RESUMO
Trilaciclib is an intravenous CDK4/6 inhibitor administered prior to chemotherapy to preserve haematopoietic stem and progenitor cells and immune system function from chemotherapy-induced damage (myelopreservation). The effects of administering trilaciclib prior to carboplatin, etoposide and atezolizumab (E/P/A) were evaluated in a randomised, double-blind, placebo-controlled Phase II study in patients with newly diagnosed extensive-stage small cell lung cancer (ES-SCLC) (NCT03041311). The primary endpoints were duration of severe neutropenia (SN; defined as absolute neutrophil count <0.5 × 109 cells per L) in Cycle 1 and occurrence of SN during the treatment period. Other endpoints were prespecified to assess the effects of trilaciclib on additional measures of myelopreservation, patient-reported outcomes, antitumour efficacy and safety. Fifty-two patients received trilaciclib prior to E/P/A and 53 patients received placebo. Compared to placebo, administration of trilaciclib resulted in statistically significant decreases in the mean duration of SN in Cycle 1 (0 vs 4 days; P < .0001) and occurrence of SN (1.9% vs 49.1%; P < .0001), with additional improvements in red blood cell and platelet measures and health-related quality of life (HRQoL). Trilaciclib was well tolerated, with fewer grade ≥3 adverse events compared with placebo, primarily due to less high-grade haematological toxicity. Antitumour efficacy outcomes were comparable. Administration of trilaciclib vs placebo generated more newly expanded peripheral T-cell clones (P = .019), with significantly greater expansion among patients with an antitumour response to E/P/A (P = .002). Compared with placebo, trilaciclib administered prior to E/P/A improved patients' experience of receiving treatment for ES-SCLC, as shown by reduced myelosuppression, and improved HRQoL and safety profiles.
RESUMO
BACKGROUND: Trilaciclib is an intravenous cell-cycle inhibitor that transiently maintains immune cells and haemopoietic stem and progenitor cells in G1 arrest. By protecting the immune cells and bone marrow from chemotherapy-induced damage, trilaciclib has the potential to optimise antitumour activity while minimising myelotoxicity. We report safety and activity data for trilaciclib plus gemcitabine and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer. METHODS: In this randomised, open-label, multicentre, phase 2 study, adult patients (aged ≥18 years) with evaluable, biopsy-confirmed, locally recurrent or metastatic triple-negative breast cancer who had no more than two previous lines of chemotherapy were recruited from 26 sites in the USA, three in Serbia, two in North Macedonia, one in Croatia, and one in Bulgaria; sites were academic and community hospitals. Availability of diagnostic samples of tumour tissue confirming triple-negative breast cancer was a prerequisite for enrolment. Eligible patients were randomly assigned (1:1:1) by an interactive web-response system, stratified by number of previous lines of systemic therapy and the presence of liver metastases, to receive intravenous gemcitabine 1000 mg/m2 and intravenous carboplatin (area under the concentration-time curve 2 µgâ×âh/mL) on days 1 and 8 (group 1), gemcitabine and carboplatin plus intravenous trilaciclib 240 mg/m2 on days 1 and 8 (group 2), or gemcitabine and carboplatin on days 2 and 9 plus trilaciclib on days 1, 2, 8, and 9 (group 3) of 21-day cycles. Patients continued treatment until disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation by the investigator. The primary objective was to assess the safety and tolerability of combining trilaciclib with gemcitabine and carboplatin chemotherapy. The primary endpoints were duration of severe neutropenia during cycle 1 and the occurrence of severe neutropenia during the treatment period. Overall survival was included as a key secondary endpoint. Analyses were in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with EudraCT, 2016-004466-26, and ClinicalTrials.gov, NCT02978716, and is ongoing but closed to accrual. FINDINGS: Between Feb 7, 2017, and May 15, 2018, 142 patients were assessed for eligibility and 102 were randomly assigned to group 1 (n=34), group 2 (n=33), or group 3 (n=35). Of all patients, 38 (37%) had received one or two lines of previous chemotherapy in the metastatic setting. Median follow-up was 8·4 months (IQR 3·8-13·6) for group 1, 12·7 months (5·5-17·4) for group 2, and 12·9 months (6·7-16·8) for group 3. Data cutoff for myelosuppression endpoints was July 30, 2018, and for antitumour activity endpoints was May 17, 2019. During cycle 1, mean duration of severe neutropenia was 0·8 day (SD 2·4) in group 1, 1·5 days (3·5) in group 2, and 1·0 day (2·6) in group 3 (group 3 vs group 1 one-sided adjusted p=0·70). Severe neutropenia occurred in nine (26%) of 34 patients in group 1, 12 (36%) of 33 patients in group 2, and eight (23%) of 35 patients in group 3 (p=0·70). Overall survival was 12·6 months (IQR 5·8-15·6) in group 1, 20·1 months (9·4-not reached) in group 2, and 17·8 months (8·8-not reached) in group 3 (group 3 vs group 1 two-sided p=0·0023). The most common treatment-emergent adverse events were anaemia (22 [73%] of 34), neutropenia (21 [70%]), and thrombocytopenia (18 [60%]) in group 1; neutropenia (27 [82%] of 33), thrombocytopenia (18 [55%]) and anaemia (17 [52%]) in group 2; and neutropenia (23 [66%] of 35), thrombocytopenia (22 [63%]), and nausea (17 [49%]) in group 3. There were no treatment-related deaths. INTERPRETATION: No significant differences were observed in myelosuppression endpoints with trilaciclib plus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer; however, the regimen was generally well tolerated and overall survival results were encouraging. Further studies of trilaciclib in this setting are warranted. FUNDING: G1 Therapeutics.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama Masculina/tratamento farmacológico , Carboplatina/administração & dosagem , Desoxicitidina/análogos & derivados , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adolescente , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama Masculina/mortalidade , Neoplasias da Mama Masculina/patologia , Carboplatina/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Progressão da Doença , Europa Oriental , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Fatores de Risco , Fatores de Tempo , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Estados Unidos , Adulto Jovem , GencitabinaRESUMO
Background We sought to determine the recommended phase II dose (RP2D) and schedule of GSK2141795, an oral pan-AKT kinase inhibitor. Patients and Methods Patients with solid tumors were enrolled in the dose-escalation phase. Pharmacokinetic (PK) analysis after a single dose (Cycle 0) informed dose escalation using accelerated dose titration. Once one grade 2 toxicity or dose-limiting toxicity was observed in Cycle 1, the accelerated dose titration was terminated and a 3 + 3 dose escalation was started. Continuous daily dosing was evaluated along with two intermittent regimens (7 days on/7 days off and 3 times per week). In the expansion phase at RP2D, patients with endometrial or prostate cancer, as well as those with select tumor types with a PIK3CA mutation, AKT mutation or PTEN loss, were enrolled. Patients were evaluated for adverse events (AEs), PK parameters, blood glucose and insulin levels, and tumor response. Results The RP2D of GSK2141795 for once-daily dosing is 75 mg. The most common (>10%) treatment-related AEs included diarrhea, fatigue, vomiting, and decreased appetite. Most AEs were low grade. The frequency of hyperglycemia increased with dose; however, at the RP2D, grade 3 hyperglycemia was only reported in 4% of patients and no grade 4 events were observed. PK characteristics were favorable, with a prolonged half-life and low peak-to-trough ratio. There were two partial responses at the RP2D in patients with either a PIK3CA mutation or PTEN loss. Conclusion GSK2141795 was safe and well-tolerated, with clinical activity seen as monotherapy at the RP2D of 75 mg daily. NCT00920257.
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Diaminas/farmacocinética , Diaminas/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Diaminas/administração & dosagem , Diaminas/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/administração & dosagem , Pirazóis/efeitos adversosRESUMO
BACKGROUND: Langerhans cell histiocytosis (LCH) is a clonal neoplasm characterized by widely varied clinical presentations, including multisystem involvement and systemic inflammatory symptoms. The AKT pathway is relevant to survival and proliferation of dendritic cells, and is also often upregulated in hematopoietic malignancies. A clinical response in an adult patient with LCH participating in the first-in-human trial of afuresertib prompted this prospective trial. PROCEDURE: The population in the current study included treatment-naïve (n = 7) and recurrent/refractory patients with LCH (n = 10), who received oral afuresertib (125 mg). The majority of patients were treated for > 24 weeks, with four patients receiving treatment for > 48 weeks. RESULTS: Pharmacokinetic analysis showed similar exposures in previously reported patients with other hematologic malignancies. Primary drug-related toxicities included Grade 1/2 nausea, diarrhea, dyspepsia, and vomiting. Grade 3 toxicities included fatigue, diarrhea, and pain (one of each). Another severe adverse event involved soft tissue necrosis. The overall response rate in evaluable subjects was 33% in treatment-naïve patients and 28% in patients with recurrent/refractory disease, which did not meet the predefined Bayesian criteria for efficacy. CONCLUSION: Afuresertib has clinical activity in some patients with newly diagnosed and advanced LCH.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Histiocitose de Células de Langerhans/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirazóis/uso terapêutico , Tiofenos/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/genética , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Tiofenos/efeitos adversos , Tiofenos/farmacocinética , Resultado do Tratamento , Estados UnidosRESUMO
The PI3K/AKT pathway is constitutively active in hematologic malignancies, providing proliferative and antiapoptotic signals and possibly contributing to drug resistance. We conducted an open-label phase 1 study to evaluate the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of afuresertib-an oral AKT inhibitor-in patients with advanced hematologic malignancies. Seventy-three patients were treated at doses ranging from 25 to 150 mg per day. The MTD was established at 125 mg per day because of 2 dose-limiting toxicities in the 150-mg cohort (liver function test abnormalities). The most frequent adverse events were nausea (35.6%), diarrhea (32.9%), and dyspepsia (24.7%). Maximum plasma concentrations and area under the plasma concentration-time curves from time 0 to 24 hours were generally dose proportional at > 75-mg doses; the median time to peak plasma concentrations was 1.5 to 2.5 hours post dose, with a half-life of approximately 1.7 days. Three multiple myeloma patients attained partial responses; an additional 3 attained minimal responses. Clinical activity was also observed in non-Hodgkin lymphoma, Langerhan's cell histiocytosis, and Hodgkin disease. Single-agent afuresertib showed a favorable safety profile and demonstrated clinical activity against hematologic malignancies, including multiple myeloma.
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Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Tiofenos/administração & dosagem , Tiofenos/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Segurança do Paciente , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours. METHODS: We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622. FINDINGS: We enrolled 206 patients (median age 58·5 years, range 19-92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded. INTERPRETATION: The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination. FUNDING: GlaxoSmithKline.
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Antineoplásicos/administração & dosagem , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Biópsia , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Meia-Vida , Humanos , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/metabolismo , Masculino , Dose Máxima Tolerável , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasias/enzimologia , Neoplasias/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Piridonas/efeitos adversos , Piridonas/farmacocinética , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Chemotherapy-induced myelosuppression (CIM) and its sequalae cause significant side effects and harm to quality of life. Trilaciclib is an intravenous CDK4/6 inhibitor that is administered prior to chemotherapy to protect hematopoietic stem and progenitor cells from chemotherapy-induced damage (myeloprotection). PATIENTS AND METHODS: Data from three randomized, double-blind, placebo-controlled studies (NCT02499770, NCT03041311, and NCT02514447) were pooled to evaluate the effects of trilaciclib administered prior to standard-of-care chemotherapy (first-line etoposide plus carboplatin [E/P], first-line E/P plus atezolizumab, and second-/third-line topotecan) in patients with extensive-stage small cell lung cancer (ES-SCLC). The primary endpoints were duration of severe neutropenia (absolute neutrophil count < 0.5 × 109 cells/L) in cycle 1 and occurrence of severe neutropenia. Additional prespecified endpoints further assessed the effect of trilaciclib on myeloprotection, health-related quality of life (HRQoL), antitumor efficacy, and safety. RESULTS: Of 242 randomized patients, 123 received trilaciclib and 119 received placebo. Compared with placebo, administration of trilaciclib prior to chemotherapy resulted in significant decreases in most measures of multilineage CIM. The reduction in hematologic toxicity translated into the reduced need for supportive care interventions and hospitalizations due to CIM or sepsis and improvements in HRQoL domains related to the protected cell lineages, including fatigue, physical wellbeing, and functional wellbeing. Antitumor efficacy was similar for patients receiving trilaciclib or placebo. CONCLUSION: Administering trilaciclib prior to chemotherapy resulted in clinically meaningful reductions in CIM and its consequences and improved patient HRQoL, with no impact on the antitumor efficacy of three individual chemotherapy regimens used in the first- or second-/third-line treatment of ES-SCLC.
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Medula Óssea/efeitos dos fármacos , Ensaios Clínicos Fase II como Assunto , Medidas de Resultados Relatados pelo Paciente , Pirimidinas/farmacologia , Pirróis/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Antineoplásicos/uso terapêutico , Método Duplo-Cego , Humanos , TopotecanRESUMO
BACKGROUND: Supportive care interventions used to manage chemotherapy-induced myelosuppression (CIM), including granulocyte colony-stimulating factors (G-CSFs), erythropoiesis-stimulating agents (ESAs), and red blood cell (RBC) transfusions, are burdensome to patients and associated with greater costs to health care systems. We evaluated the utilization of supportive care interventions and their relationship with the myeloprotective agent, trilaciclib. METHODS: Data were pooled from three independent randomized phase 2 clinical trials of trilaciclib or placebo administered prior to chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). The impact of supportive care on the duration of severe neutropenia (DSN), occurrence of severe neutropenia (SN), and occurrence of RBC transfusions on/after week 5 was analyzed across cycles 1-4. Concordance and association between grade 3/4 anemia, RBC transfusions on/after week 5, and ESA administration was also evaluated. RESULTS: The use of G-CSFs, ESAs, or RBC transfusions on/after week 5 was significantly lower among patients receiving trilaciclib versus placebo (28.5% vs. 56.3%, p < 0.0001; 3.3% vs. 11.8%, p = 0.0254; and 14.6% vs. 26.1%, p = 0.0252, respectively). Compared with placebo, trilaciclib significantly reduced DSN and SN, irrespective of G-CSF administration. RBC transfusions and ESAs were most often administered in patients with grade 3/4 anemia; however, patients typically received RBC transfusions over ESA administration. CONCLUSIONS: By improving CIM and reducing the need for associated supportive care, trilaciclib has the potential to reduce the burden of myelosuppression on patients receiving myelosuppressive chemotherapy for the treatment of ES-SCLC. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02499770; NCT03041311; NCT02514447).
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neutropenia/induzido quimicamente , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Antineoplásicos/farmacologia , Método Duplo-Cego , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pirimidinas/farmacologia , Pirróis/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/patologiaRESUMO
INTRODUCTION: Multilineage myelosuppression is an acute toxicity of cytotoxic chemotherapy, resulting in serious complications and dose modifications. Current therapies are lineage specific and administered after chemotherapy damage has occurred. Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor that is administered prior to chemotherapy to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation). METHODS: In this randomized, double-blind, placebo-controlled phase II trial, patients with previously treated extensive-stage small cell lung cancer (ES-SCLC) were randomized to receive intravenous trilaciclib 240 mg/m2 or placebo before topotecan 1.5 mg/m2 on days 1-5 of each 21-day cycle. Primary endpoints were duration of severe neutropenia (DSN) in cycle 1 and occurrence of severe neutropenia (SN). Additional endpoints were prespecified to further assess the effect of trilaciclib on myelopreservation, safety, patient-reported outcomes (PROs), and antitumor efficacy. RESULTS: Thirty-two patients received trilaciclib, and 29 patients received placebo. Compared with placebo, administration of trilaciclib prior to topotecan resulted in statistically significant and clinically meaningful decreases in DSN in cycle 1 (mean [standard deviation] 2 [3.9] versus 7 [6.2] days; adjusted one-sided P < 0.0001) and occurrence of SN (40.6% versus 75.9%; adjusted one-sided P = 0.016), with numerical improvements in additional neutrophil, red blood cell, and platelet measures. Patients receiving trilaciclib had fewer grade ≥ 3 hematologic adverse events than patients receiving placebo, particularly neutropenia (75.0% versus 85.7%) and anemia (28.1% versus 60.7%). Myelopreservation benefits extended to improvements in PROs, specifically in those related to fatigue. Antitumor efficacy was comparable between treatment arms. CONCLUSIONS: Compared with placebo, the addition of trilaciclib prior to topotecan for the treatment of patients with previously treated ES-SCLC improves the patient experience of receiving chemotherapy, as demonstrated by a reduction in chemotherapy-induced myelosuppression, improved safety profile, improved quality of life and no detrimental effects on antitumor efficacy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02514447.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Método Duplo-Cego , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Pirimidinas , Pirróis , Qualidade de Vida , Topotecan/uso terapêuticoRESUMO
Up to 25% of patients diagnosed with breast cancer have tumors that overexpress HER2. HER2-positive breast cancer is highly proliferative, difficult to treat, and confers a poor prognosis. The advent of the anti-HER2 monoclonal antibody trastuzumab (Herceptin) has markedly altered the clinical course of both early and advanced HER2-driven breast cancer. Despite the use of trastuzumab, however, patients with HER2-positive breast cancer still experience disease progression. Overcoming that resistance to therapy is our next challenge. This review examines the current understanding of HER2 biology, the mechanisms of action of and resistance to trastuzumab, as well as new therapies on the horizon.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Feminino , Humanos , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Trastuzumab , Regulação para Cima/efeitos dos fármacosRESUMO
Acute liver failure (ALF) is a medical emergency requiring immediate evaluation for liver transplantation. We describe an unusual case of a patient who presented with ascites, jaundice, and encephalopathy and was found to have ALF due to natural killer (NK)-like T cell leukemia/lymphoma. The key immunophenotype was CD2+, CD3+, CD7+, CD56+. This diagnosis, which was based on findings in the peripheral blood and ascitic fluid, was confirmed with liver biopsy, and was a contraindication to liver transplantation. A review of the literature shows that hematologic malignancies are an uncommon cause of fulminant hepatic failure, and that NK-like T-cell leukemia/lymphoma is a relatively recently recognized entity which is characteristically CD3+ and CD56+. This case demonstrates that liver biopsy is essential in diagnosing unusual causes of acute liver failure, and that infiltration of the liver with NK-like T-cell lymphoma/leukemia can cause acute liver failure.
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Leucemia-Linfoma de Células T do Adulto/complicações , Falência Hepática Aguda/etiologia , Transplante de Fígado , Contraindicações , Evolução Fatal , Humanos , Imunofenotipagem , Células Matadoras Naturais , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, ß, γ, and δ), with preclinical studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors. MATERIALS AND METHODS: Patients received oral GSK458 once or twice daily in a dose-escalation design to define the maximum tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics, pharmacokinetics, and clinical activity in histologically and molecularly defined cohorts. RESULTS: One hundred and seventy patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (grade 3 diarrhea,n= 4; fatigue and rash,n= 1) occurred in 5 patients (n= 3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (ORs) were observed across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not associated withPIK3CAmutations (OR rate: 5% wild-type vs. 6% mutant). CONCLUSIONS: Although the MTD of GSK458 was 2.5 mg once daily, twice-daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as pharmacodynamic markers of drug exposure. Select patients achieved durable responses; however,PIK3CAmutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K.
Assuntos
Antineoplásicos/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Quinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Piridazinas , Quinolinas/farmacologia , Fatores de Risco , Sulfonamidas/farmacologia , Resultado do Tratamento , Adulto JovemRESUMO
Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Cisplatino/uso terapêutico , Diaminas/uso terapêutico , Complexos Multiproteicos/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteômica , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirazóis/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Apoptose/efeitos dos fármacos , Biópsia , Antígeno Ca-125/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Proteínas de Membrana/metabolismo , Camundongos Nus , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Fenótipo , Fosforilação , Valor Preditivo dos Testes , Proteômica/métodos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
UNLABELLED: AKT (a serine/threonine-specific protein kinase) regulates many cellular processes contributing to cytotoxic drug resistance. This study's primary objective examined the relationship between GSK2141795, an oral, pan-AKT inhibitor, and (18)F-FDG PET markers of glucose metabolism in tumor tissue to determine whether (18)F-FDG PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken. METHODS: Twelve patients were enrolled in 3 cohorts; all underwent dynamic (18)F-FDG PET scans and serial pharmacokinetic sampling at baseline, week 2, and week 4 with tumor biopsies before treatment and at week 4. Response was evaluated by RECIST v1.1 and Gynecologic Cancer Intergroup criteria. Biopsy samples were analyzed for mutations and protein expression. RESULTS: GSK2141795 did not significantly influence blood glucose levels. No dose-response relationship was observed between GSK2141795 pharmacokinetics and (18)F-FDG PET pharmacodynamic measures; however, an exposure-response relationship was seen between maximum drug concentrations and maximal decrease in (18)F-FDG uptake in the best-responding tumor. This relationship also held for pharmacokinetic parameters of exposure and 1,5-anhydroglucitol (a systemic measure of glucose metabolism). Phospho-AKT upregulation at week 4 in biopsies confirmed AKT inhibition by GSK2141795. Single-agent activity was observed with a clinical benefit rate of 27% (3/11) and 30% (3/10) CA125 response in the study's platinum-resistant ovarian patients. AKT pathway activation by PIK3CA/PIK3R1 mutation did not correlate with clinical activity, whereas RAS/RAF pathway mutations did segregate with resistance to AKT inhibition. CONCLUSION: GSK2141795 demonstrated an exposure-response relationship with decreased (18)F-FDG uptake and is active and tolerable. This study's design integrating (18)F-FDG PET, pharmacokinetics, and biomarker analyses demonstrates the potential for clinical development for personalized treatment.
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Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Diaminas/administração & dosagem , Diaminas/uso terapêutico , Fluordesoxiglucose F18/farmacocinética , Neoplasias dos Genitais Femininos/diagnóstico por imagem , Neoplasias dos Genitais Femininos/tratamento farmacológico , Proteína Oncogênica v-akt/antagonistas & inibidores , Tomografia por Emissão de Pósitrons/métodos , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Compostos Radiofarmacêuticos/farmacocinética , Antineoplásicos/efeitos adversos , Biomarcadores , Biópsia , Glicemia/metabolismo , Desoxiglucose , Diaminas/efeitos adversos , Interações Medicamentosas , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Proteína Oncogênica v-akt/genética , Pirazóis/efeitos adversos , Resultado do TratamentoRESUMO
Casopitant, a novel NK-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, is a weak to moderate inhibitor of CYP3A and a moderate inducer of CYP2C9 in vitro. Furthermore, both CYP enzymes are involved in the metabolism of R- and S-warfarin, respectively. This clinical study was conducted to explore the potential drug-drug interaction between casopitant and warfarin. In total, 97 healthy participants were enrolled and 54 completed the study. Participants received individualized daily dosing of warfarin to an international normalized ratio (INR) of 1.3 to 2.3 over a 14-day period (period 1). Immediately following period 1, participants entered period 2 and were randomized to receive either regimen A (oral casopitant [150 mg day 1, 50 mg days 2 and 3] and warfarin [days 1-10]) or regimen B (oral casopitant 60 mg and warfarin [days 1-14]). INR assessments were performed daily. The steady-state C(max) and AUC of R- and S-warfarin were not altered by regimen A, but R-warfarin AUC was increased 1.31-fold (90% confidence interval [CI]: 1.22, 1.41), and S-warfarin AUC was increased 1.27-fold (90% CI: 1.18, 1.38) on day 14 in regimen B. Steady-state INR values were not affected by either casopitant regimen.
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Anticoagulantes/farmacocinética , Antieméticos/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Varfarina/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Anticoagulantes/farmacologia , Antieméticos/administração & dosagem , Área Sob a Curva , Citocromo P-450 CYP2D6/efeitos dos fármacos , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Neurocinina-1 , Piperazinas/administração & dosagem , Piperidinas/administração & dosagem , Estereoisomerismo , Fatores de Tempo , Varfarina/farmacologia , Adulto JovemRESUMO
Molecular profiling has provided biological evidence for the heterogeneity of breast cancer through the identification of intrinsic subtypes like Luminal A, Luminal B, HER2+/ER- and basal-like. It has also led to the development of clinically applicable gene expression-based prognostic panels like the Mammaprint and Oncotype Dx. The increasingly sophisticated understanding allowed by this and similar technology promises future individualized therapy.
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Neoplasias da Mama/genética , Perfilação da Expressão Gênica/métodos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , DNA de Neoplasias/genética , Feminino , Humanos , Valor Preditivo dos Testes , PrognósticoRESUMO
PURPOSE OF REVIEW: Gene expression profiling has highlighted the biologic heterogeneity of breast cancer and has begun to influence the ability of the medical community to individualize patient therapy. The review is intended to highlight the most important advances in the field over recent years with an emphasis on those most relevant to the practicing oncologist. RECENT FINDINGS: Two prognostic profiling assays, the Mammaprint and Oncotype Dx, are in phase III clinical trials designed to evaluate their contribution to therapeutic decision making. Predictive profiles for both chemotherapy and targeted therapy are also in development. In addition, application of genetic profiling techniques to a variety of tumor types is starting to identify those processes, like proliferation, that are integral to carcinogenesis as a whole. SUMMARY: The biologic heterogeneity of breast cancer has become clearer through genome-wide profiling technologies. Validation of the clinical utility of prognostic profiles may enable oncologists to better identify those patients whose prognosis justifies more intensive therapy, while predictive profiles may soon be able to determine which type of chemotherapy a patient should receive. In addition, profiling is starting to identify new therapeutic targets which will point the field of breast cancer oncology in new directions.