RESUMEN
BACKGROUND: Activating mutations in EGFR or KRAS are highly prevalent in NSCLC, share activation of the MAPK pathway and may be amenable to combination therapy to prevent negative feedback activation. METHODS: In this phase 1/1B trial, we tested the combination of binimetinib and erlotinib in patients with advanced NSCLC with at least 1 prior line of treatment (unless with activating EGFR mutation which could be treatment-naïve). A subsequent phase 1B expansion accrued patients with either EGFR- or KRAS-mutation using the recommended phase 2 dose (RP2D) from Phase 1. The primary objective was to evaluate the safety of binimetinib plus erlotinib and establish the RP2D. RESULTS: 43 patients enrolled (dose-escalation = 23; expansion = 20). 17 harbored EGFR mutation and 22 had KRAS mutation. The RP2D was erlotinib 100 mg daily and binimetinib 15 mg BID × 5 days/week. Common AEs across all doses included diarrhea (69.8%), rash (44.2%), fatigue (32.6%), and nausea (32.6%), and were primarily grade 1/2. Among KRAS mutant patients, 1 (5%) had confirmed partial response and 8 (36%) achieved stable disease as best overall response. Among EGFR mutant patients, 9 were TKI-naïve with 8 (89%) having partial response, and 8 were TKI-pretreated with no partial responses and 1 (13%) stable disease as best overall response. CONCLUSIONS: Binimetinib plus erlotinib demonstrated a manageable safety profile and modest efficacy including one confirmed objective response in a KRAS mutant patient. While clinical utility of this specific combination was limited, these results support development of combinations using novel small molecule inhibitors of RAS, selective EGFR- and other MAPK pathway inhibitors, many of which have improved therapeutic indices. CLINICAL TRIAL REGISTRATION: NCT01859026.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Clorhidrato de Erlotinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Protein kinase C-iota (PKC-ι) is an oncogene overexpressed in many cancer cells including prostate, breast, ovarian, melanoma, and glioma. Previous in-vitro studies have shown that 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1s), a PKC-ι specific inhibitor, is effective against some cancer cell lines by decreasing cell growth and inducing apoptosis. To assess ICA-1s as a possible therapeutic, in-vivo studies using a murine model were performed. ICA-1s was tested for stability in blood serum and results demonstrated that ICA-1s was stable in human plasma at 25 and 37°C over a course of 2 h. Toxicity of ICA-1s was tested for both acute and subacute exposure. The acute exposure showed patient surviving after 48 h of doses ranging from 5 to 5000 mg/kg. Subacute tests exposed the patients to 14 days of treatment and were followed by serum and tissue collection. Aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, troponin, and C-reactive protein serum levels were measured to assess organ function. ICA-1s in plasma serum was measured over the course of 24 h for both oral and intravenous treatments. Heart, liver, kidney, and brain tissues were analyzed for accumulation of ICA-1s. Finally, athymic nude mice were xenografted with DU-145 prostate cancer cells. After tumors reached ~0.2 cm, they were either treated with ICA-1s or left as control and measured for 30 days or until the tumor reached 2 cm. Results showed tumors in treated mice grew at almost half the rate as untreated tumors, showing a significant reduction in growth. In conclusion, ICA-1s is stable, shows low toxicity, and is a potential therapeutic for prostate carcinoma tumors.
Asunto(s)
Imidazoles/farmacología , Isoenzimas/antagonistas & inhibidores , Neoplasias de la Próstata/tratamiento farmacológico , Proteína Quinasa C/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Humanos , Imidazoles/sangre , Masculino , Ratones , Ratones Desnudos , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/enzimología , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Background Androgens were shown to play a key role in the growth and progression of pancreatic cancer. We evaluated the safety and tolerability of the combination of enzalutamide, a novel androgen receptor (AR) antagonist with gemcitabine and nab-paclitaxel as a first-line treatment in advanced pancreatic cancer. Methods We used the standard 3 + 3 dose escalation design with cohort expansion to evaluate 2 dose levels of enzalutamide: 80 mg and 160 mg/day orally (phase 1a) in combination with gemcitabine and nab-paclitaxel in metastatic pancreatic cancer patients. In the expansion phase (phase 1b), AR+ was a pre-requisite criterion. We also evaluated the full pharmacokinetic (PK) profile for nab-paclitaxel and enzalutamide. Results We enrolled 24 patients, 12 patients in phase 1a and 12 patients in phase 1b. The median age was 68 (range, 32-84) years. No DLTs were observed. Grade 3/4 treatment related adverse events included neutropenia (44%), anemia (40%), leukopenia (24%), nausea and vomiting (20%), diarrhea (16%), infections (12%), thrombocytopenia (8%), thromboembolic event (8%), hypertension (8%), hypokalemia (8%), hyponatremia (8%), and ALT elevation (8%). Median overall survival and progression-free survival was 9.73 [95%CI:9.73-13.5] and 7.53 (95%CI:6.05-12.8) months, respectively. PK analysis suggests that the combination therapy does not impact the kinetics of either drug evaluated. Enzalutamide reached steady-state levels between day 22 and 29 and the mean half-life of nab-paclitaxel was 19.6 ± 4.7 h. Conclusions Enzalutamide 160 mg daily in combination with gemcitabine and nab-paclitaxel can be safely administered with no unexpected toxicities. We also noticed preliminary signals of efficacy with this combination.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzamidas , Biomarcadores de Tumor/metabolismo , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Nitrilos , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/análogos & derivados , Pronóstico , Tasa de Supervivencia , Distribución Tisular , GemcitabinaRESUMEN
Bone metastasis is common during breast cancer progression. Matrix metalloproteinase-2 (MMP-2) is significantly associated with aggressive breast cancer and poorer overall survival. In bone, tumor- or host-derived MMP-2 contributes to breast cancer growth and does so by processing substrates, including type I collagen and TGFß latency proteins. These data provide strong rationale for the application of MMP-2 inhibitors to treat the disease. However, in vivo, MMP-2 is systemically expressed. Therefore, to overcome potential toxicities noted with previous broad-spectrum MMP inhibitors (MMPIs), we used highly selective bisphosphonic-based MMP-2 inhibitors (BMMPIs) that allowed for specific bone targeting. In vitro, BMMPIs affected the viability of breast cancer cell lines and osteoclast precursors, but not osteoblasts. In vivo, we demonstrated using two bone metastatic models (PyMT-R221A and 4T1) that BMMPI treatment significantly reduced tumor growth and tumor-associated bone destruction. In addition, BMMPIs are superior in promoting tumor apoptosis compared with the standard-of-care bisphosphonate, zoledronate. We demonstrated MMP-2-selective inhibition in the bone microenvironment using specific and broad-spectrum MMP probes. Furthermore, compared with zoledronate, BMMPI-treated mice had significantly lower levels of TGFß signaling and MMP-generated type I collagen carboxy-terminal fragments. Taken together, our data show the feasibility of selective inhibition of MMPs in the bone metastatic breast cancer microenvironment. We posit that BMMPIs could be easily translated to the clinical setting for the treatment of bone metastases given the well-tolerated nature of bisphosphonates. Mol Cancer Ther; 16(3); 494-505. ©2017 AACR.
Asunto(s)
Neoplasias Óseas/secundario , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Metaloproteinasa 2 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Animales , Conservadores de la Densidad Ósea/farmacología , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/mortalidad , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Difosfonatos/farmacología , Progresión de la Enfermedad , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Imidazoles/farmacología , Estimación de Kaplan-Meier , Metaloproteinasa 2 de la Matriz/genética , Ratones , Modelos Biológicos , Imagen Multimodal , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Carga Tumoral/efectos de los fármacos , Microambiente Tumoral , Ácido ZoledrónicoRESUMEN
PURPOSE: Vitamin E delta-tocotrienol (VEDT) has demonstrated chemopreventive and antineoplastic activity in preclinical models. The aim of our study was to determine the safety and pharmacokinetics of VEDT and its metabolites after single- and multiple-dose administrations in healthy subjects. METHODS: Thirty-six subjects received from 100 to 1600 mg of oral VEDT as a single dose or twice daily for 14 consecutive days. A 3 + 3 dose escalation design was utilized. Pharmacokinetic data were derived from high-performance liquid chromatography (HPLC) assays. Serial blood and urine samples were collected before and during VEDT administration, with serum and urine metabolites assessed using HPLC. RESULTS: No drug-related adverse events were observed. Pharmacokinetic parameters for single and multiple doses were, respectively, as follows (shown as range): time to maximum concentration of 4-9.3 and 4.7-7.3 h, maximum concentration of 795.6-3742.6 and 493.3-3746 ng/mL, half-life of 1.7-5.9 and 2.3-6.9 h, and 0-12 h area under the curve of 4518.7-20,781.4 and 1987.7-22,171.2 ng h/mL. Plasma tocotrienols were significantly increased after VEDT administration, indicating oral bioavailability of VEDT in humans. Plasma and urine levels of metabolites, δ-carboxyethyl hydroxychroman, and δ-carboxymethylbutyl hydroxychroman were elevated after VEDT administration in a dose-dependent manner and were 30-60 times significantly higher than δ-tocotrienol levels. VEDT can be safely administered at doses up to 1600 mg twice daily. Plasma VEDT concentrations were comparable to those obtained in VEDT-treated mice in which tumor growth was delayed. CONCLUSIONS: Our results suggest that VEDT can be safely consumed by healthy subjects and achieve bioactive levels, supporting the investigation of VEDT for chemoprevention.
Asunto(s)
Antineoplásicos/administración & dosificación , Cromatografía Líquida de Alta Presión/métodos , Vitamina E/análogos & derivados , Adulto , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Semivida , Humanos , Masculino , Ratones , Persona de Mediana Edad , Especificidad de la Especie , Vitamina E/administración & dosificación , Vitamina E/efectos adversos , Vitamina E/farmacocinética , Adulto JovenRESUMEN
PURPOSE: Indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. Primary endpoints were maximum tolerated dose (MTD) and toxicity for indoximod in patients with advanced solid tumors. Secondary endpoints included response rates, pharmacokinetics, and immune correlates. EXPERIMENTAL DESIGN: Our 3+3 phase I trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). Inclusion criteria were measurable metastatic solid malignancy, age ≥18 years, and adequate organ/marrow function. Exclusion criteria were chemotherapy ≤ 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption. RESULTS: In 48 patients, MTD was not reached at 2000 mg twice/day. At 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. Five patients showed stable disease >6 months. Indoximod plasma AUC and Cmax plateaued above 1200mg. Cmax (~12 µM at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. C reactive protein (CRP) levels increased across multiple dose levels. CONCLUSIONS: Indoximod was safe at doses up to 2000 mg orally twice/day. Best response was stable disease >6 months in 5 patients. Induction of hypophysitis, increased tumor antigen autoantibodies and CRP levels were observed.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Triptófano/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Triptófano/administración & dosificación , Triptófano/efectos adversos , Adulto JovenRESUMEN
Targeted kinase inhibitors and camptothecins have shown preclinical and clinical activity in several cancers. This trial evaluated the maximum tolerated dose (MTD) and dose-limiting toxicities of sorafenib and topotecan administered orally in pediatric patients with relapsed solid tumors. Sorafenib was administered twice daily and topotecan once daily on days 1-5 and 8-12 of each 28-day course. The study utilized a standard 3 + 3 dose escalation design. Three dose levels (DL) were evaluated: (1) sorafenib 150 mg/m(2) and topotecan 1 mg/m(2) ; (2) sorafenib 150 mg/m(2) and topotecan 1.4 mg/m(2) ; and (3) sorafenib 200 mg/m(2) and topotecan 1.4 mg/m(2) . Pharmacokinetics were ascertained and treatment response assessed. Thirteen patients were enrolled. DL2 was the determined MTD. Grade 4 thrombocytopenia delaying therapy for >7 days was observed in one of six patients on DL2, and grade 4 neutropenia that delayed therapy in two of three patients on DL3. A patient with preexisting cardiac failure controlled with medication developed a transient drop in the left ventricular ejection fraction that improved when sorafenib was withheld. Sorafenib exposure with or without topotecan was comparable, and the concentration-time profiles for topotecan alone and in combination with sorafenib were similar. One objective response was noted in a patient with fibromatosis. We determined MTD to be sorafenib 150 mg/m(2) twice daily orally on days 1-28 combined with topotecan 1.4 mg/m(2) once daily on days 1-5 and 8-12. While these doses are 1 DL below the MTD of the agents individually, pharmacokinetic studies suggested adequate drug exposure without drug interactions. The combination had limited activity in the population studied.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Administración Oral , Adolescente , Antineoplásicos/farmacología , Niño , Esquema de Medicación , Monitoreo de Drogas , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Neoplasias/diagnóstico , Niacinamida/farmacología , Niacinamida/uso terapéutico , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Sorafenib , Resultado del TratamientoRESUMEN
BACKGROUND: Vitamin E δ-tocotrienol (VEDT), a natural vitamin E from plants, has shown anti-neoplastic and chemoprevention activity in preclinical models of pancreatic cancer. Here, we investigated VEDT in patients with pancreatic ductal neoplasia in a window-of-opportunity preoperative clinical trial to assess its safety, tolerability, pharmacokinetics, and apoptotic activity. METHODS: Patients received oral VEDT at escalating doses (from 200 to 3200 mg) daily for 13 days before surgery and one dose on the day of surgery. Dose escalation followed a three-plus-three trial design. Our primary endpoints were safety, VEDT pharmacokinetics, and monitoring of VEDT-induced neoplastic cell apoptosis (ClinicalTrials.gov number NCT00985777). FINDINGS: In 25 treated patients, no dose-limiting toxicity was encountered; thus no maximum-tolerated dose was reached. One patient had a drug-related adverse event (diarrhea) at a 3200-mg daily dose level. The effective half-life of VEDT was ~ 4 h. VEDT concentrations in plasma and exposure profiles were quite variable but reached levels that are bioactive in preclinical models. Biological activity, defined as significant induction of apoptosis in neoplastic cells as measured by increased cleaved caspase-3 levels, was seen in the majority of patients at the 400-mg to 1600-mg daily dose levels. INTERPRETATION: VEDT from 200 to 1600 mg daily taken orally for 2 weeks before pancreatic surgery was well tolerated, reached bioactive levels in blood, and significantly induced apoptosis in the neoplastic cells of patients with pancreatic ductal neoplasia. These promising results warrant further clinical investigation of VEDT for chemoprevention and/or therapy of pancreatic cancer.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Cuidados Preoperatorios , Vitamina E/análogos & derivados , Anciano , Anciano de 80 o más Años , Apoptosis/efectos de los fármacos , Biomarcadores , Carcinoma Ductal Pancreático/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico , Resultado del Tratamiento , Vitamina E/farmacología , Vitamina E/uso terapéuticoRESUMEN
A phase I study was conducted to evaluate the dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD)/recommended phase II dose of bendamustine with concurrent whole brain radiation (WBR) in patients with brain metastases (BM) from solid tumors. Four doses of intravenous weekly bendamustine were administered with 3 weeks of WBR at three dose levels (60, 80, and 100 mg/m(2)) according to a standard 3 + 3 phase I design. A total of 12 patients with solid tumor BM were enrolled in the study (six with non-small cell lung cancer, four with melanoma, one with breast cancer, and one with neuroendocrine carcinoma). The first two dose levels had three patients each, and the third dose level had six total patients. Plasma pharmacokinetic studies of bendamustine demonstrated no significant differences from pharmacokinetic characteristics of bendamustine in other studies. No DLTs were noted at any dose levels, and no grade 4 toxicities occurred. The MTD of weekly bendamustine with concurrent WBR was 100 mg/m(2). The majority of trial patients died from progressive systemic disease rather than their brain disease. The combination of weekly bendamustine with concurrent WBR was acceptably tolerated. The efficacy of this combination may be evaluated in a phase II trial with stratification by histologies.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Compuestos de Mostaza Nitrogenada/administración & dosificación , Adulto , Anciano , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/farmacocinética , Clorhidrato de Bendamustina , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/patología , Carcinoma Neuroendocrino/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios de Cohortes , Terapia Combinada , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Melanoma/patología , Persona de Mediana Edad , Compuestos de Mostaza Nitrogenada/efectos adversos , Compuestos de Mostaza Nitrogenada/farmacocinética , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in patients with advanced NSCLC and head and neck cancer. EXPERIMENTAL DESIGN: Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at four planned dose levels (DL). Pharmacokinetics, blood, fat pad biopsies (FPB) for histone acetylation, and paired pre and posttherapy tumor biopsies for checkpoint kinase 1 (CHK1) expression were assessed. RESULTS: Of 42 enrolled patients, 33 were evaluable for efficacy. Dose-limiting toxicities were prolonged-QTc and nausea at DL3. Adverse events included fatigue and nausea (grades 1-3), and rash and anorexia (grades 1-2). Disease control rates were 54% for NSCLC (n = 26) and 43% for head and neck cancer (n = 7). Of 7 patients with NSCLC with EGF receptor (EGFR) mutations, 3 had partial response, 3 had stable disease, and 1 progressed. For EGFR-mutant versus EGFR wild-type patients, progression-free survival (PFS) was 4.7 versus 1.9 months (P = 0.43) and overall survival was 41 (estimated) versus 5.2 months (P = 0.39). Erlotinib pharmacokinetics was not significantly affected. Correlative studies confirmed panobinostat's pharmacodynamic effect in blood, FPB, and tumor samples. Low CHK1 expression levels correlated with PFS (P = 0.006) and response (P = 0.02). CONCLUSIONS: We determined MTD at 30 mg (panobinostat) and 100 mg (erlotinib). Further studies are needed to further explore the benefits of HDAC inhibitors in patients with EGFR-mutant NSCLC, investigate FPB as a potential surrogate source for biomarker investigations, and validate CHK1's predictive role.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Ácidos Hidroxámicos/administración & dosificación , Indoles/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Supervivencia sin Enfermedad , Clorhidrato de Erlotinib , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/efectos adversos , Humanos , Ácidos Hidroxámicos/efectos adversos , Ácidos Hidroxámicos/farmacocinética , Indoles/efectos adversos , Indoles/farmacocinética , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Panobinostat , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Resultado del TratamientoRESUMEN
Recently it has become clear that the cost associated with the Warburg effect, which is inefficient production of ATP, is offset by selective advantages that are produced by resultant intracellular metabolic alterations. In fact tumors may be addicted to the Warburg effect. In addition these alterations result in changes in the extracellular tumor microenvironment that can also produce selective advantages for tumor cell growth and survival. One such extracellular alteration is increased adenosine concentrations that have been shown to impair T cell mediated rejection and support angiogenesis. The expression of the A2A receptor in non-small cell cancer (NSCLC) tissues, cell lines and cancer associated fibroblasts (CAF) was determined by performing immunohistrochemistry and immunoblot analysis. The efficacy of the A2A receptor antagonists in vivo was evaluated in a PC9 xenograft model. To determine the mode of cell death induced by A2A receptor antagonists flow cytometry, immunoblot, and cytotoxic analysis were performed. We found that a significant number of lung adenocarcinomas express adenosine A2A receptors. Antagonism of these receptors impaired CAF and tumor cell growth in vitro and inhibited human tumor xenograft growth in mice. These observations add to the rationale for testing adenosine A2A receptor antagonists as anticancer therapeutics. Not only could there be prevention of negative signaling in T cells within the tumor microenvironment and inhibition of angiogenesis, but also an inhibitory effect on tumor-promoting, immunosuppressive CAFs and a direct inhibitory effect on the tumor cells themselves.
Asunto(s)
Adenocarcinoma/patología , Antagonistas del Receptor de Adenosina A2/farmacología , Proliferación Celular/efectos de los fármacos , Fibroblastos/metabolismo , Neoplasias Pulmonares/patología , Receptor de Adenosina A2A/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma del Pulmón , Antagonistas del Receptor de Adenosina A2/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Fibroblastos/efectos de los fármacos , Xenoinjertos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Ratones Desnudos , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Receptor de Adenosina A2A/genética , Triazinas/farmacología , Triazinas/uso terapéutico , Triazoles/farmacología , Triazoles/uso terapéuticoRESUMEN
PURPOSE: To determine the maximum tolerated dose (MTD) of topotecan in combination with ifosfamide, mesna, and etoposide (TIME), followed by autologous hematopoietic cell transplant (HCT), in patients with chemotherapy-refractory malignancies. EXPERIMENTAL DESIGN: Patients were treated with (in mg/m(2)/d) ifosfamide 3,333, mesna 3,333, and topotecan 3.3 to 28.3 during days -8 through -6 and etoposide 500 (days -5 through -3) followed by HCT on day 0. Once MTD was defined, we expanded this dosing cohort to include patients with high-risk lymphoma due to activity seen during dose escalation. Topotecan pharmacokinetic analyses were carried out, and topoisomerase I levels and activity were measured. RESULTS: The topotecan MTD in this regimen was 64 mg/m(2) (21.3 mg/m(2)/d). Mucositis was dose limiting and correlated with topotecan dose level and area under the curve (AUC). Dose level was also correlated with length of hospitalization, number of days of parenteral nutrition, and neutrophil and platelet engraftment. Topotecan AUC was significantly correlated with time to platelet recovery. The baseline peripheral blood mononuclear cell topoisomerase I level was found to be a significant positive predictor for overall and progression-free survival. Topotecan AUC was positively correlated with dose level, with a trend toward decreasing clearance with increasing dose. CONCLUSION: Topotecan can be a useful drug in the high-dose setting given its activity in some malignancies when given in standard dose. Pharmacokinetic monitoring may be a valuable tool for optimizing the use of topotecan and to avoid toxicity seen with high-systemic exposures. Baseline topoisomerase I levels may have an important role in predicting topotecan efficacy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Neoplasias/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Área Bajo la Curva , Terapia Combinada/estadística & datos numéricos , ADN-Topoisomerasas de Tipo I/sangre , Esquema de Medicación , Resistencia a Antineoplásicos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Ifosfamida/administración & dosificación , Ifosfamida/efectos adversos , Estimación de Kaplan-Meier , Masculino , Mesna/administración & dosificación , Mesna/efectos adversos , Tasa de Depuración Metabólica , Persona de Mediana Edad , Mucositis/inducido químicamente , Análisis Multivariante , Neoplasias/sangre , Neoplasias/metabolismo , Modelos de Riesgos Proporcionales , Topotecan/administración & dosificación , Topotecan/efectos adversos , Topotecan/farmacocinética , Trasplante Autólogo , Resultado del TratamientoRESUMEN
PURPOSE: Triciribine phosphate is a potent, small-molecule inhibitor of activation of all three isoforms of AKT in vitro. AKT is an intracellular protein that, when activated, leads to cellular division; it is dysregulated in a large number of malignancies, and constitutively activating AKT mutations are present in a minority of cancers. PATIENTS AND METHODS: In this phase I study triciribine phosphate monohydrate (TCN-PM) was administered to subjects whose tumors displayed evidence of increased AKT phosphorylation (p-AKT) as measured by immunohistochemical analysis (IHC). TCN-PM was administered over 30 min on days 1, 8 and 15 of a 28-day cycle. Tumor biopsy specimens, collected before treatment and on day +15, were assessed for p-AKT by IHC and western blot analyses. RESULTS: Nineteen subjects were enrolled; 13 received at least one cycle of therapy, and a total of 34 complete cycles were delivered. One subject was treated at the 45 mg/m(2) dose before the study was closed due to its primary objective having been met. No dose-limiting toxic effects were observed. Modest decreases in tumor p-AKT following therapy with TCN-PM were observed at the 35 mg/m(2) and 45 mg/m(2) dose levels, although definitive conclusions were limited by the small sample size. CONCLUSIONS: These preliminary data suggest that treatment with TCN-PM inhibits tumor p-AKT at doses that were tolerable. Although single agent activity was not observed in this enriched population, further combination studies of TCN-PM with other signal transduction pathway inhibitors in solid tumors is warranted.
Asunto(s)
Acenaftenos/farmacología , Neoplasias/tratamiento farmacológico , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ribonucleótidos/farmacología , Acenaftenos/efectos adversos , Acenaftenos/farmacocinética , Adulto , Biopsia , Relación Dosis-Respuesta a Droga , Humanos , Mutación , Neoplasias/patología , Ribonucleótidos/efectos adversos , Ribonucleótidos/farmacocinética , Resultado del TratamientoRESUMEN
PURPOSE: Src family kinase (SFK) proteins are frequently activated in cancer and can coordinate tumor cell growth, survival, invasion, and angiogenesis. Given the importance of SFK signaling in cancer, known cooperation between SFK and epidermal growth factor receptor (EGFR) signaling, and efficacy of EGFR inhibitors, we performed a phase I trial combining dasatinib, an SFK and multikinase inhibitor, with erlotinib, an EGFR inhibitor, in patients with advanced non-small-cell lung cancer. PATIENTS AND METHODS: Patients received erlotinib for 1 week before addition of dasatinib; pharmacokinetics were performed after weeks 1 and 2. Four cohorts were examined, including twice-daily and daily dasatinib dosing. Responses were assessed after 8 weeks. Plasma levels of angiogenic markers (vascular endothelial growth factor [VEGF], interleukin-8, and basic fibroblast growth factor [bFGF]) were determined before and during treatment. RESULTS: Thirty-four patients were enrolled. The average duration of treatment was 73 days. The main adverse events include GI (diarrhea, anorexia, and nausea), skin rash, cytopenias, pleural effusions, and fatigue. No effect of escalating doses of dasatinib was observed on erlotinib pharmacokinetics. Two partial responses and one bone response were observed, and the disease control rate was 63%. Reductions in plasma VEGF and bFGF were observed, and reductions in VEGF correlated with disease control. CONCLUSION: The combination of erlotinib and dasatinib is tolerable, with adverse effects consistent with the two agents. Disease control and inhibition of plasma angiogenesis markers were observed. Personalized strategies for deployment of SFK should receive further attention.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores Farmacológicos/sangre , Dasatinib , Esquema de Medicación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Receptores ErbB/antagonistas & inhibidores , Clorhidrato de Erlotinib , Femenino , Factor 2 de Crecimiento de Fibroblastos/sangre , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Tiazoles/farmacocinética , Tiazoles/farmacología , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
PURPOSE: The novel topoisomerase I inhibitor karenitecin (KTN) shows activity against melanoma. We examined whether histone deacetylase inhibition could potentiate the DNA strand cleavage, cytotoxicity as well as the clinical toxicity, and efficacy of KTN in melanoma. EXPERIMENTAL DESIGN: Apoptosis, COMET, and xenograft experiments were carried out as described previously. A phase I/II trial of valproic acid (VPA) and KTN was conducted in patients with stage IV melanoma, with any number of prior therapies, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. RESULTS: VPA pretreatment potentiated KTN-induced apoptosis in multiple melanoma cell lines and in mouse A375 xenografts. VPA increased KTN-induced DNA strand breaks. In the phase I/II trial, 39 patients were entered, with 37 evaluable for toxicity and 33 evaluable for response. Somnolence was the dose-limiting toxicity. The maximum tolerated dose for VPA was 75 mg/kg/d; at maximum tolerated dose, serum VPA was approximately 200 microg/mL (1.28 mmol/L). At the dose expansion cohort, 47% (7 of 15) of patients had stable disease; median overall survival and time to progression were 32.8 and 10.2 weeks, respectively. Histone hyperacetylation was observed in peripheral blood mononuclear cells at maximum tolerated dose. CONCLUSION: VPA potentiates KTN-induced DNA strand breaks and cytotoxicity. VPA can be combined at 75 mg/kg/d for 5 days with full-dose KTN without overlapping toxicities. In metastatic poor prognosis melanoma, this combination is associated with disease stabilization in 47% of patients. Further testing of this combination appears warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Inhibidores Enzimáticos/uso terapéutico , Inhibidores de Histona Desacetilasas , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Inhibidores de Topoisomerasa I , Ácido Valproico/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/uso terapéutico , Línea Celular Tumoral , Sinergismo Farmacológico , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Femenino , Histonas/metabolismo , Humanos , Masculino , Melanoma/metabolismo , Ratones , Ratones Desnudos , Persona de Mediana Edad , Neoplasias Cutáneas/metabolismo , Ácido Valproico/administración & dosificación , Ácido Valproico/efectos adversosRESUMEN
PURPOSE: The aim was to study the biological and molecular effects of the histone deacetylase (HDAC) inhibitor, valproic acid, in patients with solid tumor malignancies. EXPERIMENTAL DESIGN: A phase I dose escalation of valproic acid given on days 1 to 3 followed by epirubicin (day 3) was followed by a dose expansion of valproic acid combined with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC100). Pharmacodynamic and pharmacokinetic studies entailed valproic acid and epirubicin plasma levels and their interaction, the effects of valproic acid on histone acetylation in peripheral blood mononuclear cells (PBMC) and tumor cells at baseline and day 3, and baseline expression of HDAC2 and HDAC6 as therapeutic targets. RESULTS: Forty-four patients were enrolled in the phase I part, with a disease-specific cohort expansion of 15 breast cancer patients (median age, 55 years; range, 28-66 years) receiving 120 mg/kg/day valproic acid followed by FEC100. Partial responses were seen in 9 of 41 (22%) patients during the phase I part. Objective responses were seen in 9 of 14 (64%) evaluable patients at the dose expansion with a median number of 6 administered cycles. Predominant toxicities were valproic acid-associated somnolence and epirubicin-induced myelosuppression. Valproic acid plasma levels were associated with short-term, reversible depletion of WBC and neutrophils within 48 hours. Histone acetylation in tumor samples and in PBMCs correlated with valproic acid levels and was further linked to baseline HDAC2 but not to HDAC6 expression. CONCLUSION: Valproic acid is a clinically relevant HDAC inhibitor, and PBMCs may serve as a surrogate for tumor histone acetylation in solid tumor malignancies. HDAC2 should be further considered as a relevant therapeutic target.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Epirrubicina/uso terapéutico , Inhibidores de Histona Desacetilasas , Neoplasias/tratamiento farmacológico , Ácido Valproico/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Plaquetas/efectos de los fármacos , Ciclofosfamida/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Epirrubicina/administración & dosificación , Epirrubicina/farmacocinética , Femenino , Fluorouracilo/administración & dosificación , Histonas/metabolismo , Humanos , Leucocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Ácido Valproico/administración & dosificación , Ácido Valproico/farmacocinéticaRESUMEN
Tocotrienols are natural vitamin E compounds that are known to have a neuroprotective effect at nanomolar concentration and anti-carcinogenic effect at micromolar concentration. In this report, we investigated the pharmacokinetics, tumor and pancreatic tissue levels, and toxicity of delta-tocotrienol in mice because of its anti-tumor activity against pancreatic cancer. Following a single oral administration of delta-tocotrienol at 100 mg/kg, the peak plasma concentration (C(max)) was 57 +/- 5 micromol/l, the time required to reach peak plasma concentration (T(max)) was 2 h and plasma half-life (t(1/2)) was 3.5 h. The delta-tocotrienol was cleared from plasma and liver within 24 h, but delayed from the pancreas. When mice were fed delta-tocotrienol for 6 weeks, the concentration in tumor tissue was 41 +/- 3.5 nmol/g. This concentration was observed with the oral dose (100 mg/kg) of delta-tocotrienol which inhibited tumor growth by 80% in our previous studies. Interestingly, delta-tocotrienol was 10-fold more concentrated in the pancreas than in the tumor. We observed no toxicity due to delta-tocotrienol as mice gained normal weight with no histopathological changes in tissues. Our data suggest that bioactive levels of delta-tocotrienol can be achieved in the pancreas following oral administration and supports its clinical investigation in pancreatic cancer.
Asunto(s)
Páncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Vitamina E/análogos & derivados , Administración Oral , Animales , Línea Celular Tumoral , Femenino , Semivida , Hígado/metabolismo , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias Pancreáticas/prevención & control , Distribución Tisular , Trasplante Heterólogo , Vitamina E/administración & dosificación , Vitamina E/sangre , Vitamina E/farmacocinética , Vitamina E/toxicidadRESUMEN
BACKGROUND: Gemcitabine incorporation into DNA enhances cleavage complexes in vitro when combined with topoisomerase I inhibitors and demonstrates synergy in cancer cells when given with irinotecan. Topoisomerase I inhibitors require that topoisomerase I interacts with DNA to exert activity. METHODS: Patients who had received previous anthracycline therapy or were not candidates for anthracycline therapy received gemcitabine at a dose of 1000 mg/m2 intravenously over 30 minutes followed by irinotecan at a dose of 100 mg/m2 over 90 minutes on Days 1 and 8 of a 21-day cycle. The primary endpoint was improvement in response from that historically observed with gemcitabine (from 25% to 45%) as measured by Response Evaluation Criteria in Solid Tumors. Correlative studies included characterization of cellular levels and nuclear distribution of topoisomerase I and pharmacokinetic analysis of gemcitabine and irinotecan. RESULTS: Forty-nine patients were assessed for response. The response rate was approximately 25% (all partial responses [PRs], 12 patients; 95% confidence interval [95% CI], 13-39). Six patients had stable disease (SD) for > or =6 months for a clinical benefit rate (PR + SD) of 39%. The median time to disease progression was 3.7 months (95% CI, 2.5 months-4.6 months), and median survival was 11.6 months (95% CI, 8.9 months-15 months). Toxicities included neutropenia, nausea, and vomiting. Seven of 9 tissue biopsies were assessable for topoisomerase I. Tumors with the 2 lowest nuclear to cytoplasmic ratios demonstrated no response to irinotecan. CONCLUSIONS: Gemcitabine and irinotecan are active in metastatic breast cancer, but response did not meet predetermined response parameters, and the null hypothesis was accepted. Topoisomerase I localization can be measured in metastatic breast cancer. Further validation is needed to determine whether this assay can predict response.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , ADN-Topoisomerasas de Tipo I/metabolismo , Adulto , Anciano , Área Bajo la Curva , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Cromatografía Líquida de Alta Presión , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Irinotecán , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , GemcitabinaRESUMEN
PURPOSE: Endothelins and their cell membrane receptors (ET(A)R and ET(B)R) are implicated in neoplastic pathogenesis. atrasentan, a potent, selective ET(A)R antagonist, has a direct effect on tumor proliferation, apoptosis, and angiogenesis. This study was designed to assess the influence of atrasentan on paclitaxel pharmacokinetics and to determine the safety and efficacy of atrasentan in combination with paclitaxel-carboplatin. EXPERIMENTAL DESIGN: Chemonaive patients with stage IIIB (malignant pleural effusion) and IV non-small cell lung cancer were enrolled. Toxicity and response were determined using the National Cancer Institute Common Toxicity Criteria version 2.0 and Response Evaluation Criteria in Solid Tumors criteria, respectively. Treatment consisted of paclitaxel (225 mg/m(2)) and carboplatin (area under the curve, 6) administered on day 1 every 3 weeks. A fixed 10 mg daily oral dose ofAtrasentan was administered continuously, starting on day 4 of cycle 1. Paclitaxel clearance was calculated during the first two cycles (pre- and post-atrasentan) in the first 10 patients. RESULTS: All 44 patients were evaluable for survival, toxicity, and response. No significant change in mean paclitaxel clearance was detected (mean +/- SD, 21.2 +/- 4.5 L/h versus 21.3 +/- 4.9 L/h) for pre- and post-atrasentan values, respectively (P = 0.434). Grade 3/4 toxicities > or = 10% were lymphopenia (22.7%), neutropenia (20.5%), dyspnea (11.4%), and hyperglycemia (11.4%). Response rate was 18.2%, with progression-free survival of 4.2 months, median survival of 10.6 months, and 1-year survival of 43%. CONCLUSION: Atrasentan plus paclitaxel-carboplatin was safe and well tolerated, with no apparent paclitaxel-atrasentan pharmacokinetic interaction. Efficacy and survival in advanced non-small cell lung cancer were comparable with studies of chemotherapy alone.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Atrasentán , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Carboplatino/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/secundario , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/secundario , Antagonistas de los Receptores de la Endotelina A , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Pronóstico , Pirrolidinas/administración & dosificación , Tasa de SupervivenciaRESUMEN
Abnormal dendritic cell differentiation and accumulation of immature myeloid suppressor cells (ImC) is one of the major mechanisms of tumor escape. We tested the possibility of pharmacologic regulation of myeloid cell differentiation using all-trans-retinoic acid (ATRA). Eighteen patients with metastatic renal cell carcinoma were treated with ATRA followed by s.c. interleukin 2 (IL-2). Eight healthy individuals comprised a control group. As expected, the cancer patients had substantially elevated levels of ImC. We observed that ATRA dramatically reduced the number of ImC. This effect was observed only in patients with high plasma concentration of ATRA (>150 ng/mL), but not in patients with lower ATRA concentrations (<135 ng/mL). Effects of ATRA on the proportions of different dendritic cell populations were minor. However, ATRA significantly improved myeloid/lymphoid dendritic cell ratio and the ability of patients' mononuclear cells to stimulate allogeneic T cells. This effect was associated with significant improvement of tetanus-toxoid-specific T-cell response. During the IL-2 treatment, the ATRA effect was completely eliminated. To assess the role of IL-2, specimens from 15 patients with metastatic renal cell carcinoma who had been treated with i.v. IL-2 alone were analyzed. In this group also, IL-2 significantly reduced the number and function of dendritic cells as well as T-cell function. These data indicate that ATRA at effective concentrations eliminated ImC, improved myeloid/lymphoid dendritic cell ratio, dendritic cell function, and antigen-specific T-cell response. ATRA treatment did not result in significant toxicity and it could be tested in therapeutic combination with cancer vaccines.