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1.
Eur J Cancer ; 51(1): 27-36, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25459392

RESUMEN

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease. To improve the standard therapy with gemcitabine, we initiated a prospective randomised phase-II trial with gemcitabine (GEM) versus gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. The rational of adding sunitinib was its putative antiangiogenic mechanism of action. METHODS: A total of 106 eligible patients with locally advanced, unresectable or metastatic PDAC without previous system therapy were randomised to receive GEM at a dosage of 1.000mg/m(2) d1, 8, 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2) d1+8 and sunitinib 50mg p.o. d1-14, q21d. The primary end-point was progression free survival (PFS), secondary end-points were overall survival (OS), toxicity and overall response rate (ORR). RESULTS: The confirmatory analysis of PFS was based on the intend-to-treat (ITT) population (N=106). The median PFS was 13.3 weeks (95% confidence interval (95%-CI): 10.4-18.1 weeks) for GEM and 11.6 weeks for SUNGEM (95%-CI: 7.0-18.0 weeks; p=0.78 one-sided log-rank). The ORR was 6.1% (95%-CI: 0.7-20.2%) for GEM and for 7.1% (95%-CI: 0.9-23.5%) for SUNGEM (p=0.87). The median time to progression (TTP) was 14.0 weeks (95%-CI: 12.4-22.3 weeks) for GEM and 18.0 weeks (95%-CI: 11.3-19.3 weeks) for SUNGEM (p=0.60; two-sided log-rank). The median OS was 36.7 weeks (95%-CI: 20.6-49.0 weeks) for the GEM arm and 30.4 weeks (95%-CI: 18.1-37.6 weeks) for the SUNGEM (p=0.78, one-sided log-rank). In regard to toxicities, suspected SAEs were reported in 53.7% in the GEM arm and 71.2% in the SUNGEM arm. Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1% versus 27.8% in the GEM arm (p=0.045, two sided log-rank). CONCLUSIONS: The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Indoles/uso terapéutico , Pirroles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Europa (Continente) , Femenino , Humanos , Indoles/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pirroles/administración & dosificación , Sunitinib , Resultado del Tratamiento , Gemcitabina
2.
Ann Oncol ; 25(3): 742-746, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24510314

RESUMEN

BACKGROUND: In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM. PATIENTS AND METHODS: Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m(2) on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points. RESULTS: Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths. CONCLUSION: HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. EUDRACT NUMBER AND CLINICALTRIALSGOV IDENTIFIER: 2004-002245-12 and NCT00110123.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Compuestos de Nitrosourea/administración & dosificación , Compuestos Organofosforados/administración & dosificación , Neoplasias de la Úvea/tratamiento farmacológico , Administración Intravenosa , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Arteria Hepática , Humanos , Infusiones Intraarteriales , Hígado/patología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Masculino , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Compuestos de Nitrosourea/efectos adversos , Compuestos de Nitrosourea/uso terapéutico , Compuestos Organofosforados/efectos adversos , Compuestos Organofosforados/uso terapéutico , Estudios Prospectivos , Análisis de Supervivencia , Neoplasias de la Úvea/mortalidad , Neoplasias de la Úvea/patología , Adulto Joven
3.
Br J Cancer ; 110(5): 1155-62, 2014 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-24434430

RESUMEN

BACKGROUND: Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST. METHODS: Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a '3 plus 3' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels. RESULTS: Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6). CONCLUSION: Panobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/efectos adversos , Mesilato de Imatinib , Indoles/administración & dosificación , Indoles/efectos adversos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Panobinostat , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos
4.
Breast Cancer Res Treat ; 140(2): 331-9, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23868188

RESUMEN

Tivozanib is a potent selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. This Phase Ib study investigated the safety/tolerability, pharmacokinetics (PK), and activity of tivozanib with weekly paclitaxel in metastatic breast cancer (MBC). MBC patients with no prior VEGFR TKI treatment received daily oral tivozanib (3 weeks on, 1 week off) with weekly paclitaxel 90 mg/m(2). Standard 3 + 3 dose escalation was used; tivozanib cohorts (C) included C1 0.5 mg, C2 1.0 mg, and C3 1.5 mg. Assessments included Response Evaluation Criteria in Solid Tumors response, PK, and vascular function. Eighteen patients enrolled. Toxicities in >20 % of patients included fatigue, alopecia, nausea, diarrhea, peripheral sensory neuropathy, and hypertension. Grade 3/4 toxicities in >15 % of patients included fatigue and neutropenia. Maximum tolerated dose was tivozanib 1.5 mg with paclitaxel 90 mg/m(2). Four patients withdrew because of toxicity and one due to progressive disease. Thirteen patients were evaluable for response: four (30.8 %) had confirmed partial response; four had stable disease ≥6 months (30.8 %). PK data suggest no influence of paclitaxel on tivozanib concentrations. Tivozanib plus weekly paclitaxel was tolerable at all dose levels, supporting their combination at full dose. Activity in this small population was encouraging.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinolinas/administración & dosificación , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Paclitaxel/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacocinética , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
5.
Br J Cancer ; 107(2): 280-6, 2012 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-22699824

RESUMEN

BACKGROUND: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. METHODS: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ≥ 2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ≥ 12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). RESULTS: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). CONCLUSION: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Proteínas de Ciclo Celular/antagonistas & inhibidores , Neoplasias Pancreáticas/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pteridinas/uso terapéutico , Adenocarcinoma/enzimología , Adenocarcinoma/metabolismo , Anciano , Proteínas de Ciclo Celular/metabolismo , Estudios de Cohortes , Intervalos de Confianza , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Pteridinas/efectos adversos , Pteridinas/farmacocinética , Quinasa Tipo Polo 1
6.
Br J Cancer ; 106(11): 1722-7, 2012 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-22568966

RESUMEN

BACKGROUND: In a phase I dose-escalation study, regorafenib demonstrated tolerability and antitumour activity in solid tumour patients. The study was expanded to focus on patients with metastatic colorectal cancer (CRC). METHODS: Patients received oral regorafenib 60-220 mg daily (160 mg daily in the extension cohort) in cycles of 21 days on, 7 days off treatment. Assessments included toxicity, response, pharmacokinetics and pharmacodynamics. RESULTS: Thirty-eight patients with heavily pretreated CRC (median 4 prior lines of therapy, range 0-7) were enrolled in the dose-escalation and extension phases; 26 patients received regorafenib 160 mg daily. Median treatment duration was 53 days (range 7-280 days). The most common treatment-related toxicities included hand-foot skin reaction, fatigue, voice change and rash. Twenty-seven patients were evaluable for response: 1 achieved partial response and 19 had stable disease. Median progression-free survival was 107 days (95% CI, 66-161). At steady state, regorafenib and its active metabolites had similar systemic exposure. Pharmacodynamic assessment indicated decreased tumour perfusion in most patients. CONCLUSION: Regorafenib showed tolerability and antitumour activity in patients with metastatic CRC. This expanded-cohort phase I study provided the foundation for further clinical trials of regorafenib in this patient population.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacocinética , Piridinas/efectos adversos , Piridinas/farmacocinética
7.
Invest New Drugs ; 30(3): 1138-43, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21170759

RESUMEN

INTRODUCTION: Nimotuzumab is a humanized monoclonal antibody that binds to the EGFR. Based on phase I data, the recommended dose has been established at 200 mg weekly. This study was aimed at evaluating the safety and efficacy of nimotuzumab monotherapy in patients (pts) with locally advanced or metastatic pancreatic cancer. METHODS: Pts who failed first line standard chemotherapy for advanced disease and had at least one measurable lesion were eligible for the study. Nimotuzumab was given intravenously at 200 mg once weekly for 6 weeks (wks). Follow up by CT scan was performed after 8 weeks. Pts continued receiving treatment 3-weekly until disease progression or unacceptable toxicity occurred. Endpoints included tumor response (RECIST), progression-free survival (PFS), and safety. RESULTS: A total of 56 pts were enrolled for treatment (ECOG status of 1 [n = 41] or 0 [n = 15]), the majority (47 pts) had metastatic disease. Nearly half of the pts [n = 26] received ≥2 regimens. Pts evaluable for response: n = 36; CR: 0; PR: 0; SD: 6 pts. Median PFS for pts with SD was 19.2 weeks, for all pts 6.7 weeks (95% CI: 6.43-7.14 weeks). PFS after 1 year was 10.3% with a median overall survival of 18.1 weeks. Treatment-related adverse events were generally mild including rash grade 1 in 5 pts. After a single dose of 200 mg, the t(1/2) was calculated to 45 h. CONCLUSION: These data confirm that nimotuzumab is safe and very well tolerated. To improve efficacy, a randomized, placebo-controlled trial with Gem has been initiated.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Receptores ErbB/inmunología , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias Pancreáticas/patología
8.
Rofo ; 183(12): 1151-60, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22033849

RESUMEN

PURPOSE: To assess the survival of patients with hepatic uveal melanoma metastases undergoing sequential transarterial hepatic chemoperfusion. MATERIALS AND METHODS: 61 patients (mean age, 60.3 ± 13.8 y) underwent a total of 249 hepatic chemoperfusion procedures (mean: 4 chemoperfusion procedures; range, 1-7 chemoperfusion procedures; standard deviation, 2.3 chemoperfusion procedures). All patients started with melphalan. In the case of progressive disease, melphalan was replaced by a different chemoperfusion agent. 38 patients were treated with melphalan only, 23 patients were treated with a combination of melphalan and other drugs. The median overall survival time was calculated for the overall population and several sub-groups. Differences in the survival rate between the sub-groups were assessed for statistical significance. The complication rate was assessed. RESULTS: The median overall survival of the entire population was 10 months. The patients in the subgroups with a maximum number of 9 hepatic metastases as well as the patients in the subgroup without extrahepatic metastases at the beginning of therapy survived significantly longer than patients with more than 9 metastases/extrahepatic metastases (p = 0.019, p = 0.008). One patient (0.4%) died from liver failure after initial infusion of melphalan. CONCLUSION: Intraarterial sequential hepatic chemoperfusion offers a minimally invasive treatment in patients with hepatic uveal melanoma metastases with good survival times and an acceptable major complication rate.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Infusiones Intraarteriales/métodos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Melanoma/tratamiento farmacológico , Melanoma/secundario , Melfalán/administración & dosificación , Neoplasias de la Úvea/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Progresión de la Enfermedad , Femenino , Humanos , Fallo Hepático/inducido químicamente , Fallo Hepático/mortalidad , Neoplasias Hepáticas/mortalidad , Masculino , Melanoma/mortalidad , Melfalán/efectos adversos , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Neoplasias de la Úvea/mortalidad
15.
Ann Oncol ; 21(2): 275-282, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19633042

RESUMEN

BACKGROUND: High-level expression of epithelial cell adhesion molecule (EpCAM) is associated with unfavorable prognosis in breast cancer. This study was designed to investigate two doses of the fully human IgG1 anti-EpCAM antibody adecatumumab (MT201) in patients with metastatic breast cancer (MBC). METHODS: A total of 109 patients were stratified into high- and low-level EpCAM expression by immunohistochemical staining of primary tumors and subsequently randomly assigned to receive monotherapy with either high- (6 mg/kg every two weeks (q2w)) or low-dose adecatumumab (2 mg/kg/ q2w) until disease progression. RESULTS: No complete or partial tumor responses could be confirmed by central RECIST assessment. The probability for tumor progression was significantly lower in patients receiving high-dose adecatumumab and expressing high levels of EpCAM (hazard ratio 0.43; P = 0.0057 versus low dose and low EpCAM). Three of 18 patients with highest EpCAM expression treated with adecatumumab developed new metastases up to week 6, compared with 14 of 29 patients with low EpCAM. Most frequent treatment-related adverse events (high dose/low dose) were chills (59%/20%), nausea (55%/18%), fatigue (39%/23%) and diarrhea (43%/7%). CONCLUSIONS: Single-agent adecatumumab shows dose- and target-dependent clinical activity in EpCAM-positive MBC, albeit no objective tumor regression. Further investigation of adecatumumab in patients with EpCAM-overexpressing tumors and lower tumor burden is warranted.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/inmunología , Neoplasias de la Mama/tratamiento farmacológico , Moléculas de Adhesión Celular/inmunología , Moléculas de Adhesión Celular/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/patología , Moléculas de Adhesión Celular/administración & dosificación , Moléculas de Adhesión Celular/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Molécula de Adhesión Celular Epitelial , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Resultado del Tratamiento
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