RESUMEN
BACKGROUND: Pembrolizumab demonstrated durable antitumor activity in 233 patients with previously treated advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors in the phase II multicohort KEYNOTE-158 (NCT02628067) study. Herein, we report safety and efficacy outcomes with longer follow-up for more patients with previously treated advanced MSI-H/dMMR noncolorectal cancers who were included in cohort K of the KEYNOTE-158 (NCT02628067) study. PATIENTS AND METHODS: Eligible patients with previously treated advanced noncolorectal MSI-H/dMMR solid tumors, measurable disease as per RECIST v1.1, and Eastern Cooperative Oncology Group performance status of 0 or 1 received pembrolizumab 200 mg Q3W for 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as per RECIST v1.1 by independent central radiologic review. RESULTS: Three hundred and fifty-one patients with various tumor types were enrolled in KEYNOTE-158 cohort K. The most common tumor types were endometrial (22.5%), gastric (14.5%), and small intestine (7.4%). Median time from first dose to database cut-off (5 October 2020) was 37.5 months (range, 0.2-55.6 months). ORR among 321 patients in the efficacy population (patients who received ≥1 dose of pembrolizumab enrolled ≥6 months before the data cut-off date) was 30.8% [95% confidence interval (CI) 25.8% to 36.2%]. Median duration of response was 47.5 months (range, 2.1+ to 51.1+ months; '+' indicates no progressive disease by the time of last disease assessment). Median progression-free survival was 3.5 months (95% CI 2.3-4.2 months) and median overall survival was 20.1 months (95% CI 14.1-27.1 months). Treatment-related adverse events (AEs) occurred in 227 patients (64.7%). Grade 3-4 treatment-related AEs occurred in 39 patients (11.1%); 3 (0.9%) had grade 5 treatment-related AEs (myocarditis, pneumonia, and Guillain-Barre syndrome, n = 1 each). CONCLUSIONS: Pembrolizumab demonstrated clinically meaningful and durable benefit, with a high ORR of 30.8%, long median duration of response of 47.5 months, and manageable safety across a range of heavily pretreated, advanced MSI-H/dMMR noncolorectal cancers, providing support for use of pembrolizumab in this setting.
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Antineoplásicos Inmunológicos , Neoplasias , Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos/efectos adversos , Reparación de la Incompatibilidad de ADN/genética , Humanos , Inestabilidad de Microsatélites , Neoplasias/inducido químicamente , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
OBJECTIVE: Pembrolizumab demonstrated a clinically meaningful objective response rate in patients with previously treated, advanced MSI-H/dMMR endometrial cancer in the multicohort phase 2 KEYNOTE-158 study (ClinicalTrials.gov, NCT02628067). We present health-related quality of life (HRQoL) results for these patients. METHODS: This analysis included patients from cohorts D (endometrial cancer with any MSI status) and K (any MSI-H/dMMR solid tumor except colorectal) who had previously treated, advanced MSI-H/dMMR endometrial cancer. Patients received pembrolizumab 200â¯mg Q3W for 35â¯cycles. EORTC QLQ-C30 and EQ-5D-3L questionnaires were administered at baseline, at regular intervals during treatment, and 30â¯days after treatment discontinuation. Pre-specified exploratory analyses included changes from baseline to week 9 in QLQ-C30 global health status (GHS)/QoL and EQ-5D-3L visual analog scale (VAS) score for all patients and by best overall response. RESULTS: 84 of 90 enrolled patients completed ≥1 HRQoL questionnaire and were included in the analysis. QLQ-C30 and EQ-5D-3L compliance rates were 90% and 94%, respectively, at baseline, and 92% and 93% at week 9. Mean (95% CI) QLQ-C30 GHS/QoL scores improved from baseline to week 9 by 6.08 (0.71-11.46) points in the overall population, with greater improvement in patients who achieved complete or partial response (11.67 [5.33-18.00]-point increase). Mean (95% CI) EQ-5D-3L VAS scores improved by 6.00 (2.25-9.75) points in the overall population and 9.11 (5.24-12.98) points in patients with CR/PR. CONCLUSIONS: Pembrolizumab maintained or improved HRQoL in patients with previously treated, advanced MSI-H/dMMR endometrial cancer, further supporting efficacy and safety results from KEYNOTE-158 and pembrolizumab use in this setting.
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Neoplasias Endometriales , Calidad de Vida , Anticuerpos Monoclonales Humanizados , Reparación de la Incompatibilidad de ADN , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Femenino , Humanos , Inestabilidad de MicrosatélitesRESUMEN
BACKGROUND: Numerous phase I trials testing immune checkpoint inhibitors (CPI)-based combinations are currently being conducted to improve response rates observed with single agents. However, methodology varies across studies, especially regarding the use of dose escalation. MATERIALS AND METHODS: A literature search was conducted in Pubmed and major oncology meetings libraries for phase I trials reported between 2011 and 2018, containing at least one CPI [CLTA-4 blocking antibody or a PD(L)1 blocking antibody] plus at least one second agent (e.g. tyrosine kinase inhibitor, chemotherapy). Dose escalation schemes, target doses and recommended phase II doses (RP2D) were captured in our database for each study. Combination RP2D (combo-RP2D) was compared with target dose. RESULTS: We identified 113 different studies comprising a total of 120 individual cohorts. The backbone was an anti- cytotoxic T-lymphocyte antigen 4 (CTLA-4) in 40 cohorts and an anti-PD(L)1 in 80 cohorts. Dose escalation was used for the CPI in 29 (24%) cohorts [11% for anti-PD(L)1 and 50% for anti-CTLA-4] and for the second agent in 55 cohorts (46%). For 31 s agents (26%), the combo-RP2D was significantly lower than the expected target dose. Failure to reach the target dose was explained by the type of second agent form (e.g. small molecules versus monoclonal antibodies) (P < 0.001) and the choice of trial design for the second agent by investigators. CONCLUSION: Design of studies investigating new CPI-based combinations must consider the type of second agent. Dose escalation is required for combinations with small molecules but is unnecessary with vaccine/virus/dendritic therapies and monoclonal antibodies.
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Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ensayos Clínicos Fase I como Asunto/normas , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Antineoplásicos Inmunológicos/toxicidad , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Relación Dosis-Respuesta a Droga , Humanos , Dosis Máxima Tolerada , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Inhibidores de Proteínas Quinasas/toxicidad , Proyectos de Investigación/normas , Resultado del TratamientoRESUMEN
BACKGROUND: Emactuzumab is a monoclonal antibody against the colony-stimulating factor-1 receptor and targets tumor-associated macrophages (TAMs). This study assessed the safety, clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD) of emactuzumab, as monotherapy and in combination with paclitaxel, in patients with advanced solid tumors. PATIENTS AND METHODS: This open-label, phase Ia/b study comprised two parts (dose escalation and dose expansion), each containing two arms (emactuzumab, every 2 or 3 weeks, as monotherapy or in combination with paclitaxel 80 mg/m2 weekly). The dose-escalation part explored the maximum tolerated dose and optimal biological dose (OBD). The dose-expansion part extended the safety assessment and investigated the objective response rate. A PK/PD analysis of serial blood, skin and tumor biopsies was used to explore proof of mechanism and confirm the OBD. RESULTS: No maximum tolerated dose was reached in either study arm, and the safety profile of emactuzumab alone and in combination does not appear to preclude its use. No patients receiving emactuzumab monotherapy showed an objective response; the objective response rate for emactuzumab in combination with paclitaxel was 7% across all doses. Skin macrophages rather than peripheral blood monocytes or circulating colony-stimulating factor-1 were identified as an optimal surrogate PD marker to select the OBD. Emactuzumab treatment alone and in combination with paclitaxel resulted in a plateau of immunosuppressive TAM reduction at the OBD of 1000 mg administered every 2 weeks. CONCLUSIONS: Emactuzumab showed specific reduction of immunosuppressive TAMs at the OBD in both treatment arms but did not result in clinically relevant antitumor activity alone or in combination with paclitaxel. (ClinicalTrials.gov Identifier: NCT01494688).
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Anticuerpos Monoclonales Humanizados/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Macrófagos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Paclitaxel/farmacología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Factor Estimulante de Colonias de Macrófagos/sangre , Factor Estimulante de Colonias de Macrófagos/metabolismo , Macrófagos/inmunología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/inmunología , Neoplasias/patología , Paclitaxel/uso terapéutico , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Piel/citología , Piel/inmunología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Antitumor activity of molecular-targeted agents is guided by the presence of documented genomic alteration in specific histological subtypes. We aim to explore the feasibility, efficacy and therapeutic impact of molecular profiling in routine setting. PATIENTS AND METHODS: This multicentric prospective study enrolled adult or pediatric patients with solid or hematological advanced cancer previously treated in advanced/metastatic setting and noneligible to curative treatment. Each molecular profile was established on tumor, relapse or biopsies, and reviewed by a molecular tumor board (MTB) to identify molecular-based recommended therapies (MBRT). The main outcome was to assess the incidence rate of genomic mutations in routine setting, across specific histological types. Secondary objectives included a description of patients with actionable alterations and for whom MBRT was initiated, and overall response rate. RESULTS: Four centers included 2579 patients from February 2013 to February 2017, and the MTB reviewed the molecular profiles achieved for 1980 (76.8%) patients. The most frequently altered genes were CDKN2A (N = 181, 7%), KRAS (N = 177, 7%), PIK3CA (N = 185, 7%), and CCND1 (N = 104, 4%). An MBRT was recommended for 699/2579 patients (27%), and only 163/2579 patients (6%) received at least one MBRT. Out of the 182 lines of MBRT initiated, 23 (13%) partial responses were observed. However, only 0.9% of the whole cohort experienced an objective response. CONCLUSION: An MBRT was provided for 27% of patients in our study, but only 6% of patients actually received matched therapy with an overall response rate of 0.9%. Molecular screening should not be used at present to guide decision-making in routine clinical practice outside of clinical trials.This trial is registered with ClinicalTrials.gov, number NCT01774409.
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Mutación , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias/diagnóstico , Adulto , Biomarcadores de Tumor/genética , Niño , Bases de Datos Genéticas , Detección Precoz del Cáncer/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Medicina de Precisión/métodos , Estudios ProspectivosRESUMEN
BACKGROUND: Lymphopenia is a predictive factor for hematological toxicity, progression and early death in advanced cancers including metastatic breast cancer (MBC). CYT107 is a recombinant interleukin 7 (IL-7) (Cytheris, now Revimmune), well tolerated and able to expand lymphocyte pool in humans. The aims of this study were to determine the optimal schedule to deliver CYT107 and to assess its effect on clinical end points. PATIENT AND METHODS: This placebo-controlled, double blind, phase IIa was conducted in MBC patients with <1500/µl lymphocytes treated with capecitabine. Using a 2-by-2 factorial design, 20 patients were randomly allocated to four arms to receive (i) before chemotherapy: CYT107 or placebo; then (ii) during chemotherapy: CYT107 or placebo. The primary end point was CD4+ count changes before and during chemotherapy. Secondary end points were hematological toxicity, safety, overall response, progression-free survival (PFS) and overall survival (OS). Quantification and functional competence of circulating immune cells were also assessed. RESULTS: When administered before chemotherapy, CYT107 induced a significant increase of CD4+ [+148.1% in CYT107 versus +9.9% in placebo groups, (Wilcoxon, P = 0.002)] and CD8+ T-cell counts, including both naïve and memory subsets. When CYT107 was administered during chemotherapy, the magnitude of CD4+ and CD8+ increase was less important. No modulation of immune cell functional competence was observed. CYT107 was well tolerated with no related ≥grade 3 adverse events except 1 fatal suspected unexpected serious adverse reaction (SUSAR) of uncertain relationship. Of the 12 cases evaluable for response, 6 of 7 patients (86%) receiving CYT107 before chemotherapy achieved a response or stabilization, whereas two of five patients (40%) receiving placebo achieved the same result. No significant difference was observed for PFS or OS. CONCLUSION: In lymphopenic MBC, CYT107 increases CD4+ and other T-cell subset counts without altering their function. A larger clinical trial to demonstrate its impact on clinical outcome is warranted. CLINICALTRIALSGOV IDENTIFIER: NCT01362107.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Lobular/tratamiento farmacológico , Interleucina-7/uso terapéutico , Linfopenia/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Recuento de Linfocito CD4 , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/secundario , Carcinoma Lobular/mortalidad , Carcinoma Lobular/secundario , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Metástasis Linfática , Linfopenia/mortalidad , Linfopenia/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tasa de SupervivenciaRESUMEN
Transplant recipients are at risk of developing Legionnaires' disease (LD) because of impaired cellular immunity. Here, we describe a renal transplant recipient who developed LD at least 10 days after hospital admission and transplantation. The hospital water network was initially suspected, but further testing determined that the probable source was the patient's domestic water supply. Our report also suggests that the patient's immunosuppressed state may have switched potential colonization to pneumonia.
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Huésped Inmunocomprometido , Trasplante de Riñón , Enfermedad de los Legionarios/etiología , Complicaciones Posoperatorias/etiología , Infecciones Comunitarias Adquiridas/diagnóstico , Infecciones Comunitarias Adquiridas/etiología , Infecciones Comunitarias Adquiridas/inmunología , Humanos , Enfermedad de los Legionarios/diagnóstico , Enfermedad de los Legionarios/inmunología , Masculino , Persona de Mediana Edad , Tipificación Molecular , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/inmunología , Microbiología del AguaRESUMEN
BACKGROUND: Although sarcomas account for only 1% of all solid tumours, patients with sarcomas comprise a larger proportion of patients entering phase I trials, due to the limited number of registered or active drugs for these diseases. To help in patient selection, we evaluated the utility of the predictive Royal Marsden Score which had been derived in carcinoma patients. In addition, we analysed efficacy and toxicity regarding the sarcoma population enrolled in phase I trials. PATIENTS AND METHODS: We used data from a European Database comprising 2182 patients treated in phase I trials in 14 European institutions between 2005 and 2007. RESULTS: One hundred and seventy-eight patients diagnosed with advanced sarcoma or other mesenchymal tumours were identified and accounted for 217 phase I trial participations during the study period. Histological type, class of drug, number of metastatic sites, high serum lactate dehydrogenase activity (LDH), low albumin and high white blood cell count were independent prognostic factors. Poor performance status (PS), liver metastases and high leucocyte count were associated with increased risk of early death. The class of drug used was the strongest predictor of progression-free survival (PFS) duration, inhibitors of angiogenesis and histone deacetylase giving the best results. Poor PS, high serum LDH and low lymphocyte count correlated with shorter PFS. In this heterogeneous population, PFS with investigational agents appeared comparable with that previously published for patients receiving standard treatments beyond first line. CONCLUSION: Prognostic factors in sarcoma patients do not differ from a broader phase I population. Efficacy measures suggest that some patients with sarcoma derive benefit from therapy in this setting which could therefore be considered for patients with no remaining standard therapeutic option.
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Ensayos Clínicos Fase I como Asunto , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/uso terapéutico , Bases de Datos Factuales , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The role of adjuvant radiotherapy (RT) in the management of atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WD-LPS) remains controversial. METHODS: Two hundred eighty-three patients with operable ALT/WD-LPS, no history of previous cancer, chemotherapy (CT) or RT, treated between 1984 and 2011 registered in the Conticabase database were included and described. Overall (OS), progression-free survival (PFS) and time to local relapse (TTLR) were evaluated from the time of first treatment. RESULTS: Three of 20 centers enrolled 58% of the patients. Median age at diagnosis was 61 (range 25-94) years, 147 patients (52%) were males, 222 (78%) patients had their primary tumor located in an extremity while 36 (13%) and 25 (9%) had tumors involving the girdle and the trunk wall, respectively. The median size of primary tumors was 17 cm (range 2-48 cm). Adjuvant RT was given to 132 patients (47%). Patients who received adjuvant RT had larger tumors (P = 0.005), involving more often the distal limbs (P < 0.001). Use of adjuvant RT varied across centers and along the study period. Other characteristics were balanced between the two groups. Median follow-up was 61.7 months. None of the patients developed metastasis during follow-up. The 5-year local relapse-free survival rates were 98.3% versus 80.3% with and without adjuvant RT, respectively (P < 0.001). Once stratified on time period (before/after 2003), adjuvant RT, tumor site and margin status (R0 versus other) were independently associated with TTLR. No OS difference was observed (P = 0.105). CONCLUSION: In this study, adjuvant RT following resection of ALT/WD-LPS was associated with a reduction of LR risk.
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Liposarcoma/mortalidad , Liposarcoma/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Liposarcoma/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/radioterapia , Radioterapia AdyuvanteRESUMEN
BACKGROUND: Early-phase clinical trials (EPCT) represent an important part of innovations in medical oncology and a valuable therapeutic option for patients with metastatic cancers, particularly in the era of precision medicine. Nevertheless, adult patients' participation in oncology clinical trials is low, ranging from 2% to 8% worldwide, with unequal access, and up to 40% risk of early discontinuation in EPCT, mostly due to cancer-related complications. DESIGN: We review the tools and initiatives to increase patients' orientation and access to early phase cancer clinical trials, and to limit early discontinuation. RESULTS: New approaches to optimize the early-phase clinical trial referring process in oncology include automatic trial matching, tools to facilitate the estimation of patients' prognostic and/or to better predict patients' eligibility to clinical trials. Classical and innovative approaches should be associated to double patient recruitment, improve clinical trial enrollment experience and reduce early discontinuation rates. CONCLUSIONS: Whereas EPCT are essential for patients to access the latest medical innovations in oncology, offering the appropriate trial when it is relevant for patients should increase by organizational and technological innovations. The oncologic community will need to closely monitor their performance, portability and simplicity for implementation in daily clinical practice.
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Neoplasias Primarias Secundarias , Neoplasias , Adulto , Humanos , Oncología Médica , Neoplasias/terapia , Selección de Paciente , Medicina de Precisión , Ensayos Clínicos como AsuntoRESUMEN
BACKGROUND: Soft tissue sarcomas (STS) are rare tumours for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS. METHODS: We conducted a single-arm, open-label, multicentre phase II study to assess the efficacy and tolerability of panobinostat given orally, 40 mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate. RESULTS: Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21-79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20 mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anaemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10-35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months. CONCLUSION: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD.
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Antineoplásicos/uso terapéutico , Ácidos Hidroxámicos/uso terapéutico , Indoles/uso terapéutico , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Leiomiosarcoma/tratamiento farmacológico , Leiomiosarcoma/patología , Liposarcoma/tratamiento farmacológico , Liposarcoma/patología , Liposarcoma Mixoide/tratamiento farmacológico , Liposarcoma Mixoide/patología , Masculino , Persona de Mediana Edad , Neoplasias de la Vaina del Nervio/tratamiento farmacológico , Neoplasias de la Vaina del Nervio/patología , Panobinostat , Terapia Recuperativa/métodos , Sarcoma/patología , Sarcoma de Parte Blanda Alveolar/tratamiento farmacológico , Sarcoma de Parte Blanda Alveolar/patología , Sarcoma Estromático Endometrial/tratamiento farmacológico , Sarcoma Estromático Endometrial/patología , Sarcoma Sinovial/tratamiento farmacológico , Sarcoma Sinovial/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells. METHODS: We have designed a 3+3 dose-escalating phase I trial with a fixed dose of MC (50 mg two times daily) plus IM (400 mg per day; 300 and 400 mg two times daily). Enrolled patients had IM- and sutininib-refractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). Dose-limiting toxicities were monitored for the first 6 weeks. Progression-free survival (PFS) and response assessment are based on RECIST 1.0 guidelines. Pharmacokinetics of IM were measured before and after exposure to MC. RESULTS: No dose-limiting toxicity was observed. Fourteen patients of the expanded cohort received 400 mg two times daily of IM with MC. Apart from a case of possibly related acute leukaemia occurring after 4 years of treatment, we did not see unexpected toxicity. No drug-drug pharmacokinetic interaction was observed. There was no objective response. We have observed long-lasting stable disease in chordoma patients (median PFS=10.2 months; range, 4.2-18+) and short-term stable disease in heavily GIST pretreated patients (median PFS=2.3 months; range, 2.1-6.6). CONCLUSION: This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Benzamidas/administración & dosificación , Ciclofosfamida/administración & dosificación , Neoplasias/tratamiento farmacológico , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Administración Metronómica , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Cordoma/tratamiento farmacológico , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Estudios de Factibilidad , Femenino , Neoplasias Gastrointestinales/tratamiento farmacológico , Humanos , Mesilato de Imatinib , Masculino , Dosis Máxima Tolerada , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Piperazinas/efectos adversos , Piperazinas/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Neoplasias Cutáneas/tratamiento farmacológicoAsunto(s)
Aminopiridinas/uso terapéutico , Tumores de Células Gigantes/tratamiento farmacológico , Factor Estimulante de Colonias de Macrófagos/genética , Pirroles/uso terapéutico , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Membrana Sinovial/efectos de los fármacos , Translocación Genética , Femenino , Tumores de Células Gigantes/genética , Tumores de Células Gigantes/patología , Humanos , Persona de Mediana Edad , Pronóstico , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Inducción de Remisión , Membrana Sinovial/metabolismo , Membrana Sinovial/patologíaRESUMEN
BACKGROUND: Pre-clinical data have suggested a therapeutic role of Hedgehog (Hh) pathway inhibitors in chondrosarcoma. METHODS: This phase II trial included patients with progressive advanced chondrosarcoma. They received GDC-0449 150 mg/day (days 1-28, 28-day cycle). The primary end point was the 6-month clinical benefit rate (CBR) defined as the proportion of patients with non-progressive disease at 6 months. A 6-month CBR of 40% was considered as a reasonable objective to claim drug efficacy. RESULTS: Between February 2011 and February 2012, 45 patients were included. Twenty had received prior chemotherapy. Thirty-nine were assessable for efficacy. The 6-month CBR was 25.6% (95% confidence interval 13.0-42.1). All stable patients had grade 1 or 2 conventional chondrosarcoma with documented progression within the 6 months before inclusion. All but one with available data also had overexpression of the Hh ligand. Median progression-free and overall survivals were 3.5 and 12.4 months, respectively. The most frequent adverse events were grade 1 or 2 myalgia, dysgeusia and alopecia. CONCLUSIONS: GDC-0449 did not meet the primary end point of this trial. Results suggest some activity in a subset of patients with progressive grade 1 or 2 conventional chondrosarcoma. Further studies assessing its role in combination with chemotherapy are warranted. CLINICALTRIALSGOV IDENTIFIER: NCT01267955.
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Anilidas/administración & dosificación , Condrosarcoma/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Proteínas Hedgehog/biosíntesis , Piridinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Condrosarcoma/genética , Condrosarcoma/patología , Supervivencia sin Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Femenino , Francia , Regulación Neoplásica de la Expresión Génica , Proteínas Hedgehog/genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Epstein-Barr virus (EBV) is known to establish latent infections in B-lymphocytes that can cause lymphoproliferative disorders particularly in immunocompromised patients. More recently, the development of rare EBV-associated smooth muscle tumors has been reported in transplant recipients. We herein describe 2 new cases of EBV-associated post-transplant smooth muscle tumors (EBV-PTSMT), including the first in a facial composite tissue graft recipient. Among the striking features shared by these 2 patients were their young ages, the fact that they were naïve for EBV before the transplantation, that they developed a post-transplant lymphoproliferative disorder before the diagnosis of EBV-PTSMT, and that they responded favorably to reduction of immunosuppression. Radiological and histologic features of EBV-PTSMT are shown. Finally, pathophysiology and therapeutic management of EBV-PTSMT are discussed based on a comprehensive review of the literature.
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Infecciones por Virus de Epstein-Barr/diagnóstico , Trasplante Facial/efectos adversos , Trasplante de Hígado/efectos adversos , Complicaciones Posoperatorias/diagnóstico , Tumor de Músculo Liso/diagnóstico , Adulto , Aloinjertos , Infecciones por Virus de Epstein-Barr/etiología , Infecciones por Virus de Epstein-Barr/terapia , Infecciones por Virus de Epstein-Barr/virología , Femenino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Huésped Inmunocomprometido , Terapia de Inmunosupresión/efectos adversos , Lactante , Linfoma de Células B/diagnóstico , Linfoma de Células B/etiología , Linfoma de Células B/terapia , Masculino , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/terapia , Tumor de Músculo Liso/etiología , Tumor de Músculo Liso/terapia , Tumor de Músculo Liso/virologíaRESUMEN
In the context of the recent re-emergence of mpox worldwide, the French Society for Hospital Hygiene (SF2H) performed a literature review of the transmission paths and proposed specific recommendations for healthcare workers (HCWs) caring for patients with suspected or confirmed MPXV. In developed countries, the risk of contamination among HCWs in healthcare facilities seemed to be very low, limited to contamination through needle stick injuries. Two additional contamination cases were reported and not fully explained. Beyond healthcare settings, the analysis of the literature highlighted (i) a main contamination route during sexual intercourse, mainly among men who have sex with men, and (ii) a very low secondary attack rate in other contexts, such as schools or jails. Numerous studies have reported molecular or virus identification on surfaces or in the air surrounding patients, without any association with the low secondary case incidence; moreover, the minimum infectious dose through air or mucosal exposure is still unknown. Owing to the lack of evidence of MPXV respiratory transmission in the healthcare setting, the SF2H recommends the implementation of standard and contact precautions combined with medical/surgical mask use. Owing to the lack of evidence of transcutaneous contamination, the SF2H recommends the use of gloves only if contact with cutaneous lesions or mucous membranes occurs. Regarding the risk of contamination from the environment in healthcare facilities, additional studies must be conducted to investigate this.
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Mpox , Minorías Sexuales y de Género , Masculino , Humanos , Homosexualidad Masculina , Personal de Salud , Hospitales , HigieneRESUMEN
BACKGROUND: Notch signaling plays an integral role in development and tissue homeostasis. Inhibition of Notch signaling has been identified as a reasonable target for oncotherapy. Crenigacestat (LY3039478) is a potent Notch inhibitor that decreases Notch signaling and its downstream biologic effects. METHODS: I6F-MC-JJCD was a multicenter, nonrandomized, open-label, phase 1b study with 5 separate, parallel dose escalations in patients with advanced or metastatic cancer from a variety of solid tumors followed by a dose-confirmation phase in pre-specified tumor types. This manuscript reports on 2 of 5 groups. The primary objective was to determine the recommended phase 2 dose of crenigacestat combined with other anticancer agents (gemcitabine/cisplatin or gemcitabine/carboplatin). Secondary objectives included evaluation of safety, tolerability, preliminary efficacy, and pharmacokinetics. RESULTS: Patients (N = 31) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 6 patients. The recommended phase 2 dose for crenigacestat was 50 mg TIW in Part 1 (combined with gemcitabine/cisplatin) and not established in Part 2 (combined with gemcitabine/carboplatin) due to poor tolerability. Patients had at least one treatment-emergent adverse event (TEAE), and most had Grade ≥ 3 TEAEs. Over 50% of the patients experienced gastrointestinal disorders (Grade ≥ 3). No patient had complete response; 5 patients had a partial response. Disease control rates were 62.5% (Part 1) and 60.0% (Part 2). CONCLUSION: This study demonstrated that the Notch inhibitor, crenigacestat, combined with different anticancer agents (gemcitabine, cisplatin, and carboplatin) was poorly tolerated and resulted in disappointing clinical activity in patients with advanced or metastatic solid tumors. CLINICALTRIALS: gov Identification Number: NCT02784795.