RESUMO
OBJECTIVE: Retifanlimab is a humanized immunoglobulin G4 monoclonal antibody against programmed death 1 being investigated in several solid tumor types. We report final results from patients with recurrent microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) endometrial cancer treated with retifanlimab in a POD1UM-101 expansion cohort. METHODS: Eligible patients (≥18 years; histologically proven/unresectable/recurrent, MSI-H/dMMR endometrial cancer; checkpoint inhibitor naive) received retifanlimab 500 mg intravenously every 4 weeks for ≤2 years. Primary endpoint was safety/tolerability. RESULTS: At data cutoff (May 17, 2023), 76 patients had received at least one retifanlimab dose. Median (range) age was 67 (49-88) years; 88.2% of patients had recurrent metastatic disease and 80.3% had visceral metastases. Seventy-five patients (98.7%) had received at least one prior systemic therapy. Median retifanlimab exposure was 10.0 (0.03-25.9) months; 23 patients completed treatment. 38 patients (50.0%) had grade ≥3 treatment-emergent adverse events (TEAEs), most commonly anemia (n = 10 [13.2%]). 63 patients (82.9%) had treatment-related AEs (TRAEs; grade ≥3, n = 14 [18.4%]); most common was fatigue (n = 14 [18.4%]). Two patients had TEAEs that led to death; no TRAEs were fatal. 39 patients had objective responses (51.3%; 95% CI, 39.6-63.0%); 19 patients (25.0%) had complete response and 20 (26.3%) had partial response. Median progression-free survival was 12.2 months; 30 patients (76.9%) had duration of response (DOR) ≥12 months. Median DOR was not reached after median follow-up time of 26.0 months. CONCLUSIONS: Retifanlimab was generally well tolerated and demonstrated encouraging anti-tumor activity in patients with pre-treated recurrent MSI-H/dMMR endometrial cancer.
Assuntos
Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio , Instabilidade de Microssatélites , Humanos , Feminino , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Intervalo Livre de Progressão , Estudos de Coortes , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologiaRESUMO
This report is a summary of 'New Cancer Immunotherapy Agents in Development' program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy.
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Vacinas Anticâncer/uso terapêutico , Imunoterapia , Neoplasias/tratamento farmacológico , Microambiente Tumoral/imunologia , Vacinas Anticâncer/imunologia , Humanos , Neoplasias/imunologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
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
PURPOSE: To identify the maximum tolerated dose (MTD) and recommended Phase II dose of MEK/AKT inhibitor combination of trametinib and afuresertib. PATIENTS AND METHODS: Eligibility criteria were advanced solid tumors, 18 years or older, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Exclusion criteria included Type 1 diabetes, active GI disease, leptomeningeal disease, or current evidence/risk of retinal venous occlusion/central serous retinopathy. Clinical safety parameters and response were evaluated and analyzed. RESULTS: Twenty patients were enrolled. Dose-limiting toxicities (Grade 2 esophagitis; Grade 3 aspartate aminotransferase increased, mucosal inflammation and hypokalemia) were reported at starting dose (1.5 mg trametinib/50 mg afuresertib once daily continuously), exceeding the MTD. Subsequent de-escalation cohorts (1.5 mg/25 mg or 1.0 mg/50 mg trametinib/afuresertib) were defined as MTDs for continuous dosing. Intermittent dosing schedule [1.5 mg trametinib (continuous)/50 mg afuresertib (Days 1-10 every 28 days)] was evaluated and considered tolerable. No patients were enrolled in Phase II. The most common adverse events reported (≥10 % of all patients) included: diarrhea (60 %), dermatitis acneiform (55 %), maculo-papular rash (45 %), fatigue (30 %), dry skin (25 %), nausea (25 %), dyspnea (20 %), and vomiting (20 %). One partial response (BRAF wild-type melanoma) was reported; four patients had stable disease as best response. CONCLUSION: Continuous daily dosing of trametinib/afuresertib combination was poorly tolerated. Evaluation of intermittent dose schedule showed greater tolerability. Given the interest in combination treatment regimens of MAPK and PI3K/AKT pathway inhibitors, further study of intermittent dose schedule or combination of trametinib with more selective inhibitors may be warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Tiofenos/efeitos adversos , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Coortes , Relação Dose-Resposta a Droga , Término Precoce de Ensaios Clínicos , Feminino , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/enzimologia , Neoplasias/sangue , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Piridonas/administração & dosagem , Piridonas/farmacocinética , Piridonas/uso terapêutico , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacocinética , Pirimidinonas/uso terapêutico , Tiofenos/administração & dosagem , Tiofenos/farmacocinética , Tiofenos/uso terapêutico , Carga Tumoral/efeitos dos fármacosRESUMO
PURPOSE: Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients. We assessed the safety and tolerability of siltuximab in combination with docetaxel, the pharmacokinetics of docetaxel alone and with siltuximab, and the efficacy and pharmacodynamics of siltuximab plus docetaxel. PATIENTS AND METHODS: In an open-label, dose-escalation, multicenter, phase 1 study, patients with metastatic, progressive CRPC received docetaxel 75 mg/m(2) q3w plus siltuximab 6 mg/kg q2w (n=12), 9 mg/kg q3w (n=12), or 12 mg/kg q3w (n=15). Dose-limiting toxicity (DLT), PSA, and radiologic response according to WHO criteria were evaluated. RESULTS: DLT was reported in 1 of 11 patients receiving 6 mg/kg, 1 of 12 receiving 9 mg/kg, and in 1 of 14 receiving 12 mg/kg. Common Grade ≥ 3 adverse events were neutropenia (73 %), leukopenia (60 %), lymphopenia (30 %), dyspnea (19 %), and fatigue (14 %). Toxicities were not dose dependent. Siltuximab did not affect docetaxel pharmacokinetics. The pharmacokinetic profile for siltuximab in combination was similar to single-agent siltuximab pharmacokinetics. Twenty-three (62 %; 95 % CI 45 %, 78 %) of 37 combination-treated patients achieved a confirmed ≥ 50 % PSA decline. Of 17 patients with measurable disease at baseline, 2 confirmed and 2 unconfirmed radiologic partial responses ranging 190 to 193 days were achieved with 9- and 12-mg/kg siltuximab. C-reactive protein concentrations were suppressed throughout treatment in all patients. CONCLUSION: These results suggest that siltuximab in combination with docetaxel is safe and shows preliminary efficacy in patients with CRPC, although alternative siltuximab schedules may be better tolerated for future studies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Proteína C-Reativa/análise , Docetaxel , Humanos , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Orquiectomia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Taxoides/farmacocinéticaRESUMO
Signalling through the interleukin (IL)-6 pathway induces proliferation and drug resistance of multiple myeloma cells. We therefore sought to determine whether the IL-6-neutralizing monoclonal antibody siltuximab, formerly CNTO 328, could enhance the activity of melphalan, and to examine some of the mechanisms underlying this interaction. Siltuximab increased the cytotoxicity of melphalan in KAS-6/1, INA-6, ANBL-6, and RPMI 8226 human myeloma cell lines (HMCLs) in an additive-to-synergistic manner, and sensitized resistant RPMI 8226.LR5 cells to melphalan. These anti-proliferative effects were accompanied by enhanced activation of drug-specific apoptosis in HMCLs grown in suspension, and in HMCLs co-cultured with a human-derived stromal cell line. Siltuximab with melphalan enhanced activation of caspase-8, caspase-9, and the downstream effector caspase-3 compared with either of the single agents. This increased induction of cell death occurred in association with enhanced Bak activation. Neutralization of IL-6 also suppressed signalling through the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased phosphorylation of Akt, p70 S6 kinase and 4E-BP1. Importantly, the siltuximab/melphalan regimen demonstrated enhanced anti-proliferative effects against primary plasma cells derived from patients with myeloma, monoclonal gammopathy of undetermined significance, and amyloidosis. These studies provide a rationale for translation of siltuximab into the clinic in combination with melphalan-based therapies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Interleucina-6/antagonistas & inibidores , Mieloma Múltiplo/patologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Apoptose/efeitos dos fármacos , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Melfalan/administração & dosagem , Melfalan/farmacologia , Mieloma Múltiplo/metabolismo , Proteínas de Neoplasias/metabolismo , Plasmócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
PURPOSE: Interleukin-6 (IL-6) has emerged as a key factor in the pathogenesis of the atypical lymphoproliferative disorder Castleman's disease (CD). Siltuximab is a new anti-IL-6, chimeric monoclonal antibody with potential therapeutic benefit in patients with CD. METHODS: We report interim results from an open-label, dose-finding, seven-cohort, phase I study in which patients with symptomatic, multicentric or unresectable, unicentric CD received siltuximab at 1-, 2-, or 3-week intervals. The main efficacy end point of clinical benefit response (CBR) was defined as a composite of clinical and laboratory measures relevant to the management of CD. In addition, radiologic response was independently assessed by using modified Cheson criteria. RESULTS: Eighteen (78%) of 23 patients (95% CI, 56% to 93%) achieved CBR, and 12 patients (52%) demonstrated objective tumor response. All 11 patients (95% CI, 72% to 100%) treated with the highest dose of 12 mg/kg achieved CBR, and eight patients (73%) achieved objective tumor response. Overall objective-response duration ranged from 44 to > or = 889 days, and one patient had complete response for > or = 318 days. Hemoglobin increased markedly in 19 patients (median increase, 2.1 g/dL; range, 0.2 to 4.7 g/dL) in the absence of transfusion or erythropoiesis-stimulating agents. No dose-limiting toxicity was reported, and only three patients had grade 3 or higher adverse events after a median exposure of 331 days (range, 1 to 1,148 days). CONCLUSION: These interim results strongly suggest that siltuximab is an effective treatment with favorable safety for the management of CD. An additional study is planned to fully evaluate safety and efficacy at the recommended dose of 12 mg/kg every 3 weeks.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVE: To pilot a worksite smoking intervention. METHODS: Following baseline assessment, participants (N=6378) received cancer risk feedback; 2 annual evaluations were conducted. RESULTS: Using all data, smoking dropped from 13.7% to 8.4% and 9.3%, and smoker's readiness to quit increased. Using complete data, smoking initially increased from 5.7% to 6.7%, but subsequently decreased to 5.3%; the increase in smoker's readiness to quit remained. Being male, younger, and with lower education and self-efficacy predicted smoking. Lower age and higher self-efficacy predicted readiness to quit smoking. CONCLUSIONS: These findings support a formal evaluation of a worksite smoking intervention using cancer risk feedback.
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Retroalimentação Psicológica , Neoplasias , Saúde Ocupacional , Abandono do Hábito de Fumar/estatística & dados numéricos , Adulto , Feminino , Comportamentos Relacionados com a Saúde , Promoção da Saúde/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Philadelphia , Projetos Piloto , Medição de Risco , Autoeficácia , Inquéritos e QuestionáriosRESUMO
Although the NCI is presently investigating whether enhanced detection of lung tumors via spiral CT reduces lung cancer mortality, use of this technology for lung cancer screening is already widespread in the US. Few data are available concerning level of interest in, or awareness of, spiral CT for lung cancer screening, correlates of participation in screening, or potential reactions to screening results (i.e. smoking cessation) among high-risk individuals. One-hundred-and-seventy-two current or former smokers with no personal cancer history were queried about their awareness of spiral CT for lung cancer screening, received information about the procedure, and completed a survey that assessed interest in screening, correlates of screening interest (i.e. demographic, health, psychological), and expected effects of screening results on smoking. Seventy-seven percent of respondents were unaware of spiral CT for lung cancer screening and 62% expressed high interest in screening. Screening interest was positively related to screening self-efficacy, knowledge of asymptomatic illness, and perceived lung cancer risk. In the face of a positive scan, 52% of smokers said that they would quit, 43% said they would consider quitting, and 3% would continue smoking. If the scan was negative, 19% of smokers said that they would quit, 61% said they would consider quitting, and 20% would continue smoking. Finally, 59% of smokers were interested in smoking cessation counseling, with screening. These findings can help guide the design of psychological interventions to promote the utilization of spiral CT for early lung cancer detection as well as the development of protocols to promote behavior change within lung cancer screening programs, should future studies indicate that spiral CT screening can effectively reduce the overall lung cancer mortality rate.
Assuntos
Atitude Frente a Saúde , Comportamentos Relacionados com a Saúde , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/psicologia , Programas de Rastreamento , Fumar/efeitos adversos , Tomografia Computadorizada Espiral/psicologia , Adulto , Idoso , Feminino , Inquéritos Epidemiológicos , Humanos , Conhecimento , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Fatores de Risco , Autoeficácia , Abandono do Hábito de FumarRESUMO
Coadministration of eniluracil with 5-fluorouracil (5-FU) allows the oral absorption of small doses of 5-FU, resulting in therapeutic plasma levels. A phase II clinical trial of this combination using a continuous dosing schedule was carried out in patients with metastatic colorectal cancer. Fifty-three previously untreated patients and 46 patients who had received one prior regimen for metastatic disease were enrolled. Patients received 10 mg/m2 of eniluracil and 1 mg/m2 of 5-FU twice daily for 28 days, with cycles repeated after a 7-day rest until progression of disease or prohibitive toxicity. Seven of 53 previously untreated patients had an objective tumor response (13.2%): 1 complete response and 6 partial responses. The mean duration of response was 6.3 months. Only 1 of the 45 evaluable patients in the previously treated group had a partial response, with no complete responses. The duration of response was 3 months. The median progression-free survival was 3.4 months for the previously untreated group and 2.5 months for the previously treated group. Median overall survival was 11.1 months for the previously untreated group and 9.0 months for the previously treated group. Hematologic toxicity was infrequent, with 3 patients experiencing grade 3 toxicity. Incidence of grade 3/4 toxicity included 11 patients with diarrhea, 5 with nausea, and 4 with vomiting. Other common toxicities included anemia and stomatitis, but they were generally mild. This regimen is well tolerated and shows activity in previously untreated patients with metastatic colorectal cancer that is similar to that observed with other 5-FU-based regimens. This regimen has not shown to be effective in patients who have had prior chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais , Inibidores Enzimáticos/uso terapêutico , Uracila/análogos & derivados , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalos de Confiança , Esquema de Medicação , Inibidores Enzimáticos/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Uracila/administração & dosagem , Uracila/efeitos adversosRESUMO
The worksite is an ideal forum for cancer risk assessment. We describe here the baseline characteristics of a large cohort. Participants completed surveys that assessed a variety of risk factors and behavioral mediators. Personalized feedback letters identified cancer risks. A total of 4395 surveys were received. Cancer prevalence was 6.5% (range, 4.3% to 11.2%). The most common risk factors were lack of exercise (41%; 32% to 68%), obesity (28%; 24% to 39%), and smoking (14%; 13% to 32%). Cardiovascular risk was also common (25%; 15% to 48%). Screening was fair to good for all cancers except colon cancer. The perceived risk for cancer was less than that for cardiovascular disease (P < 0.0001). Most smokers were in the pre-contemplation phase, whereas action/maintenance phases predominated for breast and colon cancer screening. Modifiable cancer risk factors can be identified in the majority of workers. Inaccurate risk perception is an important target for future interventions.