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1.
Cancer ; 124(10): 2174-2183, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29533458

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific. METHODS: This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux-m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux-m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD. RESULTS: Fifty-six patients were treated. The MTD and the recommended phase 2 dose for depatux-m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR-amplified, triple-negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux-m exposures were approximately dose-proportional. CONCLUSIONS: Depatux-m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow-up confirmed that ocular AEs were reversible. Lowering the drug-antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR-amplified disease provides the opportunity to study depatux-m in diseases with a high incidence of EGFR amplification. Cancer 2018;124:2174-83. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Fadiga/epidemiologia , Imunoconjugados/administração & dosagem , Neoplasias/tratamento farmacológico , Transtornos da Visão/epidemiologia , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Fadiga/induzido quimicamente , Feminino , Seguimentos , Amplificação de Genes , Humanos , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/genética , Neoplasias/patologia , Resultado do Tratamento , Transtornos da Visão/induzido quimicamente
2.
J Neurooncol ; 131(1): 105-115, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27655223

RESUMO

Veliparib is a potent, orally bioavailable, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that crosses the blood-brain barrier and has been shown to potentiate the effects of radiation in preclinical and early clinical studies. This phase 2, randomized, global study evaluated the efficacy and safety of veliparib in combination with whole-brain radiation therapy (WBRT) in patients with brain metastases from non-small cell lung cancer (NSCLC). Three-hundred and seven patients with brain metastases from NSCLC were randomized 1:1:1 to WBRT (30 Gy in 10 fractions) plus 50 mg veliparib twice daily (BID; n = 103), 200 mg veliparib BID (n = 102), or placebo BID (n = 102). Treatment began within 28 days of diagnosis. Tumor response and safety were assessed; the primary endpoint was overall survival (OS). Patients who received ≥1 dose of treatment were included in the safety analysis. All randomized patients were included in the efficacy endpoint analyses. Patient characteristics were well balanced between treatment arms. Median OS was 185 days for patients treated with WBRT plus placebo and 209 days for WBRT plus veliparib (50 or 200 mg). No statistically significant differences in OS, intracranial response rate, and time to clinical or radiographic progression between any of the treatment arms were noted. No differences were observed in adverse events (all grades) across treatment arms; nausea, fatigue, alopecia, and headache were the most commonly reported. No new safety signals were identified for veliparib. A significant unmet need for therapies that improve the outcomes of patients with brain metastases from NSCLC remains.


Assuntos
Antineoplásicos/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas/patologia , Irradiação Craniana/métodos , Neoplasias Pulmonares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
3.
Oncologist ; 21(7): 785-6, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27261467

RESUMO

LESSONS LEARNED: Pancreatic neuroendocrine tumors versus carcinoid tumors should be examined separately in clinical trials.Progression-free survival is more clinically relevant as the primary endpoint (rather than response rate) in phase II trials for low-grade neuroendocrine tumors. BACKGROUND: The most common subtypes of neuroendocrine tumors (NETs) are pancreatic islet cell tumors and carcinoids, which represent only 2% of all gastrointestinal malignancies. Histone deacetylase (HDAC) inhibitors have already been shown to suppress tumor growth and induce apoptosis in various malignancies. In NET cells, HDAC inhibitors have resulted in increased Notch1 expression and subsequent inhibition of growth. We present here a phase II study of the novel HDAC inhibitor panobinostat in patients with low-grade NET. METHODS: Adult patients with histologically confirmed, metastatic, low-grade NETs and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were treated with oral panobinostat 20 mg once daily three times per week. Treatment was continued until patients experienced unacceptable toxicities or disease progression. The study was stopped at planned interim analysis based on a Simon two-stage design. RESULTS: Fifteen patients were accrued, and 13 were evaluable for response. No responses were seen, but the stable disease rate was 100%. The median progression-free survival (PFS) was 9.9 months, and the median overall survival was 47.3 months. Fatigue (27%), thrombocytopenia (20%), diarrhea (13%), and nausea (13%) were the most common related grade 3 toxicities. There was one grade 4 thrombocytopenia (7%). These results did not meet the prespecified criteria to open the study to full accrual. CONCLUSION: The HDAC inhibitor panobinostat has a high stable disease rate and reasonable PFS in low-grade NET, but has a low response rate.


Assuntos
Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Indóis/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/mortalidade , Panobinostat
4.
Invest New Drugs ; 33(1): 169-76, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25318436

RESUMO

BACKGROUND: RO4929097 is an oral inhibitor of γ -secretase that results in Notch signaling inhibition. Prior work has demonstrated that Notch signaling inhibition enhances chemotherapy sensitivity of cancer cells. This phase I study was conducted to determine maximum tolerated dose (MTD), toxicities and efficacy of RO4929097 and capecitabine in advanced solid tumors. METHODS: Patients with refractory solid tumors received capecitabine at a fixed dose of 1,000 mg/m(2) twice daily with escalating doses of RO4929097 on a 21-day cycle in a 3 + 3 design. Capecitabine was administered for 14 days and the RO49029097 once daily, 3 days per week, both for a 21 day cycle. RESULTS: Thirty patients were treated on six dose levels (20 to 150 mg). The maximally tolerated dose was not reached. One dose limiting toxicity was observed at each level 3 through 6 (hypophosphatemia, fatigue, and nausea/vomiting). Three confirmed partial responses were observed: two patients with fluoropyrimide-refractory colon cancer and one patient with cervical cancer. Autoinduction of RO4929097 was demonstrated with increasing dose levels and duration. CONCLUSIONS: The recommended phase 2 dose is capecitabine 1,000 mg/m(2) orally twice daily on days 1 through 14 with RO4929097 20 mg orally once daily on days 1-3, 8-10 and 15-17 with a 21 day cycle. Clinical benefit was observed in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. Plasma concentrations of RO4929097 were above those needed for Notch inhibition.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzazepinas/administração & dosagem , Benzazepinas/efeitos adversos , Benzazepinas/sangue , Benzazepinas/farmacocinética , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos
5.
Invest New Drugs ; 31(4): 943-8, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23263993

RESUMO

Chemotherapy has yielded minimal clinical benefit in pancreatic and biliary tract cancer. A high-dose, short course capecitabine schedule with oxaliplatin, has shown some efficacy with a lower incidence of palmar-plantar erythrodysesthesia. Achieving high exposures of the targeted agent sorafenib may be possible with this shorter schedule of capecitabine by avoiding dermatologic toxicity. All patients had pancreatic or biliary tract cancer. Patients in both cohorts received oxaliplatin 85 mg/m2 followed by capecitabine 2,250 mg/m2 PO every 8 h x 6 doses starting on days 1 and 15 of a 28 day cycle, or 2DOC (2 Day Oxaliplatin/Capecitabine). Cohort 1 used sorafenib 200 mg BID, and cohort 2 used sorafenib 400 mg BID. Sixteen patients were enrolled. Across all cycles the most common grade 1 or 2 adverse events were fatigue (10 pts), diarrhea (10 pts), nausea (9 pts), vomiting (8 pts), sensory neuropathy (8 pts), thrombocytopenia (7 pts), neutropenia (5 pts), and hand-foot syndrome (5 pts). Grade 3 toxicites included neutropenia, mucositis, fatigue, vomiting and diarrhea. Cohort 1 represented the MTD. Two partial responses were seen, one each in pancreatic and biliary tract cancers. The recommended phase II dose of sorafenib in combination with 2DOC is 200 mg BID. There were infrequent grade 3 toxicities, most evident with sorafenib at 400 mg BID.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Niacinamida/análogos & derivados , Compostos Organoplatínicos/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/patologia , Capecitabina , Demografia , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Niacinamida/efeitos adversos , Niacinamida/uso terapêutico , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Neoplasias Pancreáticas/patologia , Compostos de Fenilureia/efeitos adversos , Sorafenibe , Resultado do Tratamento , Wisconsin
6.
Invest New Drugs ; 31(6): 1539-46, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24114121

RESUMO

BACKGROUND: A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors. METHODS: Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m(2)). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1. RESULTS: Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m(2) to 1.5 mg/m(2). The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m(2). DLTs consisted of grade 3 fatigue in three patients (1 mg/m(2),1.3 mg/m(2) and 1.5 mg/m(2)) and grade 3 hyponatremia in one patient (1.5 mg/m(2)). The most common grade 1/2 toxicities included nausea (60.9%), fatigue (34.8%), diaphoresis (34.8%), anorexia (30.4%) and constipation (26.1%). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1. CONCLUSIONS: This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily × 14 days and bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day cycle.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ácidos Borônicos/administração & dosagem , Bortezomib , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/sangue , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/sangue , Ácidos Hidroxâmicos/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/sangue , Pirazinas/administração & dosagem , Vorinostat , Adulto Jovem
7.
Cancer ; 118(9): 2424-30, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-21953248

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC). METHODS: Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2-stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child's Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point. RESULTS: Twenty-seven patients with advanced HCC (median age, 60 years) were enrolled in this multi-institutional study. The proportion of patients with Child's A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8-7.1). Median survival time was 9.5 months (95% CI, 7.1-17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea. CONCLUSIONS: In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression-free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Quinazolinas/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Carcinoma Hepatocelular/mortalidade , Intervalo Livre de Doença , Cloridrato de Erlotinib , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
8.
Oncologist ; 16(6): 835-43, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21632454

RESUMO

INTRODUCTION: Notch1 has been shown to be a tumor suppressor in neuroendocrine tumors (NETs). Previous in vitro studies in NET cell lines have also suggested that valproic acid (VPA), a histone deacetylase inhibitor, can induce Notch1 and that Notch1 activation correlates with a decrease in tumor markers for NETs. Thus, this study aimed to evaluate the role of VPA in treating NETs and to determine whether VPA induced the Notch signaling pathway signaling in vivo. PATIENTS AND METHODS: Eight patients with low-grade NETs (carcinoid and pancreatic) were treated with 500 mg of oral VPA twice a day with dosing adjusted to maintain a goal VPA level between 50 and 100 µg/mL. All patients were followed for 12 months or until disease progression. RESULTS: Notch1 signaling was absent in all tumors prior to treatment and was upregulated with VPA. One patient had an unconfirmed partial response and was noted to have a 40-fold increase in Notch1 mRNA levels. Four patients had stable disease as best response. Tumor markers improved in 5 out of 7 patients. Overall, treatment with VPA was well tolerated. CONCLUSION: . VPA activates Notch1 signaling in vivo and may have a role in treating low-grade NETs.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Ácido Valproico/uso terapêutico , Idoso , Biomarcadores Tumorais , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Receptor Notch1/efeitos dos fármacos , Receptor Notch1/metabolismo , Transdução de Sinais/efeitos dos fármacos
9.
Oncologist ; 16(4): 452-7, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21393344

RESUMO

BACKGROUND: Low-grade neuroendocrine tumors (NETs) respond poorly to chemotherapy; effective, less toxic therapies are needed. Glycogen synthase kinase (GSK)-3ß has been shown to regulate growth and hormone production in NETs. Use of lithium chloride in murine models suppressed carcinoid cell growth, reduced GSK-3ß levels, and reduced expression of chromogranin A. This study assessed the efficacy of lithium chloride in patients with NETs. DESIGN: Eligible patients had low-grade NETs. A single-arm, open-label phase II design was used. Lithium was dosed at 300 mg orally three times daily, titrated to serum levels of 0.8-1.0 mmol/L. The primary endpoint was objective tumor response by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included overall survival, progression-free survival, GSK-3ß phosphorylation, and toxicity. RESULTS: Fifteen patients were enrolled between October 3, 2007 and July 17, 2008, six men and nine women. The median age was 58 years. Patient diagnoses were carcinoid tumor for eight patients, islet cell tumor for five patients, and two unknown primary sites. Eastern Cooperative Oncology Group performance status scores were 0 or 1. Two patients came off study because of side effects. The median progression-free survival interval was 4.50 months. There were no radiographic responses. Because of an early stopping rule requiring at least one objective response in the first 13 evaluable patients, the study was closed to further accrual. Patients had pre- and post-therapy biopsies. CONCLUSIONS: Lithium chloride was ineffective at obtaining radiographic responses in our 13 patients who were treated as part of this study. Based on the pre- and post-treatment tumor biopsies, lithium did not potently inhibit GSK-3ß at serum levels used to treat bipolar disorders.


Assuntos
Antineoplásicos/uso terapêutico , Cloreto de Lítio/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Idoso , Intervalo Livre de Doença , Feminino , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Cloreto de Lítio/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fosforilação , Falha de Tratamento
10.
Invest New Drugs ; 29(6): 1475-81, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20574790

RESUMO

PURPOSE: The transcription factor nuclear factor-kB (NFkB) is implicated in gastric cancer carcinogenesis and survival, and its inhibition by proteosome inhibition is associated with preclinical gastric cancer anti-tumor activity. We examined the single agent efficacy of bortezomib, a selective proteasome inhibitor, in gastric adenocarcinoma. EXPERIMENTAL DESIGN: We performed a phase II trial of bortezomib in patients with advanced gastric adenocarcinoma. Bortezomib 1.3 mg/m(2) was administered on days 1, 4, 8, and 11 every 21 days. The primary endpoint was objective response rate(RR); the null hypothesis was RR <1% versus the alternative ≥15%. One response in the first stage(15 patients) was required before proceeding with an additional 18 patients. If at least 2 or more responses out of 33 were observed, further study with bortezomib was warranted. Correlative studies evaluated pre-treatment tumor expression of NFkB, IkB, p53, p21, and cyclin D1. RESULTS: We enrolled 16 patients (15 evaluable for response) from four institutions. No patients demonstrated an objective response(95% CI, 0-22%); one patient achieved stable disease. Fourteen out of 16 patients experienced ≥ grade 2 toxicity. The most common toxicity was fatigue in six patients (n = 4 grade 2, n = 2 grade 3). Seven patients experienced neuropathy (n = 5 grade 1, and 1 each grade 2 and 3). Seven (60%) had high cytoplasmic staining for NFkB. CONCLUSIONS: Single agent bortezomib is inactive in metastatic gastric adenocarcinoma and should not be pursued. Future study of proteasome inhibition in gastric adenocarcinoma should be considered in combination with targeted inhibition of other non-overlapping oncogenic pathways as a potential rational approach.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Pirazinas/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/patologia , Idoso , Antineoplásicos/efeitos adversos , Ácidos Borônicos/efeitos adversos , Bortezomib , Junção Esofagogástrica/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Metástase Neoplásica , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/uso terapêutico , Pirazinas/efeitos adversos , Neoplasias Gástricas/patologia , Resultado do Tratamento
11.
J Nucl Med ; 62(6): 787-794, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33509972

RESUMO

ABT-806 is a tumor-specific antibody targeting the epidermal growth factor receptor (EGFR). This study assessed safety, biodistribution, and pharmacokinetics of 111In-radiolabeled ABT-806 (ABT-806i) and effects of repeated doses of ABT-806 on receptor occupancy. Methods: Eligible patients had advanced tumors likely to express EGFR/EGFRvIII; adequate performance status and organ function; and measurable disease by RECIST 1.1. In cohort 1, 6 patients received a bolus administration of ABT-806i and underwent SPECT followed by whole-body planar scans. In cohort 2, 12 patients were imaged similarly as in 1 initially; thereafter, they received 3 doses of unlabeled ABT-806, before another dose of ABT-806i with associated SPECT and whole-body planar scans. At the end of both cohorts, patients who had stable or responding disease were able to enroll into an extension study (M12-326) in which they received unlabeled ABT-806 every 2 wk until disease progression, withdrawal of consent, or intolerable toxicity. Results: No toxicity related to ABT-806i infusion was observed. ABT-806i showed minimal uptake in normal tissues and cleared gradually from blood with a half-life of 6.0 ± 1.5 d. The mean effective dose of ABT-806i was 0.137 mSv/MBq for males and 0.183 mSv/MBq for females. ABT-806i tumor uptake varied and did not correlate with archived tumor EGFR expression. No change in ABT-806i uptake was observed after interval ABT-806 treatment, indicating stable EGFR expression in tumor. The patient with highest tumor uptake of ABT-806i had advanced head and neck cancer and experienced a partial response. Conclusion: ABT-806i allows for real-time imaging of EGFR conformational expression in tumors, has an acceptable radiation dosimetry, and provides important additional information about antigen expression compared with standard approaches using archival tissue. Its role to assist in patient selection for EGFR-based therapeutics and investigate treatment resistance should be further investigated.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Receptores ErbB/imunologia , Imunoconjugados/farmacocinética , Radioisótopos de Índio , Adulto , Anticorpos Monoclonais Humanizados/imunologia , Estudos de Coortes , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/metabolismo , Humanos , Imunoconjugados/imunologia , Marcação por Isótopo , Masculino , Pessoa de Meia-Idade , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único
12.
Clin Cancer Res ; 15(4): 1460-5, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19228747

RESUMO

PURPOSE: 2-methoxyestradiol (2ME2; Panzem) is an endogenous, estradiol-17beta metabolite that at pharmacologic doses exerts antimitotic and antiangiogenic activities. Studies with a 2ME2 capsule formulation showed limited oral bioavailability. We report the results of a phase I study using a NanoCrystal Dispersion formulation of 2ME2 (2ME2 NCD). EXPERIMENTAL DESIGN: Patients with refractory solid tumors received 2ME2 NCD orally. Patients received drug either every 6 hours (part A) or every 8 hours (part B). Doses were escalated in successive cohorts until the maximum tolerated dose (MTD) was identified. The primary objective was identifying the MTD. Secondary objectives were to evaluate the plasma pharmacokinetics of 2ME2 and efficacy. RESULTS: In part A, 16 patients received a median of 4 cycles of 2ME2 NCD. Dose-limiting toxicities (DLT) included fatigue (2), hypophosphatemia (2), increased alanine aminotransferase (1), and muscle weakness (1). Trough levels at steady-state reached the minimum effective concentration in all cohorts. The MTD was determined to be 1,000 mg orally every 6 hours. In part B, 10 patients received a median of 1 cycle. DLTs included elevated gamma-glutamyltransferase (1), hyponatremia (1), fatigue (1), and anorexia (1). An MTD could not be defined for part B because 4 of 10 patients had DLTs at the initial dose level and dose reduction was not pursued. Thirteen patients had stable disease (A, 11; B, 2); there were no confirmed responses. CONCLUSION: For 2ME2 NCD, the MTD and recommended phase II regimen is 1,000 mg orally every 6 hours. Treatment was generally well-tolerated.


Assuntos
Estradiol/análogos & derivados , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , 2-Metoxiestradiol , Idoso , Idoso de 80 Anos ou mais , Estradiol/administração & dosagem , Estradiol/efeitos adversos , Estradiol/farmacocinética , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade
13.
Clin Adv Hematol Oncol ; 7(1): 54-64, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19274042

RESUMO

Until recently, development of chemotherapeutic agents that target mitosis has centered on inhibiting the mitotic spindle through interactions with microtubules. The taxanes, while significantly advancing the treatment of many types of cancer, suffer from problems of hematopoeitic and neurologic toxicities, development of resistance, and an inconvenient formulation. Novel microtubule inhibitors currently in clinical trial and in clinical use have the main advantage of overcoming resistance. Still, they have side effects related to the inhibition of microtubules in normal host cells. Novel antimitotics, which target the mitotic spindle through interactions with nonmicrotubule mitotic mediators like mitotic kinases and kinesins, have been identified and are now in clinical trial. They offer the prospect of surmounting more of the problems inherent with taxanes and the hope of improving upon their broad antitumor efficacy. This review will concentrate on novel agents in later clinical development that target both the spindle microtubule and nonmicrotubule constituents of mitosis.


Assuntos
Antimitóticos/uso terapêutico , Antineoplásicos/uso terapêutico , Mitose/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Taxoides/farmacologia , Humanos , Cinesinas/metabolismo , Microtúbulos/metabolismo , Fosfotransferases/metabolismo , Tubulina (Proteína)/metabolismo
14.
Clin Cancer Res ; 25(11): 3259-3265, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30796037

RESUMO

PURPOSE: Patients with glioblastoma (GBM) have a poor prognosis and are in desperate need of better therapies. As therapeutic decisions are increasingly guided by biomarkers, and EGFR abnormalities are common in GBM, thus representing a potential therapeutic target, we systematically evaluated methods of assessing EGFR amplification by multiple assays. Specifically, we evaluated correlation among fluorescence in situ hybridization (FISH), a standard assay for detecting EGFR amplification, with other methods.Experimental Design: Formalin-fixed, paraffin-embedded tumor samples were used for all assays. EGFR amplification was detected using FISH (N = 206) and whole-exome sequencing (WES, N = 74). EGFR mRNA expression was measured using reverse transcription-polymerase chain reaction (RT-PCR, N = 206) and transcriptome profiling (RNAseq, N = 64). EGFR protein expression was determined by immunohistochemistry (IHC, N = 34). Significant correlations among various methods were determined using Cohen's kappa (κ = 0.61-0.80 defines substantial agreement) or R 2 statistics. RESULTS: EGFR mRNA expression levels by RNA sequencing (RNAseq) and RT-PCR were highly correlated with EGFR amplification assessed by FISH (κ = 0.702). High concordance was also observed when comparing FISH to WES (κ = 0.739). RNA expression was superior to protein expression in delineating EGFR amplification. CONCLUSIONS: Methods for assessing EGFR mRNA expression (RT-PCR, RNAseq) and copy number (WES), but not protein expression (IHC), can be used as surrogates for EGFR amplification (FISH) in GBM. Collectively, our results provide enhanced understanding of available screening options for patients, which may help guide EGFR-targeted therapeutic approaches.


Assuntos
Biomarcadores Tumorais , Glioblastoma/etiologia , Medicina de Precisão , Ensaios Clínicos Fase I como Assunto , Receptores ErbB/genética , Receptores ErbB/metabolismo , Amplificação de Genes , Perfilação da Expressão Gênica , Testes Genéticos , Glioblastoma/diagnóstico , Glioblastoma/metabolismo , Glioblastoma/terapia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Medicina de Precisão/métodos , Medicina de Precisão/normas , Reação em Cadeia da Polimerase em Tempo Real , Sequenciamento do Exoma
15.
Neuro Oncol ; 21(1): 106-114, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982805

RESUMO

Background: Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. Methods: M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve. Results: There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions: Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Amplificação de Genes , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Estudos de Coortes , Receptores ErbB/genética , Feminino , Seguimentos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Agências Internacionais , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Temozolomida/administração & dosagem , Distribuição Tecidual , Adulto Jovem
16.
J Inorg Biochem ; 102(4): 693-8, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18061679

RESUMO

The metal chelator Triapine, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, is a potent inhibitor of ribonucleotide reductase. EPR spectra consistent with signals from Fe-transferrin, heme, and low-spin iron or cupric ion were observed in peripheral blood mononuclear cells (PBMCs) obtained from patients treated with Triapine. One signal that is unequivocally identified is the signal for Fe-transferrin. It is hypothesized that Fe uptake is blocked by reactive oxygen species generated by FeT(2) or CuT that damage transferrin or transferrin receptor. A potential source for the increase in the heme signal is cytochrome c released from the mitochondria. These results provide valuable insight into the in vivo mechanism of action of Triapine.


Assuntos
Monócitos/química , Neoplasias/tratamento farmacológico , Piridinas/uso terapêutico , Tiossemicarbazonas/uso terapêutico , Citocromos c/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica , Humanos
17.
Oncology (Williston Park) ; 22(1): 66-7, 70-1, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18251284

RESUMO

Sunitinib malate (Sutent, SU011248) is an oral multitargeted tyrosine kinase inhibitor used for treatment of renal cell carcinoma and gastrointestinal stromal tumor. We report a case of a patient who developed Guillain-Barrd syndrome after initial treatment with sunitinib, with recurrent symptoms upon reintroducing the drug. This is the first report of such an effect. The literature on chemotherapy-induced Guillain-Barri syndrome is also reviewed. Oncology providers should be aware of this rare but potentially serious possible adverse effect of sunitinib.


Assuntos
Antineoplásicos/efeitos adversos , Síndrome de Guillain-Barré/induzido quimicamente , Indóis/efeitos adversos , Pirróis/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Sunitinibe
18.
Clin Adv Hematol Oncol ; 6(1): 44-54, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18322441

RESUMO

BACKGROUND: Animal models suggest that growth hormone participates in hepatocarcinogenesis. OBJECTIVE: To correlate the effect of octreotide long-acting release (LAR) on insulin-like growth factor-I (IGF-I) and -II (IGF-II) with response and survival in patients with unresectable and metastatic hepatocellular carcinoma. METHODS: We conducted a phase II, single-institution trial of octreotide-LAR (30 mg intramuscularly every 4 weeks) in 15 patients while monitoring serum IGF-I and -II levels. RESULTS: Patients (median CLIP score 2, Okuda stage II, and ECOG performance status 1) were treated for a median of 2.0 cycles. No responses occurred. Median overall survival was 116 days (range, 27-937 days) and median progression-free survival was 60 days (range, 27-444 days). One patient had prolonged stable disease (16 months). There were no grade 4 and four grade 3 toxicities: abdominal cramping, elevated creatinine, diarrhea, and dyspnea. Median serum IGF-I decreased from baseline (42.2 ng/mL; range, 14.2-109 ng/mL) to day 29 (27.9 ng/mL; range, 5.7-71.1 ng/mL), and median serum IGF-II decreased from baseline (25,000 ng/mL; range, 12,400-93,600 ng/mL) to day 29 (18,400 ng/mL; range, 4,061-79,400 ng/mL; 2-sided P<.006 and P<.04, respectively; Wilcoxon signed rank test). This suppression did not correlate with clinical activity. Baseline serum IGF-I >30 ng/mL was associated with greater progression-free survival and overall survival (P=.0005 and P=.0173, respectively; 2-sided log-rank test). CONCLUSIONS: Octreotide-LAR lowered serum IGF-I and -II levels; however, this lowering did not correlate with clinical activity. There were no responses, and progression-free survival and overall survival were similar to historical patients not on treatment. Baseline serum IGF-I predicted prognosis.


Assuntos
Antineoplásicos Hormonais/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Fator de Crescimento Insulin-Like II/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Octreotida/farmacologia , Idoso , Preparações de Ação Retardada , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Prognóstico
19.
Mol Cancer Ther ; 17(1): 215-221, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29054986

RESUMO

This phase I study evaluates the safety, MTD, pharmacokinetics (PK), pharmacodynamics, and preliminary anticancer activity of enavatuzumab, a humanized IgG1 antibody to the TWEAK receptor, in patients with advanced solid malignancies. Patients received escalating doses of enavatuzumab given intravenously over 60 minutes every 2 weeks. Blood was obtained for PK and biomarker assessment. Three patients were enrolled per dose level in a standard 3+3 design with response assessment by RECIST version 1.0, every 8 weeks. Thirty patients were enrolled at 6 dose levels ranging from 0.1 to 1.5 mg/kg. Dose-limiting toxicities included grade 4 (G4) lipase, G3 bilirubin, and G4 amylase elevations. There was no apparent correlation of liver or pancreatic enzyme elevation with drug exposure or the presence of liver metastases. Enavatuzumab exhibited a two-compartment linear PK model. Estimated systemic clearance was 23 to 33 mL/h with an elimination half-life of 7 to 18 days. The predicted target efficacious peak and trough concentrations occurred at 1.0 mg/kg following the second dose. There were no objective responses; 4 patients had stable disease. The MTD of enavatuzumab is 1.0 mg/kg i.v. every 2 weeks. Higher doses were not tolerated due to hepatopancreatic lab abnormalities. Further evaluation of the mechanisms of the liver and pancreatic enzyme toxicities is needed before embarking on further single-agent or combination strategies. Mol Cancer Ther; 17(1); 215-21. ©2017 AACR.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/metabolismo , Neoplasias/tratamento farmacológico , Receptor de TWEAK/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia
20.
Neuro Oncol ; 20(6): 838-847, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29077941

RESUMO

Background: We recently reported an acceptable safety and pharmacokinetic profile of depatuxizumab mafodotin (depatux-m), formerly called ABT-414, plus radiation and temozolomide in newly diagnosed glioblastoma (arm A). The purpose of this study was to evaluate the safety and pharmacokinetics of depatux-m, either in combination with temozolomide in newly diagnosed or recurrent glioblastoma (arm B) or as monotherapy in recurrent glioblastoma (arm C). Methods: In this multicenter phase I dose escalation study, patients received depatux-m (0.5-1.5 mg/kg in arm B, 1.25 mg/kg in arm C) every 2 weeks by intravenous infusion. Maximum tolerated dose (MTD), recommended phase II dose (RP2D), and preliminary efficacy were also determined. Results: Thirty-eight patients were enrolled as of March 1, 2016. The most frequent toxicities were ocular, occurring in 35/38 (92%) patients. Keratitis was the most common grade 3 adverse event observed in 6/38 (16%) patients; thrombocytopenia was the most common grade 4 event seen in 5/38 (13%) patients. The MTD was set at 1.5 mg/kg in arm B and was not reached in arm C. RP2D was declared as 1.25 mg/kg for both arms. Depatux-m demonstrated a linear pharmacokinetic profile. In recurrent glioblastoma patients, the progression-free survival (PFS) rate at 6 months was 30.8% and the median overall survival was 10.7 months. Best Response Assessment in Neuro-Oncology responses were 1 complete and 2 partial responses. Conclusion: Depatux-m alone or in combination with temozolomide demonstrated an acceptable safety and pharmacokinetic profile in glioblastoma. Further studies are currently under way to evaluate its efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias Encefálicas/patologia , Feminino , Seguimentos , Glioblastoma/patologia , Humanos , Imunoconjugados/administração & dosagem , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Segurança , Taxa de Sobrevida , Temozolomida/administração & dosagem , Distribuição Tecidual , Adulto Jovem
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