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1.
J Clin Oncol ; 39(22): 2443-2451, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33844595

RESUMO

PURPOSE: The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported. METHODS: Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety. RESULTS: Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label. CONCLUSION: Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Metástase Neoplásica , Sistema de Registros , Carga Tumoral
2.
Target Oncol ; 15(6): 733-741, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33090333

RESUMO

BACKGROUND: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study, a phase II basket study, evaluates anti-tumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known as drug targets. OBJECTIVE: With no known genomic targets predictive of sensitivity to cetuximab, cetuximab was evaluated in patients with breast cancer (BC), non-small cell lung cancer (NSCLC), and ovarian cancer (OC), without KRAS, NRAS, or BRAF mutations. PATIENTS AND METHODS: Eligible patients with advanced BC, NSCLC, and OC received a cetuximab loading dose, then weekly infusions (250 mg/m2 over 60 min). A Simon two-stage design, requiring ten patients in stage I, was employed per each disease-specific cohort. The primary endpoint was disease control (objective response or stable disease for at least 16 weeks). If two or more patients in stage I achieved disease control, the cohort would enroll 18 more patients in stage II. Power and alpha of the design are 85% and 10%, respectively. Secondary endpoints included progression-free survival, overall survival, and safety. RESULTS: Patients with BC (n = 10), NSCLC (n = 10), and OC (n = 29) were enrolled between June 2016 and September 2018. No objective responses or stable disease for at least 16 weeks were observed in the BC and NSCLC cohorts. No objective responses and four patients with stable disease for at least 16 weeks were observed in the OC cohort. Six of 49 patients reported grade 3 or higher adverse events or serious adverse events at least possibly related to cetuximab. CONCLUSIONS: Cetuximab does not have clinical activity in patients with advanced BC, NSCLC, and OC without KRAS, NRAS, or BRAF mutations. CLINICAL TRIAL REGISTRATION: NCT02693535 (26 February, 2016).


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Cetuximab/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Antineoplásicos Imunológicos/farmacologia , Cetuximab/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , Sistema de Registros
3.
Cytometry B Clin Cytom ; 72(5): 354-62, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17266150

RESUMO

T cell responses against leukemia-associated antigens have been reported in chronic lymphocytic leukemia (CLL). However, the relentless accumulation of CLL B cells in some patients indicates that anti-tumor immune responses are inefficient. Inhibitory receptors from the Ig-like transcript (ILT) family, such as ILT3 and ILT4, are crucial to the tolerogenic activity of antigen presenting cells. In this study, we examined the expression of ILT3 on CD5+ B cells obtained from 47 patients with CLL. Using flow cytometry and RT-PCR, we found that B CLL cells from 23 of 47 patients expressed ILT3 protein and mature ILT3 mRNA. ILT3 protein and mRNA were not found in normal B cells obtained from donors without CLL. Expression of ILT4 in normal and B CLL cells showed a pattern similar to ILT3. The frequency of ILT3 positive CLL B cells was higher in patients with lymphoid tissue involvement, suggesting that ILT3 may have prognostic value in CLL. Our findings indicate that expression of ILT3 and ILT4 on CLL B cells represents a phenotypic abnormality that may play a role in tolerization of tumor-specific T cells.


Assuntos
Linfócitos B/imunologia , Biomarcadores Tumorais/biossíntese , Leucemia Linfocítica Crônica de Células B/imunologia , Tecido Linfoide/imunologia , Receptores de Superfície Celular/biossíntese , Idoso , Linfócitos B/patologia , Biomarcadores/análise , Biomarcadores/metabolismo , Antígenos CD5/imunologia , Doença Crônica , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem/métodos , Leucemia Linfocítica Crônica de Células B/patologia , Tecido Linfoide/patologia , Masculino , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/genética , Valor Preditivo dos Testes , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/análise , Receptores de Superfície Celular/genética , Receptores Imunológicos/análise , Receptores Imunológicos/biossíntese , Receptores Imunológicos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
4.
Leuk Lymphoma ; 49(6): 1155-60, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18452074

RESUMO

The incidence of non-HIV-associated hematologic malignancies, including chronic myeloproliferative disorders, is increasing in HIV-infected (HIV+) patients. This is thought to be due to prolonged survival in the era of highly active antiretroviral therapy (HAART). Previously, only six cases of chronic myeloid leukemia (CML) have been described in HIV+ individuals and limited information is available regarding the management of patients with concurrent CML and HIV-infection. We report three cases of CML in HIV+ patients who were treated with imatinib and HAART. Treatment was generally well tolerated, and cytogenetic response (complete in two patients) was achieved with follow-up ranging from 3 to 69 months. HIV viral load remained undetectable and CD4 cell counts were stable in all three patients. Concurrent treatment with imatinib and HAART can result in appropriate control of CML and HIV-infection as well as long-term survival.


Assuntos
Infecções por HIV/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Linfoma Difuso de Grandes Células B/complicações , Antineoplásicos/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Benzamidas , Contagem de Linfócito CD4 , Citometria de Fluxo , Seguimentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/isolamento & purificação , Humanos , Mesilato de Imatinib , Técnicas Imunoenzimáticas , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/virologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/virologia , Masculino , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Indução de Remissão , Resultado do Tratamento , Carga Viral
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