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1.
Br J Cancer ; 124(4): 728-735, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33230210

RESUMEN

BACKGROUND: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity. METHODS: Adult patients with advanced solid tumours received peposertib 100-200 mg once daily or 150-400 mg twice daily (BID) in 21-day cycles. RESULTS: Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median Tmax 1.1-2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3-6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients. CONCLUSIONS: Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing. CLINICAL TRIAL REGISTRATION: NCT02316197.


Asunto(s)
Proteína Quinasa Activada por ADN/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Piridazinas/administración & dosificación , Piridazinas/efectos adversos , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Adulto , Anciano , Proteína Quinasa Activada por ADN/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Piridazinas/farmacocinética , Quinazolinas/farmacocinética
2.
Br J Cancer ; 119(12): 1471-1476, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30425349

RESUMEN

BACKGROUND: This phase Ib study evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of pimasertib (MSC1936369B), a MEK1/2 inhibitor, in combination with voxtalisib (SAR245409), a pan-PI3K and mTORC1/mTORC2 inhibitor, in patients with advanced solid tumours. METHODS: This study included a dose escalation and expansion in patients with select tumour types and alterations in the MAPK or PI3K pathways. A 3 + 3 design was used to determine MTD. Patients were evaluated for adverse events and tumour response. RESULTS: 146 patients were treated, including 63 in dose escalation and 83 in expansion. The MTD was pimasertib 90 mg and voxtalisib 70 mg daily. Based on the safety profile, the recommended phase 2 dose (RP2D) was pimasertib 60 mg and voxtalisib 70 mg. The most frequent treatment-emergent adverse events (TEAEs) were diarrhoea (75%), fatigue (57%), and nausea (50%). Responses included a complete response in one patient (1%), partial response in five (5%), and stable disease in 51 (46%). At the RP2D, 74 patients required dose interruption (73%), 20 required dose reduction (20%), and 26 discontinued treatment due to TEAEs (26%). CONCLUSIONS: The combination of pimasertib and voxtalisib showed poor long-term tolerability and limited anti-tumour activity in patients with advanced solid tumours.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Niacinamida/análogos & derivados , Inhibidores de las Quinasa Fosfoinosítidos-3 , Quinoxalinas/administración & dosificación , Sulfonamidas/administración & dosificación , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Niacinamida/farmacocinética , Quinoxalinas/efectos adversos , Quinoxalinas/farmacocinética , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética
3.
Eur J Cancer ; 183: 24-37, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36796234

RESUMEN

INTRODUCTION: We report long-term efficacy and overall survival (OS) results from a randomised, double-blind, phase 2 study (NCT02022098) investigating xevinapant plus standard-of-care chemoradiotherapy (CRT) vs. placebo plus CRT in 96 patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). METHODS: Patients were randomised 1:1 to xevinapant 200 mg/day (days 1-14 of a 21-day cycle for 3 cycles), or matched placebo, plus CRT (cisplatin 100 mg/m2 every 3 weeks for 3 cycles plus conventional fractionated high-dose intensity-modulated radiotherapy [70 Gy/35 F, 2 Gy/F, 5 days/week for 7 weeks]). Locoregional control, progression-free survival, and duration of response after 3 years, long-term safety, and 5-year OS were assessed. RESULTS: The risk of locoregional failure was reduced by 54% for xevinapant plus CRT vs. placebo plus CRT but did not reach statistical significance (adjusted hazard ratio [HR] 0.46; 95% CI, 0.19-1.13; P = .0893). The risk of death or disease progression was reduced by 67% for xevinapant plus CRT (adjusted HR 0.33; 95% CI, 0.17-0.67; P = .0019). The risk of death was approximately halved in the xevinapant arm compared with placebo (adjusted HR 0.47; 95% CI, 0.27-0.84; P = .0101). OS was prolonged with xevinapant plus CRT vs. placebo plus CRT; median OS not reached (95% CI, 40.3-not evaluable) vs. 36.1 months (95% CI, 21.8-46.7). Incidence of late-onset grade ≥3 toxicities was similar across arms. CONCLUSIONS: In this randomised phase 2 study of 96 patients, xevinapant plus CRT demonstrated superior efficacy benefits, including markedly improved 5-year survival in patients with unresected LA SCCHN.


Asunto(s)
Antineoplásicos , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Estudios de Seguimiento , Antineoplásicos/uso terapéutico , Cisplatino , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
4.
Int J Gynecol Cancer ; 22(6): 979-86, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22694911

RESUMEN

BACKGROUND: Preclinical data show that belinostat (Bel) is synergistic with carboplatin and paclitaxel in ovarian cancer. To further evaluate the clinical activity of belinostat, carboplatin, and paclitaxel (BelCaP), a phase 1b/2 study was performed, with an exploratory phase 2 expansion planned specifically for women with recurrent epithelial ovarian cancer (EOC). METHODS: Thirty-five women were treated on the phase 2 expansion cohort. BelCap was given as follows: belinostat, 1000 mg/m² daily for 5 days with carboplatin, AUC 5; and paclitaxel, 175 mg/m² given on day 3 of a 21-day cycle. The primary end point was overall response rate (ORR), using a Simon 2 stage design. RESULTS: The median age was 60 years (range, 39-80 years), and patients had received a median of 3 prior regimens (range, 1-4). Fifty-four percent had received more than two prior platinum-based combinations, sixteen patients (46%) had primary platinum-resistant disease, whereas 19 patients (54%) recurred within 6 months of their most recent platinum treatment. The median number of cycles of BelCaP administered was 6 (range, 1-23). Three patients had a complete response, and 12 had a partial response, for an ORR of 43% (95% confidence interval, 26%-61%). When stratified by primary platinum status, the ORR was 44% among resistant patients and 63% among sensitive patients. The most common drug-related adverse events related to BelCaP were nausea (83%), fatigue (74%), vomiting (63%), alopecia (57%), and diarrhea (37%). With a median follow-up of 4 months (range, 0-23.3 months), 6-month progression-free survival is 48% (95% confidence interval, 31%-66%). Median overall survival was not reached during study follow-up. CONCLUSIONS: Belinostat, carboplatin, and paclitaxel combined was reasonably well tolerated and demonstrated clinical benefit in heavily-pretreated patients with EOC. The addition of belinostat to this platinum-based regimen represents a novel approach to EOC therapy and warrants further exploration.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Ácidos Hidroxámicos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Fitogénicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Paclitaxel/uso terapéutico , Sulfonamidas
5.
Nat Rev Clin Oncol ; 13(10): 627-42, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27245279

RESUMEN

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/radioterapia , Hipoxia de la Célula/efectos de la radiación , Ensayos Clínicos como Asunto/métodos , Terapia Combinada , Aprobación de Drogas , Humanos , Neoplasias/tratamiento farmacológico , Educación del Paciente como Asunto , Participación del Paciente , Garantía de la Calidad de Atención de Salud , Calidad de la Atención de Salud , Dosis de Radiación , Tolerancia a Radiación/efectos de la radiación , Resultado del Tratamiento
6.
Anticancer Res ; 32(9): 4019-23, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22993353

RESUMEN

AIM: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of concurrent chemoradiotherapy and cetuximab in patients with non-resectable locally advanced esophageal cancer. PATIENTS AND METHODS: Escalating doses of oxaliplatin every second week and daily tegafur/uracil were given concurrently with radiotherapy, 59.4 Gy in 33 fractions. Cetuximab was given on day 15 (400 mg/m(2)) and weekly (250 mg/m(2)) during radiotherapy. Fixed doses of oxaliplatin (130 mg/m(2)) and tegafur/uracil (300 mg/m(2)) were administered before, and after radiotherapy. RESULTS: Eleven patients were included in the study; two were excluded due to allergic reactions to cetuximab. In DL2 (tegafur/uracil 300 mg/m(2), oxaliplatin 30 mg/m(2)) two grade 3/4 fistula and one grade 3 neuropathy were observed. Six patients were enrolled in DL1 (tegafur/uracil 150 mg/m(2)/, oxaliplatin 30 mg/m(2)) with no DLTs. Four out of 9 patients had complete response. CONCLUSION: Concomitant chemoradiotherapy and cetuximab had significant activity. DL1 was established as the MTD.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/radioterapia , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Cetuximab , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Tegafur/administración & dosificación , Tegafur/efectos adversos , Uracilo/administración & dosificación , Uracilo/efectos adversos
7.
Cancer ; 112(7): 1600-6, 2008 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-18300265

RESUMEN

BACKGROUND: The purpose was to evaluate prevention of oral mucositis (OM) using chlorhexidine compared with placebo and with oral cooling (cryotherapy) during fluorouracil (5-FU)-based chemotherapy in gastrointestinal (GI) cancer. METHODS: Patients with previously untreated GI cancer receiving bolus 5-FU/leucovorin chemotherapy were randomized to chlorhexidine mouthrinse 3 times a day for 3 weeks (Arm A), double-blind placebo (normal saline) with the same dose and frequency (Arm B), or cryotherapy with crushed ice 45 minutes during chemotherapy (Arm C). Patients self-reported on severity (CTC-grading) and duration of OM. RESULTS: Among 225 patients randomized, 206 answered the questionnaire (70, 64, and 63 patients in Arms A, B, and C, respectively) and were well balanced with respect to diagnoses, stage, age, sex, smoking habits, and performance status. Mucositis grade 3-4 occurred more frequently in Arm B (33%) than in A (13%, P< .01) and C (11%, P< .005). Duration was significantly longer in B than in both A (P= .035) and C (P= .003). CONCLUSIONS: The frequency and duration of OM are significantly improved by prophylactic chlorhexidine and by cryotherapy. The latter is easy and inexpensive but has limited use, as it is drug- and schedule-dependent. The current study is the first double-blind randomized evaluation of prophylactic chlorhexidine in a large adult patient population with solid tumors receiving highly OM-inducing chemotherapy. A role for chlorhexidine in the prevention of OM is suggested, which should be evaluated further.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhexidina/uso terapéutico , Crioterapia , Fluorouracilo/efectos adversos , Neoplasias Gastrointestinales/tratamiento farmacológico , Antisépticos Bucales/uso terapéutico , Estomatitis/terapia , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Método Doble Ciego , Femenino , Neoplasias Gastrointestinales/patología , Humanos , Hielo , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Estomatitis/inducido químicamente , Resultado del Tratamiento
8.
J Cell Biochem ; 96(2): 412-27, 2005 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-16075456

RESUMEN

Overexpression or expression of activating mutations of the epidermal growth factor receptor (EGFR) is common in cancer and correlates with neoplastic progression. The present study employed Affymetrix oligonucleotide arrays to profile genes induced by ligand-activated EGFR with the receptor either moderately expressed or overexpressed at an in-itself transforming level. These changes were compared to those induced by the naturally occurring constitutively active variant EGFRvIII. This study provides novel insight on the activities and mechanisms of EGFRvIII and EGFR mediated transformation, as genes encoding proteins with functions in promoting cell proliferation, invasion, antiapoptosis, and angiogenesis featured prominently in the EGFRvIII- and EGFR-expressing cells. Surprisingly, it was found that ligand-activated EGFR induced the expression of a large group of genes known to be inducible by interferons. Expression of this module was absent in the EGFRvIII-expressing cell line and the parental cell line. Treatment with the specific EGFR inhibitor AG1478 indicated that the regulations were primary, receptor-mediated events. Furthermore, activation of this module correlated with activation of STAT1 and STAT3. The results thus demonstrate that ligand-activated EGFR at different expression levels results in different kinetics of signaling and induction of gene expression. In addition, the constitutively active variant EGFRvIII seems to activate only a subset of signal pathways and induce a subset of genes as compared to the ligand-activated EGFR.


Asunto(s)
Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulación de la Expresión Génica/genética , Mutación/genética , Transcripción Genética/genética , Animales , Línea Celular , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Fibroblastos , Perfilación de la Expresión Génica , Humanos , Ligandos , ARN Mensajero/genética , Transducción de Señal , Transactivadores/genética , Transactivadores/metabolismo
9.
Int J Cancer ; 97(1): 7-14, 2002 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-11774237

RESUMEN

In the present study we transfected the epidermal growth factor receptor (EGFR)-negative small cell lung cancer cell line, GLC3, with the type III EGFR mutation (EGFRvIII). The EGFRvIII protein could be detected by Western blot analysis as a 145-kDa protein, which by immunohistochemistry appeared to be localized at the cell surface. Ultrastructurally EGFRvIII was expressed mainly at the cell surface with clusters at cell-cell contacts. In the in vitro invasion assay, GLC3-EGFRvIII cells had a approximately 5-fold increased invasion compared with uninduced GLC3-EGFRvIII, GLC3-Tet-On and the parental cell line. GLC3-Tet-On appeared uniform in size with adherence junctions at cell-cell contacts. In uninduced GLC3-EGFRvIII cells adherence junctions were also present but less distinct. In doxycycline-pretreated GLC3-EGFRvIII cells, adherence junctions were absent. We conclude that the expression of EGFRvIII results in a more malignant phenotype. This effect appears to involve the disruption of adherence junctions.


Asunto(s)
Carcinoma de Células Pequeñas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutación , Antibacterianos/farmacología , Western Blotting , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/patología , Comunicación Celular , Colágeno/química , Cartilla de ADN/química , Doxiciclina/farmacología , Combinación de Medicamentos , Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Laminina/química , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Microscopía Electrónica , Invasividad Neoplásica , Proteoglicanos/química , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección , Células Tumorales Cultivadas
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