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INTRODUCTION: Inhibition of tumor growth factor-ß (TGF-ß) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-ß1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment. METHODS: The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. Galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-ß1, safety, overall survival (OS), response rate, and pharmacokinetics (PK). RESULTS: Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-ß1 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038). DISCUSSION: The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome.
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Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/patología , Pirazoles/uso terapéutico , Quinolinas/uso terapéutico , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Progresión de la Enfermedad , Quimioterapia Combinada/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/administración & dosificación , Pirazoles/farmacocinética , Quinolinas/administración & dosificación , Quinolinas/farmacocinética , Seguridad , Sorafenib/administración & dosificación , Sorafenib/uso terapéutico , Factor de Crecimiento Transformador beta1/sangre , Factor de Crecimiento Transformador beta1/efectos de los fármacos , Resultado del Tratamiento , alfa-Fetoproteínas/efectos de los fármacosRESUMEN
BACKGROUND: Preclinically, protein kinase C and AKT activation can be inhibited by enzastaurin and reduce tumor growth of colorectal cancer cells. In asymptomatic patients with metastatic colorectal cancer (mCRC), enzastaurin activity was evaluated by measuring the 6-month progression-free survival (PFS) rate in a window study design. PATIENTS AND METHODS: Chemonaive patients with asymptomatic mCRC who did not require immediate chemotherapy-induced tumor reduction received a 400-mg thrice daily loading dose of enzastaurin on day 1 of cycle 1, followed by 500 mg once daily for the remaining 28-day cycles. Progression was assessed on the basis of radiographic imaging, rise in carcinoembryonic antigen or lactate dehydrogenase (LDH) levels or by appearance of clinical symptoms. RESULTS: Twenty-eight patients received daily enzastaurin. The 6-month PFS rate was 28% [95% confidence interval (CI) 13%-45%] and median PFS was 1.9 months (95% CI 1.8-4.5 months). Twelve (43%) patients had stable disease with a median duration of 6.1 months. The survival rate at 20 months was 77% (95% CI 47%-92%). No grade 4 toxicity was reported and grade 3 toxic effects were observed in three patients with one patient showing probable drug-related elevation of liver transaminases. CONCLUSION: The window design in asymptomatic patients with mCRC can be safely applied to assess the activity and safety of novel cytostatic agents like enzastaurin.
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Adenocarcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Indoles/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Antígeno Carcinoembrionario/sangre , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , L-Lactato Deshidrogenasa/sangre , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Pronóstico , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C beta , Distribución TisularRESUMEN
Assessing the pharmacodynamics (PD) of a potential therapeutic through the use of a downstream biomarker is essential. This is traditionally performed in the target tissue but limited volume and invasiveness of sampling pose challenges with solid tumours. Currently, there are several small molecule receptor kinase inhibitors and large molecule therapeutic antibodies in clinical trials that interfere with TGFbeta signalling to treat various forms of cancer. With the advent of these new therapies, there is a need for a surrogate tissue that is easily accessible and indicative of tumour response. We propose the use of an ex vivo TGFbeta1 stimulation of peripheral blood mononuclear cells (PBMCs) coupled with the measurement of phosphorylated SMAD2 (Sma/Mothers Against dpp, a downstream transcriptional activator) using a sandwich ELISA. TGFbeta is involved in many different cellular responses, such as proliferation, angiogenesis, migration, invasion and immunomodulation. SMAD2 and SMAD3 are phosphorylated as a result of the canonical cascade through ligand binding and receptor kinase activation. These phosphorylated SMADs (pSMAD) associate with SMAD4, a co-SMAD, and transcriptionally activate TGFbeta-mediated genes. This paper describes the novel method for measuring the downstream effects of inhibiting canonical TGFbeta signalling using ex vivo stimulation of surrogate tissue to predict tumour response. In addition, we present the assay validation rationale and data. This novel, validated assay can be used to gain insight into clinical trials regarding TGFbeta signal modulation by multiple inhibitor platforms for both large and small molecules.
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Receptores de Activinas Tipo I/antagonistas & inhibidores , Leucocitos Mononucleares/metabolismo , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta1/farmacología , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Western Blotting , Línea Celular Tumoral , Interpretación Estadística de Datos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Ratones , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas , Ratas , Ratas Endogámicas F344 , Receptor Tipo I de Factor de Crecimiento Transformador beta , Reproducibilidad de los Resultados , Proteínas Smad/análisis , Proteína Smad2/análisis , Proteína Smad2/metabolismo , Proteína smad3/análisis , Proteína smad3/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Some anticancer agents tend to accumulate during repeated administration. We determined whether gemcitabine or its metabolites would accumulate during repeated administration. Gemcitabine was administered over two courses with each course consisting of a 30-min infusion at 1000 mg/m(2) weekly for 3 weeks followed by 1 week of rest. In 14 patients we evaluated eventual accumulation by comparing the concentrations in blood samples taken before, and at 30 and 60 min after the start of infusion on days 1, 8 and 15, in both cycles. At the end of the infusion gemcitabine concentrations at day 1 of both courses varied between 18 and 77 microM and at day 15 between 13 and 90 microM. The mean ratios day 8/day 1 and day 15/day 1 varied from 0.94 to 1.18. For the inactive metabolite 2',2'-difluoro-2'-deoxyuridine (dFdU) these values varied between 54 and 152 microM and 55 and 157, respectively, and the ratios from 0.96 to 1.08. The concentration of the active metabolite of gemcitabine, gemcitabine triphosphate (dFdCTP) in peripheral white blood cells, ranged between 37 and 283 pmol/10(6) cells at the end of infusion on day 1 and 35 and 115 pmol/10(6) cells on day 15. Potential accumulation was evaluated using a mixed effects model and no evidence was observed of accumulation for either gemcitabine or its metabolites. Gemcitabine can be administered safely without the risk that the drug will accumulate.
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Antimetabolitos Antineoplásicos/metabolismo , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/metabolismo , Anciano , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/farmacocinética , Área Bajo la Curva , Desoxicitidina/sangre , Desoxicitidina/metabolismo , Desoxicitidina/farmacocinética , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/tratamiento farmacológico , GemcitabinaRESUMEN
Twenty five adult male volunteers were given a vaccine composed of the capsular B polysaccharide non-covalently complexed to serotype 6 outer membrane proteins (OMP) of Neisseria meningitidis. Subjects were divided into three dose groups receiving 50, 100 or 150 micrograms vaccine in aluminium hydroxide in each of three injections spaced 4 weeks apart. Systemic signs/symptoms considered clinically significant were recorded on 6% (4/70) of occasions and were succeeded by withdrawal of two volunteers from the study. Local injection site reactions, mostly mild to moderate, were reported after all vaccinations with one such reaction leading to a third volunteer withdrawing from the study. Geometric mean anti-B responses before immunization and 1 week after the third immunization (9 weeks) were 3.60 and 7.12 micrograms ml-1 in the 50 micrograms group (p less than 0.05) 2.05 and 12.19 micrograms ml-1 in the 100 micrograms group (p less than 0.001), and 3.68 and 14.20 micrograms ml-1 in the 150 micrograms group (p less than 0.001). The anti-B response was predominantly of the IgM isotype and persistence above prevaccination levels was evident for at least 12 months. Anti-type 6 OMP responses were also evidenced with geometric mean multiplicative increases over prevaccination levels at 9 weeks and 6 months of 7.8 and 4.2 for the 50 micrograms group, 11.6 and 5.6 for the 100 micrograms group and 6.8 and 3.4 for the 150 micrograms group. The bulk of this response was of the IgG isotype. Passive protection of mice was achieved with both pre- and post-vaccination (9 weeks; 100 and 150 micrograms groups) pools of sera.(ABSTRACT TRUNCATED AT 250 WORDS)