270

RESUMO

PURPOSE: This study evaluated the tolerability, pharmacokinetics, and preliminary antitumor activity of EZN-2208, a water-soluble poly(ethylene) glycol conjugate of SN38. METHODS: Patients with advanced malignancies were enrolled in dose-escalating cohorts (3 + 3 design). EZN-2208 was administered as a 1-h intravenous infusion given weekly for 3 weeks per each 4-week cycle. Doses ranged from 1 to 12 mg/m(2). RESULTS: Forty-one patients received EZN-2208. All patients had received prior cancer therapy (median = 2, range = 1-11). Twenty patients (49 %) had received prior irinotecan, and one patient had received prior topotecan. One patient in the 9-mg/m(2) cohort had dose-limiting toxicity (grade 3 febrile neutropenia), and one patient in the 12-mg/m(2) cohort had grade 3 neutropenia that resulted in the inability to deliver the third dose of EZN-2208. The most commonly reported drug-related adverse events were nausea (51 %), diarrhea (46 %), fatigue (41 %), alopecia (29 %), neutropenia (24 %), and vomiting (22 %). Administration of EZN-2208 results in prolonged exposure to SN38. Stable disease, sometimes prolonged, was observed as best response. CONCLUSIONS: EZN-2208 has an acceptable safety profile in previously treated patients with advanced malignancies. The recommended phase II dose of EZN-2208 administered according to this schedule was 9 mg/m(2).


Assuntos
Antineoplásicos/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Pró-Fármacos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , Interpretação Estatística de Dados , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Irinotecano , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/uso terapêutico , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico , Resultado do Tratamento
17.
Eur J Cancer ; 49(10): 2392-402, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23540589

RESUMO

BACKGROUND: Dose-finding phase I trials in children are usually carried out once clinical data have already been accumulated in the adult population. The objectives, place and role of paediatric dose-finding trials are investigated in the era of molecularly targeted agents (MTAs). METHODS: Phase I paediatric oncology trials of MTAs approved in adults before June 15th, 2012 were reviewed. The recommended phase II dose (RPIID) was compared to the body surface area (BSA)-adjusted approved dose in adults. Toxicity profile was compared to the findings from the corresponding adult phase I trials. RESULTS: Fifteen MTAs out of a total of 25 MTAs approved in the adult population have been evaluated in 19 single-agent phase I paediatric trials. Trials included a median of 30 children with a median of four dose levels. The paediatric RPIID ranged between 90% and 130% of the BSA-adjusted approved dose in adults for 70% of the trials (75% of compounds). Overall, 63% of children did not receive an optimal dose. The most marked discrepancy involved sunitinib. Safety profiles described in phase I paediatric trials were usually similar to those reported in the adult population. CONCLUSIONS: These data suggest that dose-finding studies might not be necessary for all the MTAs in children. Except in the case of a narrow therapeutic index, early-phase trials validating pharmacokinetics, pharmacodynamic markers and efficacy findings from adults while controlling for toxicity appear to be a possible alternative to accelerate drug development in paediatric oncology.


Assuntos
Antineoplásicos/administração & dosagem , Relação Dose-Resposta a Droga , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Criança , Pré-Escolar , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Diarreia/induzido quimicamente , Exantema/induzido quimicamente , Fadiga/induzido quimicamente , Humanos , Neoplasias/metabolismo , Neutropenia/induzido quimicamente , Projetos de Pesquisa , Resultado do Tratamento
18.
PLoS One ; 8(3): e59485, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23527205

RESUMO

BACKGROUND: The lung is a frequent site of colorectal cancer (CRC) metastases. After surgical resection, lung metastases recurrences have been related to the presence of micrometastases, potentially accessible to a high dose chemotherapy administered via adjuvant isolated lung perfusion (ILP). We sought to determine in vitro the most efficient drug when administered to CRC cell lines during a short exposure and in vivo its immediate and delayed tolerance when administered via ILP. METHODS: First, efficacy of various cytotoxic molecules against a panel of human CRC cell lines was tested in vitro using cytotoxic assay after a 30-minute exposure. Then, early (operative) and delayed (1 month) tolerance of two concentrations of the molecule administered via ILP was tested on 19 adult pigs using hemodynamic, biological and histological criteria. RESULTS: In vitro, gemcitabine (GEM) was the most efficient drug against selected CRC cell lines. In vivo, GEM was administered via ILP at regular (20 µg/ml) or high (100 µg/ml) concentrations. GEM administration was associated with transient and dose-dependant pulmonary vasoconstriction, leading to a voluntary decrease in pump inflow in order to maintain a stable pulmonary artery pressure. After this modulation, ILP using GEM was not associated with any systemic leak, systemic damage, and acute or delayed histological pulmonary toxicity. Pharmacokinetics studies revealed dose-dependant uptake associated with heterogenous distribution of the molecule into the lung parenchyma, and persistent cytotoxicity of venous effluent. CONCLUSIONS: GEM is effective against CRC cells even after a short exposure. ILP with GEM is a safe and reproducible technique.


Assuntos
Antineoplásicos/farmacologia , Quimioterapia Adjuvante/métodos , Neoplasias Colorretais/patologia , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Perfusão/métodos , Análise de Variância , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Desoxicitidina/farmacocinética , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Relação Dose-Resposta a Droga , Hemodinâmica , Humanos , Suínos , Resultado do Tratamento , Vasoconstrição/efeitos dos fármacos , Gencitabina
19.
Crit Rev Oncol Hematol ; 88(1): 42-56, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23523056

RESUMO

To date, oral everolimus is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with vascular endothelial growth factor-targeted therapy, and intravenous temsirolimus for the first-line treatment of patients with poor prognosis metastatic renal cell carcinoma. However, some factors could guide the treatment choice aiming to individualize a treatment plan. Besides the crucial issue of treatment efficacy, other factors are to be considered such as disease status, histological subtype, extent of the disease, patient-specific factors, and agent-specific factors. All of these considerations have to stay in the frame of guideline recommendations which represent evidence-based medicine. The purpose of this article is to summarize the main pharmacological and pharmacokinetic characteristics of mTOR inhibitors, and to define targeted populations according to prognostic indexes.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/farmacologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento
20.
Cancer ; 118(24): 6144-51, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-22674635

RESUMO

BACKGROUND: EZN-2208 is a water-soluble, polyethylene glycol drug conjugate of SN38, which is the active moiety of irinotecan. In this study, the authors evaluated the tolerability, pharmacokinetics (PK), and activity of EZN-2208 in adult patients with advanced solid tumors. METHODS: Patients in sequential cohorts (3 + 3 design) received intravenous EZN-2208 at doses between 1.25 mg/m(2) and 25 mg/m(2) once every 21 days. RESULTS: Thirty-nine patients received EZN-2208. The median number of prior therapies was 2 (range, 0-10 prior therapies). Seventeen patients received prior irinotecan. Two maximum tolerated doses (MTDs) were defined: EZN-2208 with (16.5 mg/m(2)) and without (10 mg/m(2)) granulocyte-colony-stimulating factor (G-CSF). The dose-limiting toxicity (DLT) was febrile neutropenia. Two of 19 patients who were heterozygous for a polymorphism in the uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) gene (UGT1A1*28) developed DLTs (dose, 25 mg/m(2) with G-CSF), and 2 patients who were homozygous for UGT1A1*28 were treated without DLTs (dose, 5 mg/m(2)). PK analysis indicated a mean terminal half-life of 19.4 ± 3.4 hours. Sixteen patients (41%) achieved stable disease, including 6 of 39 patients (15%) who had stable disease that lasted ≥ 4 months. One patient with cholangiocarcinoma (no prior irinotecan) achieved a short-lived 32% tumor regression. Among 6 patients who had stable disease that lasted for ≥ 4 months, 3 had received prior irinotecan, and 1 had KRAS-positive colorectal cancer. CONCLUSIONS: EZN-2208 was well tolerated and produced stable disease that lasted for ≥ 4 months/unconfirmed partial responses in 7 of 39 heavily pretreated patients (18%) with advanced solid tumors, including those who had failed prior irinotecan therapy.


Assuntos
Camptotecina/análogos & derivados , Neoplasias/tratamento farmacológico , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/uso terapêutico , Adulto , Idoso , Camptotecina/farmacocinética , Camptotecina/uso terapêutico , DNA de Neoplasias/genética , Feminino , Seguimentos , Glucuronosiltransferase/sangue , Glucuronosiltransferase/genética , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/genética , Reação em Cadeia da Polimerase , Polimorfismo Genético/genética , Prognóstico , Segurança , Distribuição Tecidual
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