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1.
Cell ; 183(2): 347-362.e24, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33064988

RESUMO

Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).


Assuntos
Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Medicina de Precisão/métodos , Idoso , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Pessoa de Meia-Idade , Mutação , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologia
2.
Br J Cancer ; 124(4): 744-753, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33311588

RESUMO

BACKGROUND: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor. METHODS: We conducted a Phase 1 study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation. RESULTS: Fatigue (42%), decreased appetite (35%) and injection-site erythema (35%) were the most common treatment-related adverse events. Pharmacokinetic parameters demonstrated linearity over the dose range tested and support once-daily dosing. Pharmacodynamic assessments demonstrated sustained decreases in CD11b levels in peripheral blood mononuclear cells. Objective response rates were 25% (2/8), 2% (1/47) and 11% (2/19) for patients with NC, other solid tumours and DLBCL, respectively. Responding tumours had evidence of deregulated MYC expression. CONCLUSIONS: This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC-driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations. CLINICAL TRIALS REGISTRATION: NCT01987362.


Assuntos
Azepinas/administração & dosagem , Azepinas/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Proteínas Nucleares/metabolismo , Proteínas/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Azepinas/sangue , Azepinas/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Linfoma Difuso de Grandes Células B/sangue , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/metabolismo , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/efeitos adversos , Bibliotecas de Moléculas Pequenas/farmacocinética
3.
Methods ; 59(1): 10-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22796720

RESUMO

The identification of new biomarkers is essential in the implementation of personalized health care strategies that offer new therapeutic approaches with optimized and individualized treatment. In support of hypothesis generation and testing in the course of our biomarker research an online portal and respective function-tested reverse transcription quantitative real-time PCR assays (RT-qPCR) facilitated the selection of relevant biomarker genes. We have established workflows applicable for convenient high throughput gene expression analysis in biomarker research with cell lines (in vitro studies) and xenograft mouse models (in vivo studies) as well as formalin-fixed paraffin-embedded tissue (FFPET) sections from various human research and clinical tumor samples. Out of 92 putative biomarker candidate genes selected in silico, 35 were shown to exhibit differential expression in various tumor cell lines. These were further analysed by in vivo xenograft mouse models, which identified 13 candidate genes including potential response prediction biomarkers and a potential pharmacodynamic biomarker. Six of these candidate genes were selected for further evaluation in FFPET samples, where optimized RNA isolation, reverse transcription and qPCR assays provided reliable determination of relative expression levels as precondition for differential gene expression analysis of FFPET samples derived from projected clinical studies. Thus, we successfully applied function tested RT-qPCR assays in our biomarker research for hypothesis generation with in vitro and in vivo models as well as for hypothesis testing with human FFPET samples. Hence, appropriate function-tested RT-qPCR assays are available in biomarker research accompanying the different stages of drug development, starting from target identification up to early clinical development. The workflow presented here supports the identification and validation of new biomarkers and may lead to advances in efforts to achieve the goal of personalized health care.


Assuntos
Biomarcadores Farmacológicos/metabolismo , Biomarcadores Tumorais/genética , Descoberta de Drogas/métodos , Perfilação da Expressão Gênica/métodos , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , DNA Complementar/genética , Fixadores , Formaldeído , Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Inclusão em Parafina , Medicina de Precisão , RNA/genética , RNA/isolamento & purificação , RNA/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Cancer Cell ; 40(9): 1010-1026.e11, 2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-36027916

RESUMO

Neoantigens arising from mutations in tumor DNA provide targets for immune-based therapy. Here, we report the clinical and immune data from a Phase Ib clinical trial of a personalized neoantigen-vaccine NEO-PV-01 in combination with pemetrexed, carboplatin, and pembrolizumab as first-line therapy for advanced non-squamous non-small cell lung cancer (NSCLC). This analysis of 38 patients treated with the regimen demonstrated no treatment-related serious adverse events. Multiple parameters including baseline tumor immune infiltration and on-treatment circulating tumor DNA levels were highly correlated with clinical response. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination. Epitope spread to non-vaccinating neoantigens, including responses to KRAS G12C and G12V mutations, were detected post-vaccination. Neoantigen-specific CD4+ T cells generated post-vaccination revealed effector and cytotoxic phenotypes with increased CD4+ T cell infiltration in the post-vaccine tumor biopsy. Collectively, these data support the safety and immunogenicity of this regimen in advanced non-squamous NSCLC.


Assuntos
Vacinas Anticâncer , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígenos de Neoplasias , Linfócitos T CD8-Positivos , Vacinas Anticâncer/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Imunoterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética
5.
Leuk Lymphoma ; 62(7): 1740-1748, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33586590

RESUMO

Bromodomain and extra-terminal (BET) proteins can drive carcinogenesis and therapy resistance. RO6870810 (RO) is a novel, small-molecule BET inhibitor. We conducted a study in 32 patients with relapsed/refractory acute myeloid leukemia and hypomethylating agent-refractory myelodysplastic syndrome (NCT02308761). Pharmacodynamic assessments showed decreases in CD11b in peripheral blood mononuclear cells at RO concentrations above 120 ng/mL. Treatment emergent adverse events were generally mild and the most frequent were fatigue, injection site reactions, diarrhea, decreased appetite and nausea. There were no treatment-related deaths. Potential drug-related dose limiting toxicities included decreased appetite, congestive cardiac failure, hypertension, fatigue, increased conjugated bilirubin and increased gamma glutamyltransferase. One AML patient achieved complete remission after withdrawal from study. Eleven AML patients experienced SD. For AML, the median OS was 72.0 days. For MDS, two patients experienced SD. Further development of RO as monotherapy was discontinued due to lack of efficacy, but combinations with other agents are under consideration.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Antineoplásicos/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucócitos Mononucleares , Síndromes Mielodisplásicas/tratamento farmacológico
6.
Blood Adv ; 5(22): 4762-4770, 2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34581757

RESUMO

Bromodomain and extraterminal (BET) proteins are transcriptional activators for multiple oncogenic processes in diffuse large B-cell lymphoma (DLBCL), including MYC, BCL2, E2F, and toll-like receptor signaling. We report results of a phase 1b dose-escalation study of the novel, subcutaneous BET inhibitor RO6870810 (RO) combined with the BCL-2 inhibitor venetoclax, and rituximab, in recurrent/refractory DLBCL. RO was delivered for 14 days of a 21-day cycle, whereas venetoclax was delivered continuously. A 3 + 3 escalation design was used to determine the safety of the RO+venetoclax doublet; rituximab was added in later cohorts. Thirty-nine patients were treated with a median of 2.8 cycles (range, 1-11). Dose-limiting toxicities included grade 3 febrile neutropenia, grade 4 diarrhea, and hypomagnesemia for the doublet; and grade 3 hyperbilirubinemia and grade 4 diarrhea when rituximab was added. The doublet maximum tolerated dose (MTD) was determined to be 0.65 mg/kg RO+600 mg venetoclax; for RO+venetoclax+rituximab, the MTDs were 0.45 mg/kg, 600 mg, and 375 mg/m2, respectively. The most frequent grade 3 and 4 adverse events were neutropenia (28%) and anemia and thrombocytopenia (23% each). Responses were seen in all cohorts and molecular subtypes. Sustained decreases in CD11b on monocytes indicated pharmacodynamic activity of RO. Overall response rate according to modified Lugano criteria was 38.5%; 48% of responses lasted for ≥180 days. Complete response was observed in 8 patients (20.5%). Optimization of the treatment schedule and a better understanding of predictors of response would be needed to support broader clinical use. This trial is registered on www.clinicaltrials.gov as NCT03255096.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Rituximab/uso terapêutico , Sulfonamidas
8.
Clin Cancer Res ; 22(4): 858-67, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26446946

RESUMO

PURPOSE: The TWEAK-Fn14 pathway represents a novel anticancer target that is being actively investigated. Understanding the relationship between pharmacokinetics of anti-TWEAK therapeutics and tumor pharmacodynamics is critical. We investigated exposure-response relationships of RG7212, an anti-TWEAK mAb, in patients with Fn14-expressing tumors. EXPERIMENTAL DESIGN: Patients with Fn14-positive tumors (IHC ≥ 1+) treated in a phase I first-in-human study with ascending doses of RG7212 were the basis for this analysis. Pharmacokinetics of RG7212 and dynamics of TWEAK were determined, as were changes in tumor TWEAK-Fn14 signaling in paired pre- and posttreatment tumor biopsies. The objectives of the analysis were to define exposure-response relationships and the relationship between pretreatment tumor Fn14 expression and pharmacodynamic effect. Associations between changes in TWEAK-Fn14 signaling and clinical outcome were explored. RESULTS: Thirty-six patients were included in the analysis. RG7212 reduced plasma TWEAK to undetectable levels at all observed RG7212 exposures. In contrast, reductions in tumor Fn14 and TRAF1 protein expression were observed only at higher exposure (≥ 300 mg*h/mL). Significant reductions in tumor Ki-67 expression and early changes in serum concentrations of CCL-2 and MMP-9 were observed exclusively in patients with higher drug exposure who had high pretreatment tumor Fn14 expression. Pretreatment tumor Fn14 expression was not associated with outcome, but a trend toward longer time on study was observed with high versus low RG7212 exposure. CONCLUSIONS: RG7212 reduced tumor TWEAK-Fn14 signaling in a systemic exposure-dependent manner. In addition to higher exposure, relatively high Fn14 expression might be required for pharmacodynamic effect of anti-TWEAK monoclonal antibodies.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/toxicidade , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Quimiocina CCL2/sangue , Neoplasias Colorretais/sangue , Citocina TWEAK , Feminino , Expressão Gênica , Humanos , Masculino , Metaloproteinase 9 da Matriz/sangue , Dose Máxima Tolerável , Pessoa de Meia-Idade , Receptores do Fator de Necrose Tumoral/genética , Fator 1 Associado a Receptor de TNF/metabolismo , Receptor de TWEAK , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral , Adulto Jovem
9.
J Clin Oncol ; 22(16): 3366-74, 2004 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-15310782

RESUMO

PURPOSE: To determine maximum tolerated dose, pharmacokinetics (PK), and safety of Ro 31-7453, a novel, oral cell-cycle inhibitor. PATIENTS AND METHODS: Using an accelerated dose-escalation schedule, 48 patients with advanced solid tumors were treated with doses of Ro 31-7453 ranging from 25 to 800 mg/m(2)/d given for 4 consecutive days, every 3 weeks. The total daily dose was taken as a single dose (schedule A) or divided into two equal doses taken 12 hours apart (schedule B). PK samples of blood and urine were collected on the first and last days of dosing in cycles 1 and 2. RESULTS: Forty-five patients completed at least one cycle of therapy. Myelosuppression and stomatitis were dose-limiting toxicities, occurring at the 800 mg/m(2)/d dose level for both schedules. Toxicity was independent of body-surface area, leading to the recommended phase II flat dose of 1,000 mg daily for 4 days for both schedules. Common adverse events included diarrhea, nausea, vomiting, fatigue, alopecia, and elevated liver-function tests. One death, related to neutropenic sepsis, occurred on study. The PK of the parent compound and major metabolites were apparently linear, with a half-life of approximately 9 hours and a maximum concentration of approximately 4 hours. Minor antitumor activity was observed against carcinoma of the lung, breast, pancreas, and ovary. CONCLUSION: Ro 31-7453 was well tolerated, with manageable adverse effects. Significant PK variability (absorption, metabolism, and excretion) was observed, and a substantial number of additional patients are needed to confirm the recommended phase II dose. Additional pharmacology and phase II studies are under way to explore the dose-toxicity relationship.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Indóis/farmacocinética , Neoplasias/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Trombocitopenia/induzido quimicamente
10.
Clin Cancer Res ; 10(13): 4374-82, 2004 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-15240525

RESUMO

PURPOSE: This is a dose-finding Phase I study of oral Ro 31-7453, a new class of antimitotic drug with promising preclinical activity in several chemoresistant models. EXPERIMENTAL DESIGN: Two schedules of oral Ro 31-7453 (every 12 h) given for either 7 or 14 consecutive days repeated every 4 weeks were explored consecutively. RESULTS: Thirty-seven patients with refractory cancer entered the study (14 on the 7-day schedule and 23 on the 14-day schedule). Median age was 63 years (range, 40-77 years), and median Karnofsky performance status was 80 (range, 60-100); the most frequent diagnosis was colorectal carcinoma (16 patients). Dose levels of 100, 200, 240, and 280 mg/m(2) twice daily (bid) for 7 days and 70, 100, 125, and 150 mg/m(2) bid for 14 days were explored. A total of 110 cycles were administered, the median number of cycles received was 3 (range, 1-7); six patients completed 6 or more cycles. Myelosuppression and mucositis were dose-limiting with both schedules. Fatigue and gastrointestinal toxicities other than mucositis were frequent but generally mild. The maximum tolerated doses were 200 mg/m(2) bid and 125 mg/m(2) bid for the 7- and 14-day schedules, respectively. Pharmacokinetic analysis showed rapid absorption and metabolism. The area under the concentration-time curve and trough concentrations of Ro 31-7453 and two active metabolites appeared dose proportional with a t(1/2) of approximately 9 h and a t(max) of approximately 4 h. One patient with pretreated lung cancer had a partial response. CONCLUSIONS: Both Ro 31-7453 regimens were feasible, but the 14-day schedule at the recommended dose of 125 mg/m(2) bid was selected for further monotherapy Phase II evaluation because of its higher preclinical activity. This regimen is convenient, well tolerated, and has a favorable pharmacokinetic profile.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Indóis/administração & dosagem , Indóis/farmacocinética , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/farmacologia , Área Sob a Curva , Carcinoma/tratamento farmacológico , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Ácido Edético/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Químicos , Fatores de Tempo
11.
Clin Cancer Res ; 21(2): 258-66, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25388164

RESUMO

PURPOSE: Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) are a ligand-receptor pair frequently overexpressed in solid tumors. TWEAK: Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFκB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1κ monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14. EXPERIMENTAL DESIGN: Dose escalations, over a 200- to 7,200-mg range, were performed with patients enrolled in weekly (QW), bi-weekly (Q2W), or every-three-week (Q3W) schedules. Primary objectives included determination of dose and safety profile. Secondary endpoints included assessments related to inhibition of TWEAK: Fn14 signaling, tumor proliferation, tumor immune cell infiltration, and pharmacokinetics. RESULTS: In 192 treatment cycles administered to 54 patients, RG7212 was well-tolerated with no dose-limiting toxicities observed. More than 95% of related adverse events were limited to grade 1/2. Pharmacokinetics were dose proportional for all cohorts, with a t1/2 of 11 to 12 days. Pharmacodynamic changes included clearance of free and total TWEAK ligand and reductions in tumor Ki-67 and TRAF1. A patient with BRAF wild-type melanoma who received 36 weeks of RG7212 therapy had tumor regression and pharmacodynamic changes consistent with antitumor effects. Fifteen patients (28%) received 16 or more weeks of RG7212 treatment. CONCLUSION: RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced TWEAK: Fn14 signaling. Tumor regression was observed and prolonged stable disease was demonstrated in multiple heavily pretreated patients with solid tumors. These encouraging results support further study of RG7212. Clin Cancer Res; 21(2); 258-66. ©2014 AACR.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Melanoma/tratamento farmacológico , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacocinética , Neoplasias Colorretais/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Dose Máxima Tolerável , Melanoma/diagnóstico por imagem , Pessoa de Meia-Idade , Cintilografia , Compostos Radiofarmacêuticos , Resultado do Tratamento
12.
Cancer Chemother Pharmacol ; 54(5): 377-84, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15235824

RESUMO

PURPOSE: Carboxyamidotriazole (CAI) is a novel antineoplastic agent in clinical development with limited oral bioavailability. In vitro, ketoconazole has been demonstrated to inhibit CYP3A4-mediated metabolism of CAI. We performed this phase I trial to determine if ketoconazole-mediated CYP3A4 inhibition would lead to favorable alteration of CAI pharmacokinetics, and to evaluate the safety, toxicity and tolerability of the proposed combination. DESIGN: Forty-seven patients were treated using a standard three patients per cohort CAI dose-escalation scheme. In cycle 1, CAI was administered alone on day-6 followed by a single dose of ketoconazole (200 mg) on day 0. CAI and ketoconazole (200 mg/day) were subsequently coadministered on days 1 and 3-28. Plasma samples for pharmacokinetic analysis were obtained following the doses on days-6 and 1. All subsequent cycles were of 28-day duration, and consisted of daily CAI and ketoconazole coadministration. RESULTS: Pharmacokinetic analysis was performed on samples from 44 patients. In most patients administration of ketoconazole produced an increase in CAI AUC and Cmax with a decrease in CAI clearance. Seven patients experienced stable disease for up to 12 months. Gastrointestinal and constitutional toxicities were the most common toxicities. CONCLUSIONS: Coadministration of CAI with ketoconazole increased CAI exposure in most of the patients without altering the toxicity profile of CAI. The highest CAI dose administered on the trial was 300 mg/day. The clinical utility of such a modulation strategy might be explored in future clinical trials of CAI.


Assuntos
Antifúngicos/uso terapêutico , Antineoplásicos/toxicidade , Cetoconazol/uso terapêutico , Neoplasias/tratamento farmacológico , Triazóis/toxicidade , Adulto , Idoso , Cápsulas , Química Farmacêutica , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Clin Cancer Res ; 19(20): 5686-98, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23974006

RESUMO

PURPOSE: To explore the role of TWEAK in tumor growth and antitumor immune response and the activity and mechanism of RG7212, an antagonistic anti-TWEAK antibody, in tumor models. EXPERIMENTAL DESIGN: TWEAK-induced signaling and gene expression were explored in tumor cell lines and inhibition of these effects and antitumor efficacy with RG7212 treatment was assessed in human tumor xenograft-, patient-derived xenograft, and syngeneic tumor models and phase I patients. Genetic features correlated with antitumor activity were characterized. RESULTS: In tumor cell lines, TWEAK induces proliferation, survival, and NF-κB signaling and gene expression that promote tumor growth and suppress antitumor immune responses. TWEAK-inducible CD274, CCL2, CXCL-10 and -11 modulate T-cell and monocyte recruitment, T-cell activation, and macrophage differentiation. These factors and TWEAK-induced signaling were decreased, and tumor, blood, and spleen immune cell composition was altered with RG7212 treatment in mice. RG7212 inhibits tumor growth in vivo in models with TWEAK receptor, Fn14, expression, and markers of pathway activation. In phase I testing, signs of tumor shrinkage and stable disease were observed without dose-limiting toxicity. In a patient with advanced, Fn14-positive, malignant melanoma with evidence of tumor regression, proliferation markers were dramatically reduced, tumor T-cell infiltration increased, and tumor macrophage content decreased. Antitumor activity, a lack of toxicity in humans and animals and no evidence of antagonism with standard of care or targeted agents in mice, suggests that RG7212 is a promising agent for use in combination therapies in patients with Fn14-positive tumors.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Neoplasias/imunologia , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Inibidores do Fator de Necrose Tumoral , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocina TWEAK , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Neoplasias/genética , Neoplasias/patologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Fatores de Necrose Tumoral/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
J Clin Oncol ; 30(19): 2348-53, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22529266

RESUMO

PURPOSE: To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies. PATIENTS AND METHODS: Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [(18)F]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects. RESULTS: Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed. CONCLUSION: RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzazepinas/uso terapêutico , Neoplasias/tratamento farmacológico , Receptores Notch/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzazepinas/efeitos adversos , Benzazepinas/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/metabolismo , Neoplasias/patologia , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Mol Cancer Ther ; 8(9): 2517-25, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19755512

RESUMO

A genomics-based approach to identify pharmacodynamic biomarkers was used for a cyclin-dependent kinase inhibitory drug. R547 is a potent cyclin-dependent kinase inhibitor with a potent antiproliferative effect at pharmacologically relevant doses and is currently in phase I clinical trials. Using preclinical data derived from microarray experiments, we identified pharmacodynamic biomarkers to test in blood samples from patients in clinical trials. These candidate biomarkers were chosen based on several criteria: relevance to the mechanism of action of R547, dose responsiveness in preclinical models, and measurable expression in blood samples. We identified 26 potential biomarkers of R547 action and tested their clinical validity in patient blood samples by quantitative real-time PCR analysis. Based on the results, eight genes (FLJ44342, CD86, EGR1, MKI67, CCNB1, JUN, HEXIM1, and PFAAP5) were selected as dose-responsive pharmacodynamic biomarkers for phase II clinical trials.


Assuntos
Biomarcadores Tumorais/sangue , Quinases Ciclina-Dependentes/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/enzimologia , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Pirimidinas/farmacologia
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