RESUMEN
Asparaginase is essential in treating acute lymphoblastic leukaemia (ALL). Asparaginase-related hypersensitivity causes treatment discontinuation, which is associated with decreased event-free survival. To continue asparaginase treatment after hypersensitivity, a formulation of asparaginase encapsulated in erythrocytes (eryaspase) was developed. In NOR-GRASPALL 2016 (NCT03267030) the safety and efficacy of eryaspase was evaluated in 55 patients (aged 1-45 years; median: 6.1 years) with non-high-risk ALL and hypersensitivity to asparaginase conjugated with polyethylene glycol (PEG-asparaginase). Eryaspase (150 u/kg) was scheduled to complete the intended course of asparaginase (1-7 doses) in two Nordic/Baltic treatment protocols. Forty-nine (96.1%) patients had asparaginase enzyme activity (AEA) ≥100 iu/l 14 ± 2 days after the first eryaspase infusion [median AEA 511 iu/l; interquartile range (IQR), 291-780], whereas six of nine (66.7%) patients had AEA ≥100 iu/l 14 ± 2 days after the fourth infusion (median AEA 932 iu/l; IQR, 496-163). The mean terminal half-life of eryaspase following the first infusion was 15.3 ± 15.5 days. Few asparaginase-related adverse events were reported; five patients (9.1%) developed clinical allergy associated with enzyme inactivation. Replacement therapy was successfully completed in 50 patients (90.9%). Eryaspase was well tolerated, and most patients had AEA levels above the therapeutic target after the first infusion. The half-life of eryaspase confirmed that a 2-week schedule is appropriate.
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Antineoplásicos , Hipersensibilidad a las Drogas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Asparaginasa/efectos adversos , Hipersensibilidad a las Drogas/etiología , Eritrocitos , Humanos , Polietilenglicoles/efectos adversosRESUMEN
PURPOSE: This Phase IIb (NCT02195180) open-label study evaluated erythrocyte-encapsulated asparaginase (eryaspase) in combination with chemotherapy in second-line advanced pancreatic adenocarcinoma. METHODS: Eligible patients were randomized 2:1 to either eryaspase in combination with gemcitabine or mFOLFOX6 (eryaspase arm), or to gemcitabine or mFOLFOX6 alone (control arm). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with low asparagine synthetase (ASNS) expression. Secondary endpoints included OS and PFS in the entire population. RESULTS: 141 patients were randomized (eryaspase arm, n = 95; control arm, n = 46). Median OS and PFS in patients with low ASNS expression were 6.2 months (95% CI, 5.1-8.8) in the eryaspase arm versus 4.9 months (3.1-7.1) in the control arm (HR, 0.63; 95% CI, 0.39-1.01; P = 0.056) and 2.0 months (95% CI, 1.8-3.4) in the eryaspase arm versus 1.8 months (1.4-3.8) in the control arm (HR, 0.67; 95% CI, 0.40-1.12; P = 0.127), respectively. In the entire population, median OS and PFS for the eryaspase arm versus control were 6.0 months versus 4.4 months (HR, 0.60; P = 0.008) and 2.0 months versus 1.6 months (HR, 0.56; 95% CI, 0.37-0.84; P = 0.005), respectively. The combination of eryaspase and chemotherapy was well tolerated. The most frequent Grade 3/4 adverse events in the eryaspase arm (n = 93) were gamma-glutamyltransferase increase (16 [17.2%]), neutropenia (12 [12.9%]), and physical health deterioration (12 [12.9%]). CONCLUSION: Eryaspase in combination with chemotherapy is associated with improvements in OS and PFS, irrespective of ASNS expression in second-line advanced pancreatic adenocarcinoma. A Phase III trial is underway.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Asparaginasa/administración & dosificación , Neutropenia/epidemiología , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Asparaginasa/efectos adversos , Biopsia , Ligasas de Carbono-Nitrógeno con Glutamina como Donante de Amida-N/metabolismo , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neutropenia/inducido químicamente , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Páncreas/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Supervivencia sin Progresión , Criterios de Evaluación de Respuesta en Tumores Sólidos , GemcitabinaRESUMEN
HSP90 inhibitors have been shown to kill Epstein-Barr virus (EBV)-infected cells by reducing the level of EBV EBNA-1 and/or LMP1. We treated virus-infected cells with ganetespib, an HSP90 inhibitor currently being evaluated in multiple clinical trials for cancer and found that the drug killed EBV-positive B and T cells and reduced the level of both EBV EBNA-1 and LMP1. Treatment of cells with ganetespib also reduced the level of pAkt. Ganetespib delayed the onset of EBV-positive lymphomas and prolonged survival in SCID mice inoculated with one EBV-transformed B-cell line, but not another B-cell line. The former cell line showed lower levels of EBNA-1 after treatment with ganetespib in vitro. Treatment of a patient with T-cell chronic active EBV with ganetespib reduced the percentage of EBV-positive cells in the peripheral blood. These data indicate that HSP90 inhibitors may have a role in the therapy of certain EBV-associated diseases.
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Linfocitos B/efectos de los fármacos , Linfocitos B/virología , Infecciones por Virus de Epstein-Barr/sangre , Herpesvirus Humano 4/fisiología , Linfocitos T/efectos de los fármacos , Linfocitos T/virología , Triazoles/farmacología , Animales , Línea Celular Transformada , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Infecciones por Virus de Epstein-Barr/virología , Antígenos Nucleares del Virus de Epstein-Barr/genética , Antígenos Nucleares del Virus de Epstein-Barr/metabolismo , Femenino , Proteínas del Choque Térmico HSC70/genética , Proteínas del Choque Térmico HSC70/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , Recuento de Linfocitos , Ratones , Ratones SCIDRESUMEN
BACKGROUND: There are variations in the proportions of head and neck cancers caused by the human papillomavirus (HPV) between countries and regions. It is unclear if these are true variations or due to different study designs and assays. METHODS: We tested formalin-fixed paraffin-embedded diagnostic biopsies for p16 immunohistochemistry and HPV-DNA (by polymerase chain reaction [PCR] and in situ hybridization [ISH]) using validated protocols on samples from 801 patients with head and neck cancer recruited prospectively between 2006 and 2011 in 4 randomized controlled trials (RCTs). RESULTS: Twenty-one percent of patients (170 of 801) showed both HPV-DNA and p16-positivity, detected almost exclusively in oropharyngeal cancer (55%; 15 of 302); and only 1% of the patients (5 of 499) with nonoropharyngeal cancer were HPV positive. HPV-positive oropharyngeal cancer differed between Western and Eastern Europe (37%, 155 of 422 vs 6%, 8 of 144; p < .0001) and between Western Europe and Asia (37% vs 2%; 4 of 217; p < .0001). Other independent determinants of HPV positivity were tumor site and smoking. CONCLUSION: This is the first study to establish geographic variability as an independent risk factor in HPV-positive oropharyngeal cancer prevalence, with higher prevalence in Western Europe. © 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E1863-E1869, 2016.
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Carcinoma de Células Escamosas/epidemiología , Neoplasias Orofaríngeas/epidemiología , Infecciones por Papillomavirus/complicaciones , Carcinoma de Células Escamosas/virología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , ADN Viral/análisis , Europa (Continente) , Geografía , Humanos , Inmunohistoquímica , Neoplasias Orofaríngeas/virología , Papillomaviridae , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
PURPOSE: This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with resected stage II to IVA SCCHN, with a surgical margin ≤ 5 mm and/or extracapsular extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin 100 mg/m(2) per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy. RESULTS: Six hundred eighty-eight patients were enrolled (lapatinib, n = 346; placebo, n = 342). With a median follow-up time of 35.3 months, the study ended early because of the apparent plateauing of disease-free survival (DFS) events. Median DFS assessed by an independent review committee was 53.6 months and not reached for lapatinib and placebo, respectively (hazard ratio, 1.10; 95% CI, 0.85 to 1.43). Investigator-assessed results confirmed the independent review committee assessment. No significant differences in DFS by human papillomavirus status or overall survival were observed between treatment arms. Similar numbers of patients in both treatment arms experienced adverse events (AEs), with more patients in the lapatinib arm than the placebo arm experiencing serious AEs (48% v 40%, respectively). The most commonly observed treatment-related AEs were diarrhea and rash, both predominantly in the lapatinib arm. CONCLUSION: Addition of lapatinib to chemoradiotherapy and its use as long-term maintenance therapy does not offer any efficacy benefits and had additional toxicity compared with placebo in patients with surgically treated high-risk SCCHN.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Quimioradioterapia , Neoplasias de Cabeza y Cuello/terapia , Quimioterapia de Mantención , Quinazolinas/uso terapéutico , Adulto , Anciano , Carcinoma de Células Escamosas/metabolismo , Cetuximab/administración & dosificación , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Fraccionamiento de la Dosis de Radiación , Método Doble Ciego , Receptores ErbB/efectos de los fármacos , Receptores ErbB/genética , Femenino , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Cooperación Internacional , Estimación de Kaplan-Meier , Lapatinib , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Oportunidad Relativa , Carcinoma de Células Escamosas de Cabeza y Cuello , Resultado del TratamientoRESUMEN
BACKGROUND: Ganetespib is a small molecule, nongeldanamycin HSP90 inhibitor with potent inhibitory effects on HSP90-dependent oncoproteins of relevance to breast cancer pathogenesis. We therefore tested ganetespib in an unselected cohort of patients with MBC. PATIENTS AND METHODS: Patients were treated with single agent ganetespib at 200 mg/m(2) once weekly for 3 weeks, on a 28-day cycle. Therapy was continued until disease progression. The primary end point was ORR using Reponse Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Twenty-two patients were enrolled with a median age of 51(range, 38-70) years and a median Eastern Cooperative Oncology Group performance status of 0 (range, 0-1). Most patients had at least 2 previous lines of chemotherapy in the metastatic setting. Most common toxicities, largely grade 1/2, were diarrhea, fatigue, nausea, and hypersensitivity reaction. The ORR in this unselected population was 9%, with all responses coming from the subset of patients with HER2-positive MBC (2/13; 15%). One patient with TNBC had objective tumor regression in the lung metastases. The clinical benefit rate (complete response + partial response + stable disease > 6 months) was 9%, median progression-free survival was 7 weeks (95% confidence interval [CI], 7-19), and median overall survival was 46 weeks (95% CI, 27-not applicable). CONCLUSION: The study did not meet the prespecified criteria for ORR in the first stage of the Simon 2-stage model in this heavily pretreated unselected population of MBC. However, activity was observed in trastuzumab-refractory HER2-positive and TNBC. Ganetespib was well tolerated and responses in more targeted populations harboring specific HSP90-dependent oncoproteins justifies its further study, particularly as part of rational combinations.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Triazoles/uso terapéutico , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Supervivencia sin Enfermedad , Femenino , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Metástasis de la NeoplasiaRESUMEN
PURPOSE: Treatment options for patients with triple-negative breast cancer (TNBC) are largely limited to systemic chemotherapies, which have shown disappointing efficacy in the metastatic setting. Here, we undertook a comprehensive evaluation of the activity of ganetespib, a potent inhibitor of HSP90, in this malignancy. EXPERIMENTAL DESIGN: The antitumor and antimetastatic activity of ganetespib was investigated using TNBC cell lines and xenograft models. Combinatorial drug analyses were performed with chemotherapeutic agents and concomitant effects on DNA damage and cell-cycle disruption were assessed in vitro; antitumor efficacy was assessed in vivo. Metabolic and objective tumor responses were evaluated in patients with metastatic TNBC undergoing ganetespib treatment. RESULTS: Ganetespib simultaneously deactivated multiple oncogenic pathways to potently reduce cell viability in TNBC cell lines, and suppressed lung metastases in experimental models. Ganetespib potentiated the cytotoxic activity of doxorubicin via enhanced DNA damage and mitotic arrest, conferring superior efficacy to the doxorubicin-cyclophosphamide regimen in TNBC xenografts. Ganetespib also promoted mitotic catastrophe and apoptosis in combination with taxanes in vitro, and these effects translated to significantly improved combinatorial activity in vivo. Marked tumor shrinkage of metastatic lung and lymphatic lesions were seen in patients on ganetespib monotherapy. CONCLUSION: The preclinical activity profile and clinical evidence of tumor regression suggest that ganetespib offers considerable promise as a new therapeutic candidate to target TNBC.
Asunto(s)
Antineoplásicos/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Triazoles/farmacología , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Antineoplásicos/uso terapéutico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Femenino , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Ratones , Mitosis/efectos de los fármacos , Metástasis de la Neoplasia , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Triazoles/uso terapéutico , Neoplasias de la Mama Triple Negativas/diagnóstico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Hypoxia-inducible factors (HIFs) and STAT-3 play essential roles in angiogenesis. HIF-1α and STAT-3 are clients of the heat shock protein 90 (HSP90). We hypothesized that ganetespib, a potent HSP90 inhibitor, would disrupt angiogenesis in colorectal cancer (CRC) through inhibition of HIF-1α and STAT-3. CRC cell lines (HCT116 and HT29) were used in all the experiments. Egg CAM and HUVEC assays revealed decreased angiogenesis in ganetespib treated cell lines. Ganetespib inhibited matrigel plug vascularization and tumor growth of xenografts. Significant inhibition of PDGFA, FGF2, Ang-1, Ang-2, TGFß1, VEGF, HIF-1α and STAT-3 expression was observed in both cell lines treated ganetespib. HIF-1α overexpression resulted in the increase VEGF and STAT-3 expression and this was inhibited by ganetespib. HIF-1α knockdown inhibited VEGF and STAT-3 expression. STAT-3 knockdown inhibited VEGF but not HIF-1α expression. HSP90, STAT-3 and VEGF expression was significantly higher in CRC compared to adjacent normal tissue. Significant downregulation of PDGFA, FGF2, Ang-1, Ang-2, TGFß1, VEGF, STAT-3 and HIF-1α mRNA was observed in the post ganetespib treatment tumor samples from patients with rectal cancer. These results collectively suggest that inhibition of HSP90 is a promising antiangiogenic strategy in CRC. HSP90 angiogenic effects are mediated through HIF-1α and STAT-3.
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Adenocarcinoma/irrigación sanguínea , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Neoplasias Colorrectales/irrigación sanguínea , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Factor de Transcripción STAT3/antagonistas & inhibidores , Triazoles/farmacología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Embrión de Pollo , Membrana Corioalantoides/irrigación sanguínea , Colágeno , Neoplasias Colorrectales/patología , Regulación hacia Abajo , Combinación de Medicamentos , Femenino , Factor 2 de Crecimiento de Fibroblastos/antagonistas & inhibidores , Factor 2 de Crecimiento de Fibroblastos/biosíntesis , Factor 2 de Crecimiento de Fibroblastos/genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células HEK293 , Proteínas HSP90 de Choque Térmico/fisiología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Laminina , Ratones Desnudos , Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Factor de Crecimiento Derivado de Plaquetas/biosíntesis , Factor de Crecimiento Derivado de Plaquetas/genética , Proteoglicanos , ARN Mensajero/biosíntesis , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/genética , Neoplasias del Recto/patología , Ribonucleasa Pancreática/antagonistas & inhibidores , Ribonucleasa Pancreática/biosíntesis , Ribonucleasa Pancreática/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/fisiología , Organismos Libres de Patógenos Específicos , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Factor de Crecimiento Transformador beta1/biosíntesis , Factor de Crecimiento Transformador beta1/genética , Triazoles/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/genética , Proteínas de Transporte Vesicular/antagonistas & inhibidores , Proteínas de Transporte Vesicular/biosíntesis , Proteínas de Transporte Vesicular/genéticaRESUMEN
PURPOSE: Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m(2) ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies. RESULTS: Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia. CONCLUSIONS: Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Triazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Reordenamiento Génico , Genotipo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Proteínas Tirosina Quinasas Receptoras/genética , Resultado del Tratamiento , Triazoles/administración & dosificación , Triazoles/efectos adversosRESUMEN
UNLABELLED: EML4-ALK gene rearrangements define a unique subset of patients with non-small cell lung carcinoma (NSCLC), and the clinical success of the anaplastic lymphoma kinase (ALK) inhibitor crizotinib in this population has become a paradigm for molecularly targeted therapy. Here, we show that the Hsp90 inhibitor ganetespib induced loss of EML4-ALK expression and depletion of multiple oncogenic signaling proteins in ALK-driven NSCLC cells, leading to greater in vitro potency, superior antitumor efficacy, and prolonged animal survival compared with results obtained with crizotinib. In addition, combinatorial benefit was seen when ganetespib was used with other targeted ALK agents both in vitro and in vivo. Importantly, ganetespib overcame multiple forms of crizotinib resistance, including secondary ALK mutations, consistent with activity seen in a patient with crizotinib-resistant NSCLC. Cancer cells driven by ALK amplification and oncogenic rearrangements of ROS1 and RET kinase genes were also sensitive to ganetespib exposure. Taken together, these results highlight the therapeutic potential of ganetespib for ALK-driven NSCLC. SIGNIFICANCE: In addition to direct kinase inhibition, pharmacologic blockade of the molecular chaperone Hsp90 is emerging as a promising approach for treating tumors driven by oncogenic rearrangements of ALK. The bioactivity profi le of ganetespib presented here underscores a new therapeutic opportunity to target ALK and overcome multiple mechanisms of resistance in patients with ALK-positive NSCLC.
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Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Tirosina Quinasas Receptoras/genética , Triazoles/administración & dosificación , Adulto , Quinasa de Linfoma Anaplásico , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Crizotinib , Resistencia a Antineoplásicos , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto JovenRESUMEN
BACKGROUND: This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies. METHODS: Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity. RESULTS: Fifty-three patients were treated at doses escalating from 7 to 259 mg/m(2). The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m(2)), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m(2)). The MTD was 216 mg/m(2) and the recommended phase 2 dose was established at 200 mg/m(2) given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ≥ 16 weeks) was 24.4%. CONCLUSIONS: Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m(2), and is associated with an acceptable tolerability profile. TRIAL REGISTRATION: NCT00687934.
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Neoplasias/tratamiento farmacológico , Triazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Esquema de Medicación , Femenino , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/sangre , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/metabolismo , Resultado del Tratamiento , Triazoles/administración & dosificación , Triazoles/efectos adversos , Triazoles/farmacocinéticaRESUMEN
BACKGROUND: Little information has been reported on regional and time trends of human papillomavirus (HPV) prevalence rates of oropharyngeal cancer (OPC) and non-OPC. METHODS: The study consisted of a systematic review and meta-analysis using random effects logistic regression models. RESULTS: Overall HPV prevalence in OPC (47.7%; 95% confidence interval [CI], 42.9-52.5%) increased significantly over time: from 40.5% (95% CI, 35.1-46.1) before 2000, to 64.3% (95% CI, 56.7-71.3) between 2000 and 2004, and 72.2% (95% CI, 52.9-85.7) between 2005 and 2009 (p < .001). Prevalence increased significantly in North America and Europe, and the significant gap between them that existed before 2000 (50.7% vs 35.3%, respectively, p = .008) has now disappeared (69.7% vs 73.1%, respectively, p = .8). Prevalence in non-OPC (21.8%; 95% CI, 18.9-25.1%) has not increased over time (p = .97). CONCLUSIONS: The sharp increase in the proportion of HPV-positive OPC over the last decade has occurred at a faster rate in Europe compared with that in North America. In contrast, the relatively low prevalence of HPV in non-OPC remains unchanged.
Asunto(s)
Carcinoma de Células Escamosas/virología , Neoplasias de Cabeza y Cuello/virología , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/complicaciones , Europa (Continente)/epidemiología , Humanos , Modelos Logísticos , América del Norte , Infecciones por Papillomavirus/epidemiología , Prevalencia , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
BACKGROUND: This randomised Phase II study assessed the activity and safety of concurrent chemoradiotherapy (CRT) and lapatinib followed by maintenance treatment in locally advanced, unresected stage III/IVA/IVB head and neck cancer. PATIENTS AND METHODS: Patients were randomised 1:1 to concurrent CRT and placebo followed by placebo or concurrent CRT and lapatinib followed by lapatinib. Treatment continued until disease progression or study withdrawal. Primary end-point was complete response rate (CRR) by independent review 6 months post-CRT. RESULTS: Sixty-seven patients (median age 56 years; 97% Eastern Cooperative Oncology Group performance status ≤1; 82% stage IV) were recruited. CRT dose intensities were unaffected by lapatinib: median radiation dose 70 Gy (lapatinib, placebo), duration 49 (lapatinib) and 50 days (placebo); median cisplatin dose 260 mg/m(2) (lapatinib) and 280 mg/m(2) (placebo). Lapatinib combined with CRT was well-tolerated. Grade 3/4 toxicities during CRT were balanced between arms, with the exception of an excess of grade 3 diarrhoea (6% versus 0%) and rash (9% versus 3%) and two grade 4 cardiac events in the lapatinib arm. CRR at 6 months post-CRT was 53% with lapatinib versus 36% with placebo in the intent-to-treat population. The progression-free survival (PFS) and overall survival rates at 18 months were 55% versus 41% and 68% versus 57% for the lapatinib and placebo arms, respectively. The difference between study arms was greatest in p16-negative disease (median PFS >20.4 months [lapatinib] versus 10.9 [placebo]). CONCLUSION: Lapatinib combined with CRT is well-tolerated with numeric increases in CRR at 6 months post-CRT and median PFS in p16-negative disease.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Quimioradioterapia/métodos , Neoplasias de Cabeza y Cuello/terapia , Quinazolinas/uso terapéutico , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Quimioradioterapia/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Diarrea/etiología , Supervivencia sin Enfermedad , Método Doble Ciego , Esquema de Medicación , Receptores ErbB/análisis , Exantema/etiología , Femenino , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Inmunohistoquímica , Lapatinib , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Papillomaviridae/fisiología , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Dosificación Radioterapéutica , Resultado del TratamientoRESUMEN
BACKGROUND: In this phase I/II study, the addition of lapatinib (LAP) was investigated in combination with the sequential use of both approaches TPF induction chemotherapy (ICT) followed by chemoradiation (CRT) in locally advanced larynx or hypopharynx squamous cell carcinoma. PATIENTS AND METHODS: Objectives were to assess maximum tolerated dose, dose-limiting toxicity (DLT) and to recommend a safe dose of LAP when administered with 4 cycles of TPF followed by CRT. RESULTS: Seven male patients were included. Three patients were included in the first cohort, at dose level 1 (LAP 500 mg daily plus TPF). Renal toxicity was observed among these three patients (grade 3 [n=1], grade 2 [n=1] and grade 1 [n=1]), with 1 DLT, leading to treatment interruption in this group. Nephrotoxicity was reversible after stopping LAP and hydration of the patients. In a second cohort of four patients administering docetaxel from the second cycle, 3 more DLTs were observed (grade 2 renal toxicity and grade 3 diarrhea, grade 3 anorexia and grade 3 stomatitis, and grade 4 neutropenia). Based on the occurrence of 4 DLTs at the first dose level of LAP, patient recruitment was closed. CONCLUSION: These data indicate that LAP cannot be combined safely with full dose TPF.
Asunto(s)
Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Quimioradioterapia , Neoplasias Hipofaríngeas/terapia , Neoplasias Laríngeas/terapia , Inhibidores de Proteínas Quinasas/efectos adversos , Quinazolinas/efectos adversos , Cisplatino/uso terapéutico , Fluorouracilo/uso terapéutico , Humanos , Quimioterapia de Inducción , Lapatinib , Masculino , Taxoides/uso terapéuticoRESUMEN
BACKGROUND: Limited data exist on the burden of comorbidity among patients with squamous cell head and neck cancer (SCCHN) before and during cancer treatment. METHODS: The precancer prevalence and incidence rates of 8 comorbid conditions were estimated among a population-based cohort of 1499 patients with SCCHN in the Netherlands. Patients with cancer, treatments, and comorbidities were identified in the PHARMO Record Linkage System (RLS) using hospital admissions and/or dispensing codes. Prevalence proportions and incidence rates were also compared against a matched cancer-free population. RESULTS: Cardiovascular (41%) and respiratory diseases (12%) were the most prevalent comorbidities. Incidence rates of most comorbidities were highest the first 6 months after cancer diagnosis and decreased over time. Patients receiving chemotherapy-based treatment had significantly higher incidence rates of anemia and other malignant diseases. CONCLUSIONS: High rates of acute and chronic comorbidity were observed; knowledge of comorbidity burden aids in establishing a benefit-risk profile for investigational SCCHN therapies.
Asunto(s)
Carcinoma de Células Escamosas/epidemiología , Neoplasias de Cabeza y Cuello/epidemiología , Anciano , Carcinoma de Células Escamosas/psicología , Enfermedades Cardiovasculares/epidemiología , Comorbilidad , Depresión/epidemiología , Diabetes Mellitus/epidemiología , Femenino , Neoplasias de Cabeza y Cuello/psicología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Lesiones Precancerosas/epidemiología , Prevalencia , Enfermedades Respiratorias/epidemiología , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
OBJECT: Pharmacokinetic parameters from dynamic contrast-enhanced MRI (DCE-MRI) were used to assess the perfusion effects due to treatment response using a tyrosine kinase inhibitor. A Bayesian hierarchical model (BHM) is proposed, as an alternative to voxel-wise estimation procedures, to test for a treatment effect while explicitly modeling known sources of variability. MATERIALS AND METHODS: Nine subjects from a randomized, blinded, placebo-controlled, multicenter, phase II study of lapatinib were examined before and after treatment. Kinetic parameters were estimated, with an extended compartmental model and subject-specific arterial input function, on a voxel-by-voxel basis. RESULTS: The group treated with lapatinib had a decrease in median K(trans) of 0.17 min⻹, when averaged across all voxels in the tumor ROIs, compared with no change in the placebo group based on nonlinear regression. A hypothesis test of equality between pre- and posttreatment K (trans) could not be rejected against a one-sided alternative (P = 0.09). Equality between median K(trans) in placebo and lapatinib groups posttreatment could also not be rejected using the BHM (P = 0.32). Across all scans acquired in the study, estimates of K(trans) at one site were greater on average than those at the other site by including a site effect in the BHM. The inter-voxel variability is of similar order (within 15%) when compared to the inter-patient variability. CONCLUSION: Though the study contained a small number of subjects and no significant difference was found, the Bayesian hierarchical model provided estimates of variability from known sources in the study and confidence intervals for all estimated parameters. We believe the BHM provides a straightforward and thorough interrogation of the imaging data at the level of voxels, patients or sites in this multicenter clinical study.
Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Imagen por Resonancia Magnética/métodos , Modelos Biológicos , Quinazolinas/uso terapéutico , Adulto , Anciano , Antineoplásicos/farmacocinética , Teorema de Bayes , Biomarcadores/metabolismo , Carcinoma de Células Escamosas/metabolismo , Medios de Contraste/farmacocinética , Determinación de Punto Final , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Lapatinib , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Quinazolinas/farmacocinética , Resultado del TratamientoRESUMEN
Expression of epidermal growth factor receptor (EGFR) may be of prognostic value in renal cell cancer (RCC). Gene amplification of EGFR was investigated in a cohort of 315 patients with advanced RCC from a previously reported randomised study. Using fluorescent in situ hybridisation, only 2 patients (0.6%) had gene amplification; therefore gene amplification is of no prognostic value in RCC.
Asunto(s)
Carcinoma de Células Renales/genética , Receptores ErbB/biosíntesis , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/metabolismo , Receptores ErbB/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Neoplasias Renales/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Análisis de SupervivenciaRESUMEN
Thrombopoietin (TPO) receptor agonists represent a new approach for the treatment of thrombocytopenia, which may develop as a consequence of immune thrombocytopenia, chemotherapy treatment, chronic hepatitis C infection, or myelodysplastic syndromes. There are concerns that use of certain growth factors can hasten disease progression in some types of hematologic malignancies and solid tumors. In this study, expression of MPL (TPO-R) mRNA was examined in tumor cell lines, patient tumor samples (renal cell carcinoma, prostatic carcinoma, soft tissue and bony/cartilage sarcoma, colon cancer, and lymphoma), and normal tissues using microarray analysis and qRT-PCR. MPL mRNA is expressed at very low or undetectable levels compared with erythropoietin receptor (EPOR), human epidermal growth factor (ERBB2; HER2), and insulin-like growth factor-1 receptor (IGF1R) in these patient samples. These data suggest TPO-R agonists will likely preferentially stimulate proliferation and differentiation of cells of megakaryocytic lineage, potentially demonstrating their utility for correcting thrombocytopenia in clinical settings.
RESUMEN
PURPOSE: Aim of this study was to correlate dose to pharyngeal constrictors (PC) with subjective and observer-based assessments of swallowing in patients with head and neck cancer undergoing concomitant chemo-IMRT. MATERIALS AND METHODS: Dose-volume histograms (DVHs) for superior constrictor (SC), middle constrictor (MC) and inferior constrictor (IC) were generated for 37 patients. Mean doses to SC, MC and IC were correlated to objective dysphagia grade (1 year, RTOG scoring) and global, total physical (TP) and most relevant components of the physical section (P6, P8) of the MD Anderson dysphagia inventory (MDADI) which was evaluated post-treatment. Odds ratios of dysphagia (>grade 0), poor global (<3), TP (<32), P6 (<3) and P8 (<3) for patients with mean dose>60 Gy to SC and IC were calculated. RESULTS: There was no significant correlation between mean dose to PC and any of the analysed MDADI parameters and observer-assessed dysphagia grade. Odds ratio of dysphagia (>grade 0), poor global (<3), TP (<32), P6 (<3) and P8 (<3) for patients with mean dose>60 Gy to IC and SC were not significantly higher than those for patients receiving <60 Gy. CONCLUSION: This study did not find a statistically significant correlation between radiation dose to the PC and observer-assessed dysphagia grade or patient-reported MDADI questionnaire at 1 year.