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1.
Clin Cancer Res ; 24(20): 4937-4948, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29950349

RESUMO

Purpose: Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 and MDA-5 that can activate immune cells, such as dendritic cells, and trigger natural killer cells to kill tumor cells.Patients and Methods: In this pilot study, eligible patients included those with recurrent metastatic disease in whom prior systemic therapy (head and neck squamous cell cancer and melanoma) failed. Patients received 2 treatment cycles, each cycle consisting of 1 mg poly-ICLC 3× weekly intratumorally (IT) for 2 weeks followed by intramuscular (IM) boosters biweekly for 7 weeks, with a 1-week rest period. Immune response was evaluated by immunohistochemistry (IHC) and RNA sequencing (RNA-seq) in tumor and blood.Results: Two patients completed 2 cycles of IT treatments, and 1 achieved clinical benefit (stable disease, progression-free survival 6 months), whereas the remainder had progressive disease. Poly-ICLC was well tolerated, with principal side effects of fatigue and inflammation at injection site (

Assuntos
Carboximetilcelulose Sódica/análogos & derivados , Fatores Imunológicos/administração & dosagem , Imunomodulação/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Poli I-C/administração & dosagem , Polilisina/análogos & derivados , Idoso , Biópsia , Carboximetilcelulose Sódica/administração & dosagem , Carboximetilcelulose Sódica/efeitos adversos , Esquema de Medicação , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Fatores Imunológicos/efeitos adversos , Injeções Intralesionais , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/mortalidade , Projetos Piloto , Poli I-C/efeitos adversos , Polilisina/administração & dosagem , Polilisina/efeitos adversos , Prognóstico , Tomografia Computadorizada por Raios X , Resultado do Tratamento
2.
Am J Cancer Res ; 3(3): 323-38, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23841031

RESUMO

Rigosertib (ON 01910.Na), a synthetic novel benzyl styryl sulfone, was administered to 28 patients with advanced cancer in a Phase I trial in order to characterize its pharmacokinetic profile, determine the dose-limiting toxicities (DLT), define the recommended phase II dose (RPTD) and to document any antitumor activity. Patients with advanced malignant neoplasms refractory to standard therapy were given escalating doses of rigosertib (50, 100, 150, 250, 325, 400, 650, 850, 1,050, 1,375, 1,700 mg/m(2)/24h) as a 3-day continuous infusion (CI) every 2 weeks. An accelerated Fibonacci titration schedule with specified decreases for toxicities was used for escalation until grade ≥2 toxicity occurred. Intrapatient dose escalation was allowed if toxicity was grade ≤2 and the disease remained stable. Plasma pharmacokinetics (PK) and urinary PK assessments were studied in the 1st and 4th cycles. Twenty-nine patients (12 men and 17 women; age 36-87 y with a median of 63 y) were registered, but one died before study drug was given. Twenty-eight patients received a median of 3 cycles of therapy. Most common grade ≥2 toxicities attributable to rigosertib included fatigue, anorexia, vomiting and constipation. DLTs included muscular weakness, hyponatremia, neutropenia, delirium and confusional state. Risk factors for severe toxicities include pre-existing neurological dysfunction or advanced gynecologic cancer after pelvic surgery. Rigosertib pharmacokinetics showed rapid plasma distribution phases and urinary excretion. Elevations in plasma Cmax and AUC due to decreases in plasma clearance were associated with acute grade ≥3 toxicities. Of 22 evaluable patients, 9 (41%) achieved a best overall response of stable disease; all other patients (n=13; 59%) progressed. The median progression-free survival time was 50 days (95% confidence interval [CI]: 37-80 days). Nine (41%) patients survived for over 1 y. In summary, prolonged IV infusions of rigosertib were generally well tolerated. Nine (41%) patients achieved stable disease and 9 (41%) patients survived for over 1 year. The RPTD appears to be 850 mg/m(2)/24hr CI x 3 days. (ClinicalTrials.gov identifier: NCT01538537).

3.
Am J Clin Oncol ; 34(5): 443-8, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20881475

RESUMO

OBJECTIVE: To define the safety [dose limiting toxicity (DLT)] and recommended phase II dose of the combination of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma (RCC). METHODS: In this phase I dose-escalation study, cohorts of 3 to 6 patients with metastatic RCC received sorafenib (200 or 400 mg po BID), gemcitabine (750 or 1000 mg/m(2) intravenous on days 1 and 8), and capecitabine (415 or 622 mg/m(2) po BID days 1-14) every 21 days using a standard 3+3 design. RESULTS: Fifteen patients with advanced RCC (93% with clear cell histology and 87% treatment naive) received treatment. The recommended phase II doses for the combination were sorafenib 200 mg/m(2) BID continuously plus gemcitabine 750 mg/m(2) intravenous days 1 and 8 and capecitabine 415 mg/m(2) BID days 1 to 14, every 21 days. Of the 15 patients, 3 developed dose-limiting hand-foot syndrome during the first 2 cycles; 2 additional DLT's were grade 3 mucositis and transaminase elevation. Four of 14 evaluable patients had a partial response by response evaluation criteria in solid tumors (29%; 95% confidence interval (CI): 8, 58%). Median progression-free survival was 7.5 months (95% CI-0, 18.7), and median overall survival has not been reached at a median follow-up of 28.8 months. The median number of treatment cycles given was 7 (range, 2-38+). CONCLUSIONS: The combination of sorafenib plus gemcitabine and capecitabine is tolerable, but requires attenuation of sorafenib and capecitabine dosing because of the overlapping toxicity of hand-foot syndrome. Antitumor activity was observed leading to an ongoing phase II trial.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Benzenossulfonatos/administração & dosagem , Neoplasias Ósseas/secundário , Capecitabina , Carcinoma de Células Renais/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Seguimentos , Humanos , Neoplasias Renais/patologia , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/administração & dosagem , Sorafenibe , Taxa de Sobrevida , Resultado do Tratamento , Gencitabina
4.
J Clin Oncol ; 26(18): 2992-8, 2008 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-18565886

RESUMO

PURPOSE: To determine the clinical and biologic effects of bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Adults with organ-confined HCC, Eastern Cooperative Oncology Group performance status of 0 to 2, and compensated liver disease were eligible. Patients received bevacizumab 5 mg/kg (n = 12) or 10 mg/kg (n = 34) every 2 weeks until disease progression or treatment-limiting toxicity. The primary objective was to determine whether bevacizumab improved the 6-month progression-free survival (PFS) rate from 40% to 60%. Secondary end points included determining the effects of bevacizumab on arterial enhancement and on plasma cytokine levels and the capacity of patients' plasma to support angiogenesis via an in vitro assay. RESULTS: The study included 46 patients, of whom six had objective responses (13%; 95% CI, 3% to 23%), and 65% were progression free at 6 months. Median PFS time was 6.9 months (95% CI, 6.5 to 9.1 months); overall survival rate was 53% at 1 year, 28% at 2 years, and 23% at 3 years. Grade 3 to 4 adverse events included hypertension (15%) and thrombosis (6%, including 4% with arterial thrombosis). Grade 3 or higher hemorrhage occurred in 11% of patients, including one fatal variceal bleed. Bevacizumab was associated with significant reductions in tumor enhancement by dynamic contrast-enhanced magnetic resonance imaging and reductions in circulating VEGF-A and stromal-derived factor-1 levels. Functional angiogenic activity was associated with VEGF-A levels in patient plasma. CONCLUSION: We observed significant clinical and biologic activity for bevacizumab in nonmetastatic HCC and achieved the primary study end point. Serious bleeding complications occurred in 11% of patients. Further evaluation is warranted in carefully selected patients.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Bevacizumab , Carcinoma Hepatocelular/sangue , Quimiocina CXCL12/sangue , Intervalo Livre de Doença , Humanos , Infusões Intravenosas , Neoplasias Hepáticas/sangue , Angiografia por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/sangue , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Fator A de Crescimento do Endotélio Vascular/sangue
5.
Oncologist ; 10(9): 718-27, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16249352

RESUMO

PURPOSE: To evaluate thalidomide in advanced hepatocellular carcinoma (HCC) and to evaluate combined thalidomide and low-dose interferon-alpha2a (IFN-alpha2a) after tumor progression on thalidomide. Systemic therapy is minimally effective in HCC and tumor angiogenesis is a potential therapeutic target. PATIENTS AND METHODS: Patients with unresectable HCC were eligible if they had preserved hepatic and renal function. The initial thalidomide dosage was 200 mg daily and was adjusted for toxicity. Upon progression, patients could continue thalidomide with additional low-dosage (one million units twice daily) IFN-alpha2a. RESULTS: Thirty-eight enrolled patients were predominantly hepatitis C virus infected (53%), Child-Pugh class A (79%), and Eastern Cooperative Oncology Group performance status 0-1 (92%); 60% had extrahepatic metastasis. Confirmed disease control was seen in seven patients (18%) and included one complete and one partial response (5% response rate). The median progression-free survival was 2.1 months, and median overall survival was 5.5 months. Tumor invasion of the portal vein or vena cava, large (>10 cm) tumor, and younger age were associated with shorter overall survival. Toxicity included fatigue in 74% of patients. Six patients stopped therapy because of side effects, including two patients (5%) with grade 4 arteriothrombotic events. Five patients continued thalidomide upon progression with the addition of IFN-alpha2a; there was no disease control and 80% had grade 3 toxicity. CONCLUSIONS: Thalidomide is not well tolerated and confers limited disease control in advanced HCC. Combination thalidomide and low-dose IFN-alpha2a is neither safe nor efficacious in this population.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Interferon-alfa/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Talidomida/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/mortalidade , Citocinas/sangue , Progressão da Doença , Quimioterapia Combinada , Feminino , Humanos , Interferon alfa-2 , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Talidomida/administração & dosagem , Talidomida/efeitos adversos
6.
Anticancer Drugs ; 13(8): 791-5, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12394262

RESUMO

Neo-adjuvant, dose-dense docetaxel, 100 mg/m(2) every 2 weeks x 4 cycles, was administered to 12 patients with locally advance breast cancer (LABC) (10 stage IIIa and three stage IIIb). Eligibility requirements included a PS 0-2, normal hepatic and renal function, and radiologic absence of metastatic disease. Filgrastim [granulocyte colony stimulating factor (G-CSF)] was started 1 day after chemotherapy and was given for 6 days. Complete blood counts were determined weekly. Surgery was planned upon recovery from the last dose of docetaxel and followed by 4 cycles of adjuvant doxorubicin plus cyclophosphamide (AC) and radiotherapy. Patients with ER status received tamoxifen. The median age was 45 (range 34-73) and pre-treatment pathology revealed poorly differentiated infiltrating duct carcinoma in 11 and infiltrating lobular cancer in one, with positive ER/PR status in five. Twelve patients were treated, and all are evaluable for response and toxicity. Nine patients had a major clinical tumor response with five PR and four pathologic complete responses (pCR rate of 33%). Three patients (of whom two with stage IIIb) had progressive disease and went on to receive neo-adjuvant therapy with AC. There was one instance of grade 3 hematologic toxicity (neutropenic fever in one G-CSF non-compliant patient). There were two instances of grade 3 extra-hematologic toxicity: one patient had severe pain and one had treatment-related fatigue. After a median follow-up of 20 months (range 7-49 months) all patients are alive and eight of nine responders remain progression-free. Despite the small size of our study, we believe that dose-dense neo-adjuvant docetaxel is well tolerated and its activity warrants confirmation in a larger number of patients.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Paclitaxel/análogos & derivados , Paclitaxel/administração & dosagem , Taxoides , Adulto , Idoso , Neoplasias da Mama/mortalidade , Docetaxel , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/efeitos adversos , Proteínas Recombinantes
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