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1.
Gan To Kagaku Ryoho ; 47(9): 1351-1353, 2020 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-33130698

RESUMO

The characteristic adverse events of olaparib, a PARP inhibitor, are nausea, vomiting, and anemia, and interstitial pneumonia is rarely reported. We report a case of interstitial pneumonia following the treatment of a metastatic breast cancer with olaparib. The patient was a 34-year-old woman. In March 2018, she was diagnosed with stage Ⅳ breast cancer(multiple lung metastases). She was treated with epirubicin and cyclophosphamide followed by paclitaxel. In November 2018, brain and spinal cord metastases were detected, and she was treated with radiation. In December 2018, a BRCA1 deleterious mutation was confirmed, and treatment with olaparib was initiated. Six weeks later, olaparib was discontinued due to anemia; it also caused interstitial pneumonia. The interstitial pneumonia resolved following multidisciplinary treatment during hospitalization. Subsequently, she was treated with cyclophosphamide/methotrexate/fluorouracil. It is necessary to consider interstitial pneumonia as an adverse effect of olaparib.


Assuntos
Neoplasias da Mama , Doenças Pulmonares Intersticiais , Adulto , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Doenças Pulmonares Intersticiais/induzido quimicamente , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos
2.
Artigo em Inglês | MEDLINE | ID: mdl-32942346

RESUMO

Introduction: Bipolar disorder is a complex mood disorder characterized by a chronic and subtle course of fluctuating manic/hypomanic and depressive symptoms. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist with serotonin 5-HT1A receptor partial agonist and serotonin 5-HT2A antagonist properties, is approved to treat manic and depressive episodes of bipolar disorder. Post hoc analyses evaluated efficacy across symptoms in bipolar depression. Methods: Pooled data were analyzed from 3 phase 2 or 3, randomized, double-blind, placebo-controlled studies of adults with bipolar disorder and a major depressive episode. Mean change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score and individual item scores were analyzed in individual dose groups (1.5 mg/d, 3 mg/d) and overall cariprazine (1.5-3 mg/d). Pooled safety was evaluated via adverse events. Results: A significantly greater difference in mean change from baseline in MADRS total score was seen for each cariprazine dose group versus placebo (least squares mean difference vs placebo: 1.5-3 mg/d = -2.6, 1.5 mg/d = -2.8, 3 mg/d = -2.4) (P < .001 all). Significant differences versus placebo were seen on all individual MADRS items except inner tension for the overall cariprazine group (P < .05). Cariprazine was generally well tolerated. Conclusions: Cariprazine demonstrated broad efficacy across symptoms of depression in bipolar disorder. In previous post hoc analyses, cariprazine also demonstrated broad efficacy across manic symptoms, suggesting that it is effective across the wide range of symptoms on the bipolar spectrum. A 1.5-mg/d starting dose and slow titration resulted in lower rates of some adverse events in the bipolar depression studies versus the mania studies. Trial Registration: ClinicalTrials.gov identifiers: NCT01396447, NCT02670538, NCT02670551.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Neurotransmissores/farmacologia , Piperazinas/farmacologia , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurotransmissores/administração & dosagem , Neurotransmissores/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Resultado do Tratamento
3.
Anticancer Res ; 40(9): 5291-5294, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878819

RESUMO

BACKGROUND/AIM: Palbociclib is an FDA-approved cyclin-dependent kinase inhibitor for the treatment of advanced breast cancer. Limited information is available regarding the toxicity of palbociclib and concurrent radiation therapy. CASE REPORT: Herein, we report a case of esophageal toxicity in a patient treated with palbociclib and radiation therapy. A 63-year-old woman was treated with palbociclib followed by palliative radiation therapy. The patient presented three days after completing radiation therapy with severe odynophagia, and dysphagia and was found to have grade 2-3 esophageal ulcers. Palbociclib and radiation therapy was held on admission, and a resolution of her symptoms and improvement in her oral intake was noted at which time she was restarted on palbociclib with no further radiation treatment. CONCLUSION: Caution is advised when patients are undergoing concurrent palbociclib and even low-dose palliative radiation treatment. In these patients, providers should maintain a high index of suspicion for toxicities such as dermatitis or mucositis.


Assuntos
Antineoplásicos/efeitos adversos , Mucosite/diagnóstico , Mucosite/etiologia , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas/efeitos adversos , Radioterapia Adjuvante/efeitos adversos , Idoso , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/complicações , Neoplasias da Mama/terapia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Endoscopia Gastrointestinal , Feminino , Humanos , Cuidados Paliativos , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Dosagem Radioterapêutica , Radioterapia Adjuvante/métodos , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
5.
Lancet Oncol ; 21(9): 1155-1164, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32771088

RESUMO

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer. METHODS: The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004. FINDINGS: Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3-90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks. INTERPRETATION: Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy. FUNDING: AstraZeneca.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Adulto Jovem
6.
Dermatol Online J ; 26(3)2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32609449

RESUMO

Disseminated superficial actinic porokeratosis (DSAP) is an uncommon skin condition that can be inherited or may occur sporadically with multiple red-brown, thin plaques in a photodistribution. The condition more often affects middle-aged women and is often recalcitrant to therapy. In rare literature reports, systemic medications can trigger exacerbation or promote inflammation in pre-existing lesions of DSAP. We present a novel case of chemotherapy-associated DSAP inflammation in a 66-year-old woman after triple therapy with durvalumab (PD-L1 inhibitor), olaparib (PARP inhibitor) and paclitaxel, showing similarities to primary lichen planus-like eruption from immune checkpoint inhibitors.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inflamação/diagnóstico , Erupções Liquenoides/diagnóstico , Paclitaxel/efeitos adversos , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Poroceratose/patologia , Idoso , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Diagnóstico Diferencial , Erupção por Droga , Feminino , Humanos , Inflamação/induzido quimicamente , Poroceratose/complicações , Pele/patologia
7.
BMC Neurol ; 20(1): 282, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32664877

RESUMO

BACKGROUND: Ischemic stroke is a leading cause of morbidity and mortality. Thrombolytic therapy improves disability and survival rates; however, to be effective, it must be given within 4.5 h of onset. Moreover, thrombolytic therapy is frequently contraindicated. Therefore, alternative therapeutic options are required. In China, cinepazide maleate injection has been shown to improve the cerebral collateral circulation and further reduce disability in stroke patients; however, very few studies investigating this therapy have been conducted to date. Therefore, this study aimed to further confirm the efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke. METHODS: Patients with acute ischemic stroke were administered an intravenous infusion of 320 mg cinepazide maleate or placebo once daily for 14 days. All patients were also administered basic therapy (citicoline sodium). The primary efficacy endpoint was the proportion of patients with a modified Rankin scale (mRS) ≤2 on day 90. Secondary efficacy endpoints included Barthel Index ≥95. Safety was evaluated by recording all adverse events (AEs), monitoring laboratory parameters and vital signs, and electrocardiogram. RESULTS: In total, 937 patients with an acute ischemic stroke were included, with a mean (standard deviation, SD) National Institutes of Health Stroke Scale score of 8.8 (2.4) and a mean (SD) stroke onset of 30.9 (11.4) hours prior. Following treatment for 90 days, the proportion of patients with an mRS score ≤ 2 was significantly higher in the cinepazide maleate group than in the control group (60.9% vs. 50.1%; p = 0.0004). Moreover, the proportion of patients with a Barthel Index of ≥95 on day 90 was also significantly higher in the cinepazide maleate group than in the control group (53.4% vs. 46.7%; p = 0.0230). There were no statistically significant differences in safety parameters between the cinepazide maleate and control groups. CONCLUSIONS: The results of this study show that cinepazide maleate injection is superior to placebo in improving neurological function and activities of daily living, reducing disability, and promoting functional recovery in patients with acute ischemic stroke. Cinepazide maleate injection was safe and well tolerated with no unexpected AEs reported. TRIAL REGISTRATION: Chinese Clinical Trial Registry CTR20160292 and ChiCTR1900023827 . Retrospectively registered June 13, 2019.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Piperazinas , Acidente Vascular Cerebral/tratamento farmacológico , Vasodilatadores , China , Método Duplo-Cego , Humanos , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Vasodilatadores/efeitos adversos , Vasodilatadores/uso terapêutico
8.
Gan To Kagaku Ryoho ; 47(6): 997-999, 2020 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-32541183

RESUMO

An 89-year-old woman with recurrent hormone receptor-positive and HER2-negative breast cancer was treated with fulvestrant-palbociclib combination therapy. However, 3 months after therapy initiation, she presented to our emergency room with dyspnea and fever and was admitted to our hospital because of respiratory failure. After radiological and microbiological evaluation, she was diagnosed with palbociclib-related pneumonitis. Accordingly, corticosteroids were administered, and the patient exhibited initial clinical and radiological improvement. However, pneumonitis recurred following corticosteroid tapering; her condition did not improve with high-dose intravenous corticosteroid administration, leading to death. Palbociclib- related pneumonitis is rare, but clinicians need to pay attention to this potentially lethal adverse event.


Assuntos
Neoplasias da Mama , Doenças Pulmonares Intersticiais , Piperazinas/efeitos adversos , Piridinas/efeitos adversos , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Intervalo Livre de Doença , Estradiol , Feminino , Humanos , Doenças Pulmonares Intersticiais/induzido quimicamente , Recidiva Local de Neoplasia , Receptor ErbB-2
9.
Psychiatr Danub ; 32(1): 36-45, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32303028

RESUMO

BACKGROUND: Cariprazine is a new atypical antipsychotic drug approved for the treatment of schizophrenia and bipolar disorders. METHODS: we searched the published randomized controlled-trials (RCT) to review cariprazine efficacy and tolerability using the databases (PubMed, EUDRACT, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials) for cariprazine role in managing the following psychiatric conditions (schizophrenia, bipolar mania, bipolar depression and major depressive disorder). A meta-analysis was conducted using the identified 13 clinical trials to assess efficacy using with the outcomes: positive and negative syndrome scale (PANSS), clinical global impressions - severity of Illness (CGI-S), young mania rating scales (YMRS), Montgomery Asberg depression rating scale (MADRS) and Hamilton rating scale for depression (HAM-D). The risk of discontinuation due to adverse effects and common side effects were examined. RESULTS: The mean difference in change from baseline for PANSS was -6.23 (95% Confidence Interval (CI) -7.18, -5.28) favoring cariprazine treatment (p<0.00001). Similarly, mean difference for CGI-S was -0.36 (95% CI -0.41, -0.30), YMRS -5.64 (95% CI -6.86, -4.43), MADRS -1.43 (95% CI -1.88, -0.99) and HAM-D -1.52 (95% CI -2.28, -0.76). The risk ratio (RR) of discontinuing due to adverse events was 1.18 (95% CI 1.01, 1.38) meaning risk increased by 18% in cariprazine group with RR for EPS related side effects 2.82 (95% CI 2.47, 3.22) reflecting an increased risk of experiencing EPS related side effects by 182%. Cariprazine was also associated with an increased incidence of side effects such as akathisia, nausea and insomnia. CONCLUSION: Cariprazine demonstrates significant improvements in symptom intensity control in patients suffering from psychiatric conditions including schizophrenia, bipolar disorders and depression and is considered well-tolerated with similar rates of trials discontinuation; however, cariprazine was associated with a higher risk of EPS side effects. These findings will guide psychiatrists and pharmacists in their clinical role for supporting psychiatric patients care.


Assuntos
Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/psicologia , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
10.
J Clin Psychiatry ; 81(3)2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32237292

RESUMO

OBJECTIVE: To compare longitudinal metabolic effects of 7 antipsychotics, including body mass index (BMI), waist circumference (WC), blood pressure (BP), glucose, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C); to investigate risk factors for metabolic syndrome (MetS); and to make recommendations on frequency and timing of monitoring metabolic measurements. METHODS: This randomized, open-label, pharmacologic trial was conducted among patients with schizophrenia (DSM-IV) in 32 hospitals across China. Patients were randomly assigned to 7 groups and assessed at baseline, 2, 4, and 6 weeks. Linear mixed-effect models were used to assess changes of metabolic measures over time. Multivariable logistic regression analysis was performed to investigate the risk factors for MetS. RESULTS: In total, 2,550 (718 drug-naïve) of 2,774 patients finished the study between July 6, 2010, and November 30, 2011. We found significant (P < .05) changes for BMI, WC, TG, and LDL-C, with TG and LDL-C reaching a plateau. Interactions between baseline metabolic condition and changes over time were observed for BMI (χ² = 43.11, P < .001), WC (χ² = 36.34, P < .001), systolic BP (χ² = 11.92, P = .002), glucose (χ² = 6.09, P = .01), and TG (χ² = 6.01, P = .01). Antipsychotics generally had greater adverse effects on patients who were initially screened as metabolically normal. After controlling for other associated factors, we found that antipsychotics resulted in differing risk for incident MetS, with a similar pattern to findings in other populations: olanzapine (odds ratio [OR] = 3.36, P < .001) > quetiapine (OR = 3.29, P < .001) > perphenazine (OR = 2.73, P = .007) > risperidone (OR = 2.21, P = .02) > aripiprazole (OR = 1.74, P = .15) ≈ haloperidol (OR = 1.75, P = .22) ≈ ziprasidone (OR = 1, reference). CONCLUSIONS: Metabolic traits should be monitored frequently in early stages of antipsychotic treatment due to rapid and substantial changes. Clinicians should not assume low risk for patients with normal metabolic parameters at baseline. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR-TRC-10000934.


Assuntos
Antipsicóticos/efeitos adversos , Síndrome Metabólica/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/uso terapêutico , Aripiprazol/efeitos adversos , Aripiprazol/uso terapêutico , Glicemia/efeitos dos fármacos , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Masculino , Olanzapina/efeitos adversos , Olanzapina/uso terapêutico , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Fumarato de Quetiapina/efeitos adversos , Fumarato de Quetiapina/uso terapêutico , Fatores de Risco , Risperidona/efeitos adversos , Risperidona/uso terapêutico , Esquizofrenia/metabolismo , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico , Triglicerídeos/sangue
11.
Am J Trop Med Hyg ; 103(1): 378-393, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32314694

RESUMO

Malaria volunteer infection studies (VISs) accelerate new drug and vaccine development. In the induced blood-stage malaria (IBSM) model, volunteers are inoculated with erythrocytes infected with Plasmodium falciparum. Observations of elevated liver enzymes in the IBSM model with new chemical entities (NCEs) promoted an analysis of available data. Data were reviewed from eight IBSM studies of seven different NCEs, plus two studies with the registered antimalarial piperaquine conducted between June 2013 and January 2017 at QIMR Berghofer, Brisbane, Australia. Alanine aminotransferase (ALT) was elevated (> 2.5 times the upper limit of normal [×ULN]) in 20/114 (17.5%) participants. Of these, 8.9% (10/114) had moderate increases (> 2.5-5 × ULN), noted in seven studies of six different NCEs ± piperaquine or piperaquine alone, and 8.9% (10/114) had severe elevations (> 5 × ULN), occurring in six studies of six different NCEs ± piperaquine. Aspartate aminotransferase (AST) was elevated (> 2.5 × ULN) in 11.4% (13/114) of participants, across six of the 10 studies. Bilirubin was > 2 × ULN in one participant. Published data from other VIS models, using sporozoite inoculation by systemic administration or mosquito feeding, also showed moderate/severe liver enzyme elevations. In conclusion, liver enzyme elevations in IBSM studies are most likely multifactorial and could be caused by the model conditions, that is, malaria infection/parasite density and/or effective parasite clearance, or by participant-specific risk factors, acetaminophen administration, or direct hepatotoxicity of the test drug. We make recommendations that may mitigate the risk of liver enzyme elevations in future VISs and propose measures to assist their interpretation, should they occur.


Assuntos
Alanina Transaminase/metabolismo , Antimaláricos/efeitos adversos , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Voluntários Saudáveis , Malária Falciparum/tratamento farmacológico , Parasitemia/tratamento farmacológico , Acrilamidas/efeitos adversos , Adamantano/efeitos adversos , Adamantano/análogos & derivados , Adulto , Aminopiridinas/efeitos adversos , Aminoquinolinas/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Transfusão de Eritrócitos , Eritrócitos/parasitologia , Feminino , Compostos Ferrosos/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Indóis/efeitos adversos , Isoquinolinas/efeitos adversos , Masculino , Metalocenos/efeitos adversos , Peróxidos/efeitos adversos , Piperazinas/efeitos adversos , Plasmodium falciparum , Primaquina/efeitos adversos , Pirimidinas/efeitos adversos , Quinolinas/efeitos adversos , Compostos de Espiro/efeitos adversos , Sulfonas/efeitos adversos , Triazóis/efeitos adversos , Adulto Jovem
12.
N Engl J Med ; 382(22): 2091-2102, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32343890

RESUMO

BACKGROUND: Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers. METHODS: We conducted a randomized, open-label, phase 3 trial evaluating the PARP inhibitor olaparib in men with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. Cohort A (245 patients) had at least one alteration in BRCA1, BRCA2, or ATM; cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue. Patients were randomly assigned (in a 2:1 ratio) to receive olaparib or the physician's choice of enzalutamide or abiraterone (control). The primary end point was imaging-based progression-free survival in cohort A according to blinded independent central review. RESULTS: In cohort A, imaging-based progression-free survival was significantly longer in the olaparib group than in the control group (median, 7.4 months vs. 3.6 months; hazard ratio for progression or death, 0.34; 95% confidence interval, 0.25 to 0.47; P<0.001); a significant benefit was also observed with respect to the confirmed objective response rate and the time to pain progression. The median overall survival in cohort A was 18.5 months in the olaparib group and 15.1 months in the control group; 81% of the patients in the control group who had progression crossed over to receive olaparib. A significant benefit for olaparib was also seen for imaging-based progression-free survival in the overall population (cohorts A and B). Anemia and nausea were the main toxic effects in patients who received olaparib. CONCLUSIONS: In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone. (Funded by AstraZeneca and Merck Sharp & Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).


Assuntos
Antineoplásicos/uso terapêutico , Mutação com Perda de Função , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Androstenos/efeitos adversos , Androstenos/uso terapêutico , Antineoplásicos/efeitos adversos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Genes BRCA1 , Genes BRCA2 , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Feniltioidantoína/efeitos adversos , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia
13.
Gynecol Oncol ; 157(2): 500-507, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32173049

RESUMO

BACKGROUND: Olaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2-mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease. METHODS: Median progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non­platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations. RESULTS: Non­platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3-3.5× times greater than intravenous non­platinum-based regimens. CONCLUSION: High costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/economia , Administração Oral , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Bevacizumab/economia , Carcinoma Epitelial do Ovário/economia , Análise Custo-Benefício , Custos de Medicamentos , Feminino , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Indazóis/economia , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/economia , Infusões Intravenosas , Cadeias de Markov , Modelos Estatísticos , Recidiva Local de Neoplasia/economia , Neoplasias Ovarianas/economia , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Ftalazinas/economia , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperazinas/economia , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/economia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Qualidade de Vida , Estados Unidos
14.
Breast Cancer Res ; 22(1): 27, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164785

RESUMO

BACKGROUND: Palbociclib improves outcomes for women with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC). Dose reductions are recommended for the management of hematologic toxicities. A previous pooled analysis from the PALOMA clinical trials showed that 36.9% of patients required dose reduction, predominantly during the first 6 months of treatment and with decreasing frequency during subsequent 28-day treatment cycles (C). Previous data have shown that palbociclib dose reductions do not affect efficacy. This pooled, post hoc analysis evaluated the frequency of hematologic adverse events (AEs) before and after palbociclib dose reduction in PALOMA-1, PALOMA-2, and PALOMA-3. METHODS: This analysis evaluated the frequency of hematologic AEs 30 days before dose reduction and during each subsequent treatment from C1 to C6 among patients who required palbociclib dose reduction. Data were pooled from 3 randomized studies. PALOMA-1 was a phase 2, open-label study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or letrozole alone. PALOMA-2 was a phase 3, double-blind study of postmenopausal patients untreated for ABC receiving palbociclib plus letrozole or placebo plus letrozole. PALOMA-3 was a phase 3, double-blind study of pre/perimenopausal or postmenopausal patients, whose disease progressed on prior endocrine therapy, receiving palbociclib plus fulvestrant or placebo plus fulvestrant. RESULTS: A total of 311 (35.5%) patients with HR+/HER2- ABC required a palbociclib dose reduction (93.6% due to AEs) from 125 to 100 mg. Mean patient age was 59.9 years, and 46.9% of patients had visceral disease. Median time to dose reduction was 70 days. The majority of dose reductions occurred within 3 months of starting palbociclib treatment. Incidences of all-grade and grades 3/4 hematologic AEs were lower following dose reduction. CONCLUSIONS: A decrease in frequency and severity of hematologic AEs, including febrile neutropenia, following palbociclib dose reduction was observed, supporting the recommended use of dose reduction in AE management. TRIAL REGISTRATION: These studies were sponsored by Pfizer. ClinicalTrials.gov: NCT00721409; registration date July 24, 2008. ClinicalTrials.gov: NCT01740427; registration date December 4, 2012. ClinicalTrials.gov: NCT01942135; registration date September 13, 2013.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/metabolismo , Doenças Hematológicas/induzido quimicamente , Piperazinas/efeitos adversos , Piridinas/efeitos adversos , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Segurança do Paciente , Receptores de Progesterona/metabolismo , Resultado do Tratamento
15.
Support Care Cancer ; 28(5): 2435-2442, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32048043

RESUMO

Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved as maintenance therapy of recurrent ovarian cancer (OC) patients with a BRCA mutation. To achieve the maximum clinical benefit, adherence to olaparib must be persistent. However, in clinical practice, this is challenged by the frequent suboptimal management of toxicities. In view of the expanding use of olaparib also in Italy, physicians must learn how to adequately and promptly manage drug toxicities not to unnecessarily interrupt or reduce the dose. The experts agreed that nausea,vomiting, anemia, and fatigue are the most frequent events experienced by OC patients on olaparib, and that these toxicities usually develop early during treatment, are mainly of grade 1-2 and transient and can be managed with simple non-pharmacological interventions. By sharing their real-world experiences, the panel prepared, for each toxicity, an algorithm organized by grade and besides the procedures indicated in the local label, included supportive care interventions based also on nutritional and lifestyle modifications and psycho-oncology consultation. Moreover, in view of the tablet entry into the Italian market, the full and reduced dosages of capsules and tablets were compared. This practical guidance is intended to be a tool to support especially less-experienced physicians in the management of these complex patients, with the aim to help preventing the worsening of patients' conditions and the unnecessary interruption/reduction of olaparib dosage, which may jeopardize treatment efficacy.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Anemia/induzido quimicamente , Antineoplásicos/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Fadiga/induzido quimicamente , Feminino , Humanos , Itália , Mutação , Náusea/induzido quimicamente , Náusea/terapia , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/genética , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Vômito/induzido quimicamente
16.
Sci Rep ; 10(1): 2585, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066817

RESUMO

Polypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles.


Assuntos
Antineoplásicos/química , Indazóis/química , Indóis/química , Ftalazinas/química , Piperazinas/química , Piperidinas/química , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/química , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Sítios de Ligação , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Células HEK293 , Humanos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Indóis/administração & dosagem , Indóis/efeitos adversos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/patologia , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Polifarmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Especificidade por Substrato
17.
Gynecol Oncol ; 157(1): 214-221, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31959492

RESUMO

OBJECTIVE: We assessed the safety and maximum tolerated dose (MTD) of the poly ADP-ribose polymerase (PARP) inhibitor olaparib with intravenous (IV)/intraperitoneal (IP) cisplatin/paclitaxel and IV bevacizumab, followed by olaparib and bevacizumab maintenance, in patients with newly diagnosed ovarian cancer who had undergone primary debulking surgery. METHODS: Treatment included: (Cycles 1-6) Day 1, IV paclitaxel 135 mg/m2/3 h + (from Cycle 2 onward) bevacizumab 15 mg/kg; Day 2, IP cisplatin 75 mg/m2; Days 2-8, olaparib (50/100/200 mg BID); Day 8, IP paclitaxel 60 mg/m2 of a 21-day cycle. Maintenance (Cycles 7-22) included: olaparib 300 mg BID and bevacizumab 15 mg/kg Day 1. The primary endpoint was MTD of olaparib, chemotherapy, and bevacizumab. RESULTS: Seventeen women were treated (Cohort 1 [50 mg olaparib], 8 patients; Cohort 2 [100 mg], 3 patients; and Cohort 3 [200 mg], 6 patients). Median age was 57 years (47-73); 94% had stage III disease; 29% had a germline BRCA mutation. Two of 6 patients in Cohort 3 experienced a dose-limiting toxicity (DLT). Grade 3/4 toxicities included: neutropenia (56%), lymphopenia (31%), anemia (25%), and fatigue (19%). Most patients started (88%, 81%) and completed (75%, 50%) maintenance olaparib and bevacizumab, respectively; 36% of patients on olaparib maintenance required a dose reduction. Median PFS was 33 months (26.2-NA). CONCLUSIONS: The MTD of intermittently dosed olaparib with concurrent IV/IP cisplatin/paclitaxel and bevacizumab is 100 mg BID. Non-hematologic toxicities were predominantly low grade. One-third of patients on olaparib maintenance required dose reduction.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Infusões Parenterais , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos
18.
Molecules ; 25(3)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991816

RESUMO

The increasing risk of radiation exposure underlines the need for novel radioprotective agents. Hence, a series of novel 1-(2-hydroxyethyl)piperazine derivatives were designed and synthesized. Some of the compounds protected human cells against radiation-induced apoptosis and exhibited low cytotoxicity. Compared to the previous series of piperazine derivatives, compound 8 exhibited a radioprotective effect on cell survival in vitro and low toxicity in vivo. It also enhanced the survival of mice 30 days after whole-body irradiation (although this increase was not statistically significant). Taken together, our in vitro and in vivo data indicate that some of our compounds are valuable for further research as potential radioprotectors.


Assuntos
Piperazinas/química , Piperazinas/farmacologia , Protetores contra Radiação/química , Protetores contra Radiação/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Humanos , Dose Máxima Tolerável , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Radiação Ionizante , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/efeitos adversos , Relação Estrutura-Atividade , Análise de Sobrevida
19.
J Cancer Res Clin Oncol ; 146(2): 503-514, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31745703

RESUMO

PURPOSE: Fusion genes can be therapeutically relevant if they result in constitutive activation of oncogenes or repression of tumor suppressors. However, the prevalence and role of fusion genes in female cancers remain largely unexplored. Here, we investigate the fusion gene landscape in triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC), two subtypes of female cancers with high molecular similarity but limited treatment options at present. METHODS: RNA-seq was utilized to identify fusion genes in a cohort of 18 TNBC and HGSOC patients treated with the PI3K inhibitor buparlisib and the PARP inhibitor olaparib in a phase I clinical trial (NCT01623349). Differential gene expression analysis was performed to assess the function of fusion genes in silico. Finally, these findings were correlated with the reported clinical outcomes. RESULTS: A total of 156 fusion genes was detected, whereof 44/156 (28%) events occurred in more than one patient. Low recurrence across samples indicated that the majority of fusion genes were private passenger events. The long non-coding RNA MALAT1 was involved in 97/156 (62%) fusion genes, followed in prevalence by MUC16, FOXP1, WWOX and XIST. Gene expression of FOXP1 was significantly elevated in patients with vs. without FOXP1 fusion (P= 0.02). From a clinical perspective, FOXP1 fusions were associated with a favorable overall survival. CONCLUSIONS: In summary, this study provides the first characterization of fusion genes in a cohort of TNBC and HGSOC patients. An improved mechanistic understanding of fusion genes will support the future identification of innovative therapeutic approaches for these challenging diseases.


Assuntos
Cistadenocarcinoma Seroso/genética , Fusão Gênica , Neoplasias Ovarianas/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Cistadenocarcinoma Seroso/tratamento farmacológico , Feminino , Fatores de Transcrição Forkhead/genética , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , RNA-Seq/métodos , Proteínas Repressoras/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
20.
Anticancer Drugs ; 31(1): 85-89, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31609762

RESUMO

CDK4/6 inhibitors in association with aromatase inhibitors have led to a paradigm shift in the management of metastatic positive hormone-receptors breast cancer. Liver toxicity is common with these agents, but no data are reported on the sequential use of these CDK4/6 inhibitors in case of confirmed efficacy and intolerable toxicity. In this article, we report the successful use of Palbociclib in a metastatic positive hormone-receptors breast cancer patient after initial response to Ribociclib, which was interrupted for grade 4 liver toxicity.


Assuntos
Aminopiridinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Piperazinas/efeitos adversos , Purinas/efeitos adversos , Piridinas/efeitos adversos , Aminopiridinas/administração & dosagem , Neoplasias da Mama/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Feminino , Humanos , Letrozol/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/enzimologia , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/administração & dosagem , Piridinas/administração & dosagem , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Ácido Zoledrônico/administração & dosagem
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