Abstract：
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.
journal_name
Br J Cancerjournal_title
British journal of cancerauthors
van Bussel MTJ,Awada A,de Jonge MJA,Mau-Sørensen M,Nielsen D,Schöffski P,Verheul HMW,Sarholz B,Berghoff K,El Bawab S,Kuipers M,Damstrup L,Diaz-Padilla I,Schellens JHMdoi
10.1038/s41416-020-01151-6subject
Has Abstractpub_date
2020-11-24 00:00:00eissn
0007-0920issn
1532-1827pii
10.1038/s41416-020-01151-6pub_type
杂志文章abstract：:In the BUPA Study, a prospective study of 22,000 men attending a screening centre in London, serum samples were collected and stored. The concentration of beta-carotene was measured in the stored serum samples from 271 men who were subsequently notified as having cancer and from 533 unaffected controls, matched for ag...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1988.97
更新日期：1988-04-01 00:00:00
abstract：:Helicobacter has been suggested to play a possible role in hepatitis, gallstones, and hepatobiliary tumours. We assessed whether seropositivity to 15 H. pylori proteins was associated with subsequent incidence of 74 biliary tract and 105 liver cancer cases vs. 357 matched controls in the Prostate, Lung, Colorectal, an...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/s41416-020-0961-0
更新日期：2020-09-01 00:00:00
abstract：BACKGROUND:In 2006, the National Health Service Bowel Cancer Screening Programme in England (NHSBCSP) began offering routine population-based biennial faecal occult blood testing (FOBt) at ages 60-69. There is, however, limited information on how characteristics of individuals affect participation and outcomes of scree...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2015.69
更新日期：2015-04-28 00:00:00
abstract：:The hypothesis is advanced that abnormalities of the chromosome group 17,18 play a special role in the genesis and/or evolution of some reticuloendothelial neoplasms. Aberrations of the group 17,18 chromosomes in tumour cells exceed in variety the reported anomaliesof any other chromosome. Both the frequency of these ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1970.11
更新日期：1970-03-01 00:00:00
abstract：:The prognostic value of C-reactive protein, compared with ECOG performance status (ECOG-ps), in patients receiving alpha-interferon treatment for advanced renal cancer was assessed in 58 patients. In all, 55 patients died on follow-up. On multivariate analysis with ECOG-ps and C-reactive protein entered as covariates,...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章
doi：10.1038/sj.bjc.6602152
更新日期：2004-10-04 00:00:00
abstract：:Activation of Met by its ligand HGF has been shown to elicit both mitogenic and motogenic responses in thyrocytes in vitro. In the present study we have investigated the expression of Met in human anaplastic thyroid carcinoma cells in culture. There was a variation in expression level and size of Met in the different ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6690406
更新日期：1999-05-01 00:00:00
abstract：BACKGROUND:The co-chaperone protein Bcl-2-associated athanogene-1 (BAG-1) is overexpressed in breast cancer and has been incorporated in the oncotype DX and PAM50 breast cancer prognostic assays. Bcl-2-associated athanogene-1 exists as multiple protein isoforms that interact with diverse partners, including chaperones ...
journal_title：British journal of cancer
pub_type： 杂志文章,meta分析,评审
doi：10.1038/bjc.2017.130
更新日期：2017-06-06 00:00:00
abstract：:The large numbers of papillary thyroid carcinomas that have occurred in those exposed to high levels of short-lived isotopes in fallout after Chernobyl provide a unique opportunity to correlate latency and tumour biology. We show that short latency is associated with tumours with a phenotype that is significantly less...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6601860
更新日期：2004-06-01 00:00:00
abstract：:Recombinant adeno-associated virus (rAAV) vectors have emerged as vehicles for gene therapy. In addition, anti-neoplastic properties have been attributed to wild-type AAV. To take advantage of both features and to overcome technical problems associated with rAAV preparation, we developed a production method in which r...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1054/bjoc.2001.2082
更新日期：2001-11-16 00:00:00
abstract：BACKGROUND:The risk and prognosis of ovarian cancer have not been well established in women with endometriosis. Thus, we investigated the impact of endometriosis on the risk and prognosis for ovarian cancer, and evaluated clinicopathologic characteristics of endometriosis-associated ovarian cancer (EAOC) in comparison ...
journal_title：British journal of cancer
pub_type： 杂志文章,meta分析
doi：10.1038/bjc.2014.29
更新日期：2014-04-02 00:00:00
abstract：:The aim of this paper was to provide epidemiological evidence to support the notion that cervical intraepithelial neoplasia (CIN) without human papillomavirus (HPV) is a true entity. If a diagnosis of HPV-negative cervical neoplasia is erroneous, one would not expect there to be any differences in risk factors between...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1996.146
更新日期：1996-03-01 00:00:00
abstract：:The development of resistance to vincristine, actinomycin D and cisplatin has been examined in a human epidermoid lung carcinoma xenograft line (HXL 55) growing in nude mice. Treatment of HXL 55 with 1 mg kg-1 vincristine or 0.5 mg kg-1 actinomycin D once in each in vivo passage resulted in a rapid reduction in tumour...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1988.155
更新日期：1988-07-01 00:00:00
abstract：BACKGROUND:Necdin (NDN) expression is downregulated in telomerase-immortalised normal human urothelial cells. Telomerase-immortalised normal human urothelial cells have no detected genetic alterations. Accordingly, many of the genes whose expression is altered following immortalisation are those for which epigenetic si...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2013.104
更新日期：2013-04-02 00:00:00
abstract：:Broad-spectrum neuropeptide growth factor antagonists, such as [D-Arg1, D-Phe5, D-Trp7,9, Leu11]substance P (antagonist D) and [Arg6, D-Trp7,9, NmePhe8]substance P(6-11) (antagonist G), are currently being investigated as possible anti-tumour agents. These compounds are hoped to be effective against neuropeptide-drive...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1996.126
更新日期：1996-03-01 00:00:00
abstract：:Plasma concentrations of certain hormones linked to breast cancer risk were measured in age-pooled samples from 3,250 rural Chinese women in 65 counties, and 300 British women, all aged 35-64. In age-groups 35-44, 45-54 and 55-64 respectively, mean oestradiol concentrations were 36% (P = 0.043), 90% (P less than 0.001...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1990.344
更新日期：1990-10-01 00:00:00
abstract：:Serum concentrations of oestradiol-17β were measured by radio-immunoassay during 40 menstrual cycles from 38 normal premenopausal women. Repeated samples were studied from 25 normal postmenopausal women. The method was highly specific and extremely sensitive. In premenopausal women the pattern of serum oestradiol-17β ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1974.98
更新日期：1974-06-01 00:00:00
abstract：:Astrocytomas develop intense vascular proliferation, essential for tumour growth and invasiveness. Angiotensin II (ANGII) was initially described as a vasoconstrictor; recent studies have shown its participation in cellular proliferation, vascularisation, and apoptosis. We conducted a prospective study to evaluate the...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6604431
更新日期：2008-07-08 00:00:00
abstract：:This paper illustrates the efficacy of DNA vaccination through electroporation in the prevention of oral transplantable carcinoma in Syrian hamsters. At 21 and 7 days before tumour challenge, 19 hamsters were vaccinated with plasmids coding for the extracellular and transmembrane domains of rat HER-2 receptor (EC-TM p...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6602853
更新日期：2005-11-28 00:00:00
abstract：:Large primary breast tumours and extensive lymph node involvement are linked to a high rate of local recurrence after surgery. In 10-20% of such high-risk breast cancer patients, local relapse will occur despite postoperative radiotherapy. In the present study, we investigated whether molecular features, such as angio...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章
doi：10.1038/sj.bjc.6600755
更新日期：2003-03-10 00:00:00
abstract：:The co-injection of extracellular matrix components, such as Matrigel, with human tumour cells into nude mice has been reported to facilitate tumour formation and growth, but it is unknown whether such components exert similar effects on tumour progression and metastasis. Metastatic behaviour is known to be enhanced w...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1994.284
更新日期：1994-08-01 00:00:00
abstract：:DNA flow cytometry was performed on formalin fixed, paraffin embedded melanocytic naevi. DNA aneuploidy was detected in all three types of naevus but was significantly more frequent in those naevi accepted as precursors of malignancy: that is, dysplastic and congenital pigmented hairy naevi. It may be that the presenc...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1988.268
更新日期：1988-11-01 00:00:00
abstract：:Rhizoxin is a tubulin-binding anti-neoplastic agent which is active in a range of murine tumour models. The recommended schedule, of intravenous (i.v.) bolus administration at a dose of 2 mg m-2 every 3 weeks, has been assessed in three phase II trials of ovarian, renal and colorectal cancer. In general terms the drug...
journal_title：British journal of cancer
pub_type： 临床试验,杂志文章
doi：10.1038/bjc.1995.498
更新日期：1995-11-01 00:00:00
abstract：:The Second Meeting of the British Society for Immunology Tumour Immunology Affinity Group (TIAG) took place at King's College (London, UK) on 17-18 June 1997 and brought together over 100 tumour immunologists from the UK and abroad. In contrast to previous meetings the focus of the meeting was on the role of adhesion ...
journal_title：British journal of cancer
pub_type： 杂志文章,评审
doi：10.1038/bjc.1998.300
更新日期：1998-06-01 00:00:00
abstract：:Germline mutations in the LKB1 (STK11) gene (chromosome sub-band 19p13.3) cause characteristic hamartomas and pigmentation to develop in patients with Peutz-Jeghers syndrome. Peutz-Jeghers syndrome carries an overall risk of cancer that may be up to 20 times that of the general population and Peutz-Jeghers patients ar...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/sj.bjc.6690323
更新日期：1999-04-01 00:00:00
abstract：:Accumulating evidence suggests that the p53 gene is a good target for molecular epidemiological studies. We previously reported an association between the presence of p53 mutations and lifetime cigarette consumption. Although over 675 p53 mutations have been reported in lung cancers in the literature thus far, very li...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1998.258
更新日期：1998-05-01 00:00:00
abstract：BACKGROUND:Ovarian cancer is frequently advanced at presentation when treatment is rarely curative. Response to first-line platinum-based chemotherapy significantly influences survival, but clinical response is unpredictable and is frequently limited by the development of drug-resistant disease. METHODS:We used qRT-PC...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.2012.410
更新日期：2012-10-09 00:00:00
abstract：:We have studied the actions of C-1311, an imidazoacridinone analogue with potent in vivo antitumour activity, against a human tumour line (HeLa S3), in an examination of the events associated with the lethality of this agent. Continuous exposures (24 h) induced complete G2 arrest, although the concentration range of t...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1996.550
更新日期：1996-11-01 00:00:00
abstract：BACKGROUND:Erythropoietin-stimulating agents (ESAs) effectively decrease the transfusion requirements of patients with chemotherapy-induced anaemia (CIA). Recent studies indicate that ESAs increase mortality and accelerate tumour progression. The studies also identify a 1.6-fold increased risk of venous thromboembolism...
journal_title：British journal of cancer
pub_type： 杂志文章,多中心研究,随机对照试验
doi：10.1038/bjc.2011.395
更新日期：2011-10-25 00:00:00
abstract：:The results of treating two series of patients with Burkitt's lymphoma are presented in the form of survival curves. The second series shows an improved survival rate which seems to be due to a potentiating effect by potassium iodide on oral cyclophosphamide. So far no reason for this effect has been found. ...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1971.6
更新日期：1971-03-01 00:00:00
abstract：:Forty-two patients with small cell lung cancer were treated with a combination of carboplatin, ifosfamide and etoposide. Vincristine was given on day 14 of each course, the courses being repeated every 28 days for a maximum of six. Thoracic radiotherapy was given 4 weeks after the last course of chemotherapy but no pr...
journal_title：British journal of cancer
pub_type： 杂志文章
doi：10.1038/bjc.1989.228
更新日期：1989-07-01 00:00:00
