RESUMO
BACKGROUND: This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable or metastatic conventional chondrosarcoma. METHODS: Eligible patients had conventional chondrosarcoma of any grade with measurable tumors that were unresectable or metastatic. Patients with mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes and patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessments every 2 cycles. The primary endpoint was the disease control rate (DCR) at week 16 (4 cycles). RESULTS: Forty-seven patients were enrolled. The DCR at 16 weeks was 43% (95% confidence interval [CI], 28%-58%), which was superior to the null hypothesis rate of 30%, but the 2-sided P value (exact test) was .09 (1-sided P = .045). One patient had a partial response. The median overall survival was 17.6 months (95% CI, 11.3-35.0 months), and the median progression-free survival was 7.9 months (95% CI, 3.7-12.6 months). Grade 3 or higher adverse events were infrequent; hypertension (26%) and elevated alanine aminotransferase (9%) were most common. CONCLUSIONS: This study provides evidence of positive drug activity for pazopanib in conventional chondrosarcoma.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Condrossarcoma/tratamento farmacológico , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Condrossarcoma/patologia , Feminino , Humanos , Indazóis , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Estudos Prospectivos , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversosRESUMO
BACKGROUND: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]). PATIENTS AND METHODS: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours. RESULTS: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4-4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3-1.6) for placebo (HR = 0.64, 95% CI: 0.38-1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6-4.2) months for brivanib and 2.0 months (95% CI: 1.2-2.7) for placebo (HR: 0.56, 95% CI: 0.26-1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6-4.2) and was 2.0 months (95% CI: 1.2-2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25-1.17; p = 0.11). CONCLUSION: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib.
Assuntos
Alanina/análogos & derivados , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Triazinas/uso terapêutico , Suspensão de Tratamento/estatística & dados numéricos , Idoso , Alanina/uso terapêutico , Biomarcadores Tumorais/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Prognóstico , Taxa de SobrevidaRESUMO
Despite years of research aimed at decreasing the cancer mortality rates, the disparity between African-Americans and whites continues to grow. The fundamental psychosocial and belief differences that may mediate these disparities are poorly studied and rarely disentangle race versus specific socioeconomic status (SES) effects. In this study, breast, colon, and lung cancer patients presenting for their first oncology appointment completed a self-administered survey utilizing previously validated instruments regarding psychosocial and belief factors. Results were analyzed by self-identified race, income, and education. In total, 161 African-American (37 %) and 269 white (63 %) new oncology patients with breast (47 %), colon (16 %), or lung (37 %) cancer enrolled. African-Americans were more likely to be in the US$<20,000 income group (45 vs. 9 %) but 21 % had incomes US$>60,000. Apparent racial differences in health literacy and cancer knowledge were primarily mediated by income and education. Significant racial differences in God's perceived role in their cancer remained after adjustments for income and education with African-Americans more likely to feel that God was in control of their cancer (67 vs. 30 %). These findings suggest the need for a more nuanced understanding of how race and socioeconomic status exert both independent and interrelated effects in the health care setting. Only then can effective interventions that reduce disparities in survival be designed. This study adds further substantive evidence to the crucial importance of God's perceived role in the cancer experience for African-Americans. An important area for future research is to examine whether these racial differences in religious belief are also associated with differences in health-related behavior and medical decision-making.
Assuntos
Negro ou Afro-Americano , Conhecimentos, Atitudes e Prática em Saúde/etnologia , Letramento em Saúde , Controle Interno-Externo , Neoplasias , Religião , Classe Social , População Branca , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama , Neoplasias do Colo , Tomada de Decisões , Escolaridade , Feminino , Humanos , Renda , Neoplasias Pulmonares , Masculino , Pessoa de Meia-Idade , Apoio Social , Inquéritos e Questionários , População UrbanaRESUMO
This first-in-human, phase I clinical trial was designed to determine the dose-limiting toxicities (DLTs) and the dose for phase II trials (P2D) of elisidepsin (PM02734) administered as a 30-min or as a 3-h intravenous infusion every 3 weeks (q3wk). Between March 2006 and April 2011, 53 patients with advanced malignant solid tumors were enrolled and treated with elisidepsin on the two different q3wk infusion schedules: 22 (30-min) and 31 (3-h), respectively. Doses evaluated ranged from 0.1 to 1.6 mg/m(2) (30-min q3wk) and from 2.0 to 11.0 mg flat dose (FD) (3-h q3wk). In the 30-min q3wk schedule, transient grade 3/4 increases in hepatic transaminases were the DLT, which appeared at the highest doses tested (from 1.1 to 1.6 mg/m(2)). No DLTs were observed on the 3-h schedule at doses up to 11.0 mg q3wk. Common adverse events were grade 1/2 pruritus, nausea, fatigue and hypersensitivity. Of note, myelotoxicity was not observed. Plasma maximum concentration and total drug exposure increased linearly with dose. Prolonged (≥3 months) disease stabilization was observed in pretreated patients with pleural mesothelioma (n = 1) in the 30-min q3wk arm, and with colorectal adenocarcinoma (n = 3), esophagus adenocarcinoma, endometrium adenocarcinoma, pleural mesothelioma, and head and neck carcinoma (n = 1 each) in the 3-h q3wk arm. In conclusion, elisidepsin doses of 1.1 mg/m(2) (equivalent to a FD of 2.0 mg) and 11.0 mg FD are the dose levels achieved for further phase II trials testing the 30-min q3wk and 3-h q3wk schedules, respectively.
Assuntos
Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Depsipeptídeos/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Adulto JovemRESUMO
PURPOSE: The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-38, the active metabolite of irinotecan. We aimed to identify the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan in patients with advanced solid tumors stratified by the *1/*1, *1/*28, and *28/*28 genotypes. PATIENTS AND METHODS: Sixty-eight patients received an intravenous flat dose of irinotecan every 3 weeks. Forty-six percent of the patients had the *1/*1 genotype, 41% had the *1/*28 genotype, and 13% had the *28/*28 genotype. The starting dose of irinotecan was 700 mg in patients with the *1/*1 and *1/*28 genotypes and 500 mg in patients with the *28/*28 genotype. Pharmacokinetic evaluation was performed at cycle 1. RESULTS: In patients with the *1/*1 genotype, the MTD was 850 mg (four DLTs per 16 patients), and 1,000 mg was not tolerated (two DLTs per six patients). In patients with the *1/*28 genotype, the MTD was 700 mg (five DLTs per 22 patients), and 850 mg was not tolerated (four DLTs per six patients). In patients with the *28/*28 genotype, the MTD was 400 mg (one DLT per six patients), and 500 mg was not tolerated (three DLTs per three patients). The DLTs were mainly myelosuppression and diarrhea. Irinotecan clearance followed linear kinetics. At the MTD for each genotype, dosing by genotype resulted in similar SN-38 areas under the curve (AUCs; r(2) = 0.0003; P = .97), but the irinotecan AUC was correlated with the actual dose (r(2) = 0.39; P < .001). Four of 48 patients with disease known to be responsive to irinotecan achieved partial response. CONCLUSION: The UGT1A1*28 genotype can be used to individualize dosing of irinotecan. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in patients receiving irinotecan.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Glucuronosiltransferase/genética , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Relação Dose-Resposta a Droga , Genótipo , Glucuronosiltransferase/metabolismo , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/genéticaRESUMO
XK469 (NSC 697887) is a selective topoisomerase II ß inhibitor eliminated mainly by aldehyde oxidase I (AOX1). We performed a candidate gene study to investigate whether AOX1 genetic variation contributes to interindividual variability in XK469 clearance. Forty-one AOX1 single nucleotide polymorphisms (SNPs) and seven liver expression quantitative trait loci were genotyped in White patients with advanced refractory solid tumors (n=59) and leukemia (n=33). We found a significant decrease in clearance (τ=-0.32, P=0.003) in solid tumor patients with rs10931910, although it failed to replicate in the leukemia cohort (τ=0.18, P=0.20). Four other AOX1 SNPs were associated with clearance (P=0.01-0.02) in only one of the two cohorts. Our study provides a starting point for future investigations on the functionality of AOX1 SNPs. However, variability in XK469 clearance cannot be attributed to polymorphisms in AOX1.
Assuntos
Aldeído Oxidase/genética , Antineoplásicos/farmacocinética , Fígado/metabolismo , Neoplasias/genética , Quinoxalinas/farmacocinética , Antineoplásicos/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Estudos de Coortes , Variação Genética , Genótipo , Humanos , Neoplasias/tratamento farmacológico , Farmacogenética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Quinoxalinas/administração & dosagemRESUMO
BACKGROUND: Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. METHODS: We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. FINDINGS: Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%). INTERPRETATION: The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. FUNDING: National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ósseas , Sarcoma , Sirolimo/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/imunologia , Receptor IGF Tipo 1/metabolismo , Sarcoma/tratamento farmacológico , Sarcoma/mortalidade , Sarcoma/patologia , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismoRESUMO
PURPOSE: Sirolimus is the eponymous inhibitor of the mTOR; however, only its analogs have been approved as cancer therapies. Nevertheless, sirolimus is readily available, has been well studied in organ transplant patients, and shows efficacy in several preclinical cancer models. EXPERIMENTAL DESIGN: Three simultaneously conducted phase I studies in advanced cancer patients used an adaptive escalation design to find the dose of oral, weekly sirolimus alone or in combination with either ketoconazole or grapefruit juice that achieves similar blood concentrations as its intravenously administered and approved prodrug, temsirolimus. In addition, the effect of sirolimus on inhibition of p70S6 kinase phosphorylation in peripheral T cells was determined. RESULTS: Collectively, the three studies enrolled 138 subjects. The most commonly observed toxicities were hyperglycemia, hyperlipidemia, and lymphopenia in 52%, 43%, and 41% of subjects, respectively. The target sirolimus area under the concentration curve (AUC) of 3,810 ng-h/mL was achieved at sirolimus doses of 90, 16, and 25 mg in the sirolimus alone, sirolimus plus ketoconazole, and sirolimus plus grapefruit juice studies, respectively. Ketoconazole and grapefruit juice increased sirolimus AUC approximately 500% and 350%, respectively. Inhibition of p70 S6 kinase phosphorylation was observed at all doses of sirolimus and correlated with blood concentrations. One partial response was observed in a patient with epithelioid hemangioendothelioma. CONCLUSION: Sirolimus can be feasibly administered orally, once weekly with a similar toxicity and pharmacokinetic profile compared with other mTOR inhibitors and warrants further evaluation in studies of its comparative effectiveness relative to recently approved sirolimus analogs.
Assuntos
Antibióticos Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Sirolimo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antibióticos Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Citrus paradisi , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Hiperlipidemias/induzido quimicamente , Cetoconazol/administração & dosagem , Linfopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/farmacocinética , Serina-Treonina Quinases TOR/metabolismoRESUMO
BACKGROUND: The prognosis of peritoneal sarcomatosis is generally poor and conventional treatments for this disease process are mostly ineffective. The use of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as an aggressive locoregional treatment option remains controversial. METHODS: We reviewed 13 patients with peritoneal sarcomatosis who underwent CRS and closed-abdomen HIPEC with cisplatin and doxorubicin between March 2007 and March 2010. None of the patients was diagnosed with GIST or uterine leiomyosarcoma. Both disease-free survival (DFS) and overall survival (OS) were evaluated. Completeness of cytoreduction (CC) and peritoneal cancer index (PCI) were assessed. RESULTS: There was no operative mortality. Median follow-up was 12 (range, 443) months. Peritoneal disease progression occurred in six patients, distant metastases alone in none, and both in two patients. Median DFS and OS were 11 and 12 months, respectively. Completeness of cytoreduction significantly affected survival. Mean DFS and OS in those patients where a CC-0 was achieved was 27.25 ± 5.71 (median, 20) months and 35.25 ± 4.75 months (median, not reached). In contrast, patients with gross residual disease (CC ≥ 1) had a DFS of 4.25 ± 1.43 months (median, 4 months; P = 0.03) and an OS of 5.25 ± 2.36 months (median, 4 months; P = 0.02). In addition, PCI influenced survival when evaluated by univariate analysis. Using multivariate analysis, completeness of cytoreduction was the only covariate influencing overall survival (P = 0.012). CONCLUSIONS: A complete cytoreduction and low PCI score appear to be important factors in considering CRS and HIPEC for patients with peritoneal sarcomatosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Peritoneais/terapia , Sarcoma/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Hipertermia Induzida , Infusões Parenterais , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/patologia , Sarcoma/mortalidade , Sarcoma/patologia , Taxa de SobrevidaRESUMO
BACKGROUND: Cilengitide (EMD121974) is a cyclized pentapeptide that is a potent and selective integrin antagonist which has shown activity in malignant gliomas. In all previous studies, cilengitide has been administered in an intermittent fashion. However, cilengitide has a short half-life of 3-5 h with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion cilengitide. METHODS: Cilengitide was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2 h after infusion bag change. RESULTS: Thirty-five patients were treated (median age 56; 23 males) at dose levels of 1, 2, 4, 8, 12, 18, 27, and 40 mg/h. Toxicities were limited to grade ≤ 2 and showed no relation to dose. Fatigue was most common (17%), while all other toxicities were reported in <10% of patients. No dose-limiting toxicities were observed, and therefore the maximum tolerated dose was not reached. Pharmacokinetic analysis showed that values for clearance and volume of distribution were comparable across dose levels, and the steady-state concentration increased proportionally with dose. CONCLUSIONS: Cilengitide can be safely administered as a continuous infusion at doses up to at least 40 mg/h, which represents the maximum feasible dose due to drug solubility and delivery limitations. The pharmacokinetics of continuous infusion cilengitide are linear and consistent with the results obtained using a twice weekly infusion.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Venenos de Serpentes/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Chicago , Feminino , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/patologia , Venenos de Serpentes/efeitos adversos , Venenos de Serpentes/sangue , Venenos de Serpentes/farmacocinética , Resultado do TratamentoRESUMO
PURPOSE: Sirolimus is the prototypical mTOR inhibitor. Sorafenib and sunitinib are small molecule inhibitors of multiple kinases including VEGF receptor (VEGFR) kinases. These agents have different mechanisms of action, providing a strong rationale for combination. EXPERIMENTAL DESIGN: Patients with advanced cancer were assigned to receive either sirolimus or the VEGFR inhibitor alone for a 2-week lead-in period, followed by combination therapy. The primary end point of each trial was to determine whether a drug interaction exists between sirolimus and either sorafenib or sunitinib, as defined by a difference in C(max) for each drug alone compared with its C(max) during combination therapy. RESULTS: The sorafenib and sunitinib trials enrolled 34 and 23 patients, respectively. There were no clinically significant differences in C(max) for any of the drugs alone compared with the C(max) during combination therapy. Toxicity profiles were similar to those expected for each drug alone. One patient with adrenal cortical cancer had a partial response to sirolimus and sunitnib. CONCLUSIONS: Sirolimus can be safely combined with sorafenib or sunitinib. Our trial design is feasible and informative in screening for potential drug-drug interactions, using a relatively small number of patients and limited pharmacokinetic sampling.
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 , Área Sob a Curva , Benzenossulfonatos/administração & dosagem , Interações Medicamentosas , Feminino , Humanos , Indóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Sirolimo/administração & dosagem , Sorafenibe , Sunitinibe , Resultado do Tratamento , Adulto JovemRESUMO
The quinoxaline anti-tumor agent (R+)XK469 mediates its effects by topoisomerase IIB inhibition. This report describes a 14-year old with relapsed neuroblastoma who experienced disease stabilization for 14 months while receiving (R+)XK469 monotherapy. Due to this favorable response, laboratory studies were undertaken to determine efficacy in the preclinical setting. (R+)XK469 inhibited proliferation, caused G(2) cell cycle arrest of neuroblastoma cells in vitro, and inhibited growth of neuroblastoma xenograft tumors. These preclinical results, coupled with the favorable clinical response, demonstrate that (R+)XK469 and similar anti-tumor agents may be effective in the treatment of high-risk neuroblastoma and warrant further testing.
Assuntos
Proliferação de Células/efeitos dos fármacos , Neuroblastoma/tratamento farmacológico , Quinoxalinas/farmacologia , Adolescente , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Evolução Fatal , Humanos , Metástase Neoplásica , Neuroblastoma/patologia , Quinoxalinas/uso terapêutico , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Disease recurrence after allogeneic hematopoietic cell transplant (alloHCT) remains common, making improvements in conditioning regimens desirable. A dose-response relationship between busulfan exposure and outcome is known. Using individual real-time monitoring of the busulfan area under the curve (AUC), we aimed to determine the maximum-tolerated busulfan AUC in a conditioning regimen with fludarabine/alemtuzumab. Thirty-six patients with advanced hematologic malignancies were treated. Busulfan levels after a test dose and conditioning dose 1 allowed targeting of subsequent AUCs and dose-escalation above the starting AUC of 4800 µmol-min/L. Clearance of busulfan test doses was not always sufficiently predictive of treatment dose AUC and, on average, test dose clearance was faster than treatment dose clearance. When the study was modified to use conditioning dose 1 pharmacokinetics instead, accurately targeted treatment AUCs were achieved, and dose-escalation was possible. Severe, late-occurring sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) was the dose-limiting toxicity seen in 5/8 patients at an AUC level of 6800 µmol-min/L. The risk for SOS/VOD correlated with the highest observed AUC (AUC(max)) rather than with the average cumulative AUC (AUC(avg)). Busulfan dose-escalation to a maximum-tolerated AUC of 5800 µmol-min/L-higher than that achieved by current standard busulfan regimens-was accurate and achievable using real-time pharmacokinetics monitoring of the first conditioning dose. This AUC is now being studied in phase II for patients receiving busulfan/fludarabine/alemtuzumab as alloHCT conditioning.
Assuntos
Anticorpos Monoclonais , Anticorpos Antineoplásicos , Bussulfano , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/induzido quimicamente , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Alemtuzumab , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/administração & dosagem , Anticorpos Antineoplásicos/efeitos adversos , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Bussulfano/farmacocinética , Relação Dose-Resposta a Droga , Regulação para Baixo , Combinação de Medicamentos , Feminino , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/metabolismo , Transplante de Células-Tronco Hematopoéticas/métodos , Hepatopatia Veno-Oclusiva/epidemiologia , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Incidência , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/farmacocinéticaRESUMO
PURPOSE: Various neoadjuvant approaches have been evaluated for the treatment of locally advanced soft-tissue sarcomas. This retrospective study describes a uniquely modified version of the Eilber regimen developed at the University of Chicago. METHODS AND MATERIALS: We treated 34 patients (28 Stage III and 6 Stage IV) with locally advanced soft-tissue sarcomas of an extremity between 1995 and 2008. All patients received preoperative therapy including ifosfamide (2.5 g/m2 per day for 5 days) with concurrent radiation (28 Gy in 3.5-Gy daily fractions), sandwiched between various chemotherapy regimens. Postoperatively, 47% received further adjuvant chemotherapy. RESULTS: Most tumors (94%) were Grade 3, and all were T2b, with a median size of 10.3 cm. Wide excision was performed in 29 patients (85%), and 5 required amputation. Of the resected tumor specimens, 50% exhibited high (> or =90%) treatment-induced necrosis and 11.8% had a complete pathologic response. Surgical margins were negative in all patients. The 5-year survival rate was 42.3% for all patients and 45.2% for Stage III patients. For limb-preservation patients, the 5-year local control rate was 89.0% and reoperation was required for wound complications in 17.2%. The 5-year freedom-from-distant metastasis rate was 53.4% (Stage IV patients excluded), and freedom from distant metastasis was superior if treatment-induced tumor necrosis was 90% or greater (84.6% vs. 19.9%, p = 0.02). CONCLUSIONS: This well-tolerated concurrent chemoradiotherapy approach yields excellent rates of limb preservation and local control. The resulting treatment-induced necrosis rates are predictive of subsequent metastatic risk, and this information may provide an opportunity to guide postoperative systemic therapies.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sarcoma/tratamento farmacológico , Sarcoma/radioterapia , Adulto , Idoso , Quimioterapia Adjuvante , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Epirubicina/administração & dosagem , Extremidades , Feminino , Humanos , Ifosfamida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Necrose , Dosagem Radioterapêutica , Radioterapia Adjuvante , Estudos Retrospectivos , Sarcoma/patologia , Sarcoma/cirurgia , Taxa de Sobrevida , Carga Tumoral , Adulto JovemRESUMO
PURPOSE: Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. This prospective, single-center, cohort study characterized ambulatory blood pressure monitoring as an early pharmacodynamic biomarker of VEGF signaling pathway inhibition by sorafenib. EXPERIMENTAL DESIGN: Fifty-four normotensive advanced cancer patients underwent 24-hour ambulatory blood pressure monitoring before and between days 6 and 10 of sorafenib therapy. After blood pressure changes were detected among the first cohort within 10 days, ambulatory blood pressure monitoring was done during the first 24 hours of treatment for the second cohort. RESULTS: For the entire patient population, the blood pressure increase [mean systolic, +10.8 mm Hg; 95% confidence interval (95% CI), 8.6-13.0; range, -5.2 to +28.7 mm Hg; mean diastolic, +8.0 mm Hg; 95% CI, 6.3-9.7; range, -4.4 to +27.1 mm Hg] was detected between days 6 and 10 (P < 0.0001 for both) and plateaued thereafter. Variability in blood pressure change did not associate with: age, body size, sex, self-reported race, baseline blood pressure, or steady-state sorafenib plasma concentrations. In the second cohort, the blood pressure elevation was detected during the first 24 hours (mean systolic, +8.2 mm Hg; 95% CI, 5.0-11.3; mean diastolic, +6.5 mm Hg; 95% CI, 4.7-8.3; P < 0.0001 for both). CONCLUSIONS: Ambulatory blood pressure monitoring detects the blood pressure response to VEGF signaling pathway inhibition by sorafenib during the first 24 hours of treatment. The magnitude of blood pressure elevation is highly variable and unpredictable but could be important in optimizing the therapeutic index of VEGF signaling pathway inhibitor therapy.
Assuntos
Benzenossulfonatos/efeitos adversos , Monitorização Ambulatorial da Pressão Arterial , Hipertensão/induzido quimicamente , Hipertensão/diagnóstico , Neoplasias/fisiopatologia , Piridinas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Benzenossulfonatos/farmacocinética , Benzenossulfonatos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Ritmo Circadiano , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/farmacocinética , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sorafenibe , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
INTRODUCTION: XK469 is a novel topoisomerase II inhibitor structurally akin to several propionic acid derivatives, such as ibuprofen and diclofenac, which are metabolised by CYP2C9. We report eight subjects who experienced significant elevation of INR while receiving concomitant R(+)XK469 and warfarin. The aim of the study is to investigate whether R(+)XK469 interacts with S-warfarin by inhibition of CYP2C9. METHODS: The effect of R(+)XK469 on S-warfarin hydroxylation was determined by the measurement of S-7-hydroxywarfarin formation in pooled human liver microsomes and cDNA-expressed CYP2C9. RESULTS: R(+)XK469 competitively inhibited S-warfarin hydroxylation. The K(i) values of R(+)XK469 were estimated to be 959+/-426 microM for human liver microsomes and to be 377+/-92 microM for CYP2C9. CONCLUSION: At the recommended phase II dose of R(+)XK469, the ratio of C(max)/K(i) is >1. This suggests that coadministration of R(+)XK469 and warfarin results in a clinically significant pharmacokinetic interaction due to CYP2C9 inhibition by R(+)XK469.
Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Microssomos Hepáticos/enzimologia , Quinoxalinas/uso terapêutico , Inibidores da Topoisomerase II , Varfarina/análogos & derivados , Anticoagulantes/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Ligação Competitiva , Células Cultivadas , Citocromo P-450 CYP2C9 , DNA Topoisomerases Tipo II , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Inibidores Enzimáticos/uso terapêutico , Humanos , Hidroxilação , Coeficiente Internacional Normatizado , Quinoxalinas/farmacologia , Análise de Regressão , Varfarina/análise , Varfarina/uso terapêuticoRESUMO
PURPOSE Since activity of sorafenib was observed in sarcoma patients in a phase I study, we performed a multicenter phase II study of daily oral sorafenib in patients with recurrent or metastatic sarcoma. PATIENTS AND METHODS We employed a multiarm study design, each representing a sarcoma subtype with its own Simon optimal two-stage design. In each arm, 12 patients who received 0 to 1 prior lines of therapy were treated (0 to 3 for angiosarcoma and malignant peripheral-nerve sheath tumor). If at least one Response Evaluation Criteria in Solid Tumors (RECIST) was observed, 25 further patients with that sarcoma subtype were accrued. Results Between October 2005 and November 2007, 145 patients were treated; 144 were eligible for toxicity and 122 for response. Median age was 55 years; female-male ratio was 1.8:1. The median number of cycles was 3. Five of 37 patients with angiosarcoma had a partial response (response rate, 14%). This was the only arm to meet the RECIST response rate primary end point. Median progression-free survival was 3.2 months; median overall survival was 14.3 months. Adverse events (typically dermatological) necessitated dose reduction for 61% of patients. Statistical modeling in this limited patient cohort indicated sorafenib toxicity was correlated inversely to patient height. There was no correlation between phosphorylated extracellular signal regulated kinase expression and response in six patients with angiosarcoma with paired pre- and post-therapy biopsies. CONCLUSION As a single agent, sorafenib has activity against angiosarcoma and minimal activity against other sarcomas. Further evaluation of sorafenib in these and possibly other sarcoma subtypes appears warranted, presumably in combination with cytotoxic or kinase-specific agents.
Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Piridinas/uso terapêutico , Sarcoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Benzenossulfonatos/farmacocinética , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/farmacocinética , Sarcoma/mortalidade , Sorafenibe , Adulto JovemRESUMO
PURPOSE: To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose. METHODS: R(+)XK469 was initially administered as a 30 min intravenous infusion on days 1-5 of a 21-d cycle. Based on the demonstration of a long half-life, the dosing schedule was subsequently amended to infusion on days 1, 3 and 5 of a 21-d cycle. An alternate single-dose schedule of once every 21 d was also explored. Blood samples were collected for pharmacokinetic studies. RESULTS: Dose-limiting toxicity (DLT) was neutropaenia. There was significant interindividual variability in clearance as evidenced by a coefficient of variation of 46%. A flat-dosing scheme (not based on body surface area) was justified by the absence of correlation between clearance and body surface area. A partial response was observed in a patient with nasopharyngeal carcinoma. CONCLUSIONS: The recommended phase II doses are 850-1100 mg/d on days 1, 3 and 5 of a 21-d cycle and 2500 mg on day 1 of a 21-d cycle. The observed interpatient pharmacokinetic variability should prompt investigation into the presence of genetic polymorphism in relevant metabolizing enzymes.
Assuntos
Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Quinoxalinas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Resultado do TratamentoRESUMO
A phase I study was performed to determine the safety and pharmacokinetics of XK469R in patients with refractory acute leukemia. The study aimed to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of XK469R given intravenously over 30 to 60 min on days 1, 3, and 5 of a 21 day cycle. Patients were treated in successive cohorts of six until DLT was observed. Once the MTD was determined, an additional cohort of six patients was enrolled at the previous dose level and that dose was considered the recommended phase 2 dose (RPTD). Forty-six patients were treated at dose levels of 1,400, 1,750, 2,200, and 2,750 mg. The DLTs were: mucositis, colitis and hyperbilirubinemia. Reversible myelosuppression was noted at all dose levels. One (2%) of 42 patients achieved a complete remission and five patients (11%) had hematologic improvement. The half-life of the drug was long with a mean value of 48 h. The mean clearance was 206 mL/h with a coefficient of variation of 32%. No correlation was observed between the development of DLT and pharmacokinetics. The RTPD is 1,750 mg. XK469R induced hematological responses in patients with refractory leukemia at tolerable doses.
Assuntos
Antineoplásicos/administração & dosagem , Leucemia/tratamento farmacológico , Quinoxalinas/administração & dosagem , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Quinoxalinas/efeitos adversos , Quinoxalinas/farmacocinética , Indução de Remissão/métodos , Estereoisomerismo , Resultado do TratamentoRESUMO
BACKGROUND: The authors studied a dose-intense regimen of epirubicin and ifosfamide with hypofractionated preoperative radiotherapy for high-risk soft tissue sarcomas. The primary objective was estimation of the rate of >or=95% pathologic necrosis. METHODS: Twenty-five patients with intermediate-grade or high-grade, localized soft tissue sarcomas of the extremity or body wall measuring >5 cm were treated with epirubicin at a dose of 30 mg/m(2)/day on Days 1 to 4 and ifosfamide at a dose of 2.5 g/m(2)/day on Days 1 to 4 every 21 days for 3 preoperative and 3 postoperative cycles. A total of 28 grays of radiation was administered over 8 fractions during Cycle 2 of preoperative therapy (epirubicin was omitted). RESULTS: Sixteen patients (64%) completed all chemotherapy cycles and the average delivered dose intensity relative to intended therapy was 69%. Twenty-one patients (84%) experienced grade 4 toxicity (using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 2.0]), which was predominantly hematologic. Notable toxicities included neutropenic fever (40%), ifosfamide-induced encephalopathy (24%), and grade 3/4 anemia (64%). Postoperative wound complications requiring a surgical procedure occurred in 20% of patients. The rate of >or=95% pathologic necrosis was 40% (95% confidence interval [95% CI], 21-59%). Estimates of 2-year overall and disease-free survival were 84% (95% CI, 66-100%) and 62% (95% CI, 37-86%), respectively. CONCLUSIONS: A high rate of >or=95% pathologic necrosis was noted with this aggressive chemoradiotherapy regimen. The occurrence of significant acute toxicities limited the delivery of the intended dose intensity.