PubMed | Mount Vernon Hospital, University Hospitals Leuven, University of New South Wales, University of Edinburgh and 8 more.
Type: Journal Article | Journal: Targeted oncology | Year: 2016
Olaparib is poorly soluble, requiring advanced drug delivery technologies for adequate bioavailability. Sixteen capsules/day are required for the approved 400mg twice-daily dose; a tablet formulation was developed to reduce pill burden. This clinical trial evaluated the optimal dose and administration schedule of the tablet formulation.Two stages of sequentially enrolled cohorts: stage 1, pharmacokinetic properties of tablet and capsule formulations were compared in patients with advanced solid tumours; stage 2, tablet dose escalation with expansion cohorts at doses/schedules of interest in patients with solid tumours and BRCAm breast/ovarian cancers.Olaparib 200mg tablets displayed similar Cmax,ss, but lower AUCss and Cmin,ss than 400mg capsules. Following multiple dosing, steady-state exposure with tablets 300mg matched or exceeded that of 400mg capsules. After dose escalation, while 400mg twice daily was the tablet maximum tolerated dose based on haematological toxicity, 65% of patients in the randomized expansion phase eventually required dose reduction to 300mg. Intermittent tablet administration did not significantly improve tolerability. Tumour shrinkage was similar for 300 and 400mg tablet and 400mg capsule cohorts.The recommended monotherapy dose of olaparib tablet for Phase III trials was 300mg twice daily, simplifying drug administration from 16 capsules to four tablets per day.NCT00777582 (ClinicalTrials.gov).
PubMed | Imperial College London, University of Manchester, University of Western Australia, University Paris - Sud and 5 more.
Type: Journal Article | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016
Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients.The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined.Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21-84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by 80% from baseline. Minor responses were observed in a patient with melanoma (-26%) and three patients with mesothelioma (-13%, -15%, and -17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6).GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.
PubMed | University of Liverpool, Weston Park Hospital, Guys and St Thomas NHS Foundation Trust, University of Nottingham and 6 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017
LBA4004 Background: GV1001, a promiscuous class II epitope encompassing aa 611-626 of hTERT led to the development of CD4+ clones recognizing hTERT in patients with advanced pancreatic cancer (APC). Preclinically gemcitabine increases antigen cross-presentation, enhances T cell trafficking/activation, and reduces MDSCs and Tregs.Patients with APC were randomized 1:1:1 to: Arm 1 GemCap; 2 GemCap for 8/52 followed by GV1001 followed by further GemCap if no PD at week 8; 3 concurrent administration of GemCap and GV1001. 735 (69.2%) had metastatic disease and 948 (89.3%) had ECOG PS=0 or 1. Randomization was stratified by stage and PS. Primary endpoint was overall survival (OS); secondary endpoints included ORR, TTP, and AEs. Recruitment target was 1,110 patients (780 deaths) to permit detection of a hazard ratio of 0.748 between either GV1001 arm and Arm 1 using a 2-sided =0.025 level of significance with at least 80% power.1,062 pts from 51 centers were randomized. Trial maturity was high (72.7% patients died): median follow-up was 6.11 months. The overall response rates were Arm 1=17.6%; Arm 2=8.9% (p=0.001); Arm 3: 15.5% (p=0.460 compared with Arm 1).OS with concurrent GemCap/GV1001 was not different to that with GemCap alone. OS with sequential GV1001 was not statistically different to GemCap alone as it did not meet the criterion for statistical significance (p<0.0175). The addition of a T helper epitope vaccine to GemCap did not improve outcome compared to GemCap alone.43482138. [Table: see text].
PubMed | Universitair Ziekenhuis Antwerpen, The Royal Marsden and Institute of Cancer Research, Herlev and Gentofte Hospital, Copenhagen University and 11 more.
Type: | Journal: Clinical therapeutics | Year: 2016
The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA-mutated ovarian cancer, is mediated by cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses.Two Phase I, open-label, non-randomized trials were conducted in patients with advanced solid tumors. In Study 7, patients received olaparib alone and co-administered with itraconazole; in Study 8, a separate group of patients received olaparib alone and co-administered with rifampin. No interaction between itraconazole and olaparib was concluded if two-sided 90% CIs for the treatment ratios of AUC and/or AUCIn Study 7 (N = 59; 17 male, 42 female), 56 and 53 patients were evaluable for PK analysis following treatment with olaparib alone and olaparib plus itraconazole, respectively; in Study 8 (N = 22; 4 male, 18 female), all patients were evaluable. Co-administration of olaparib with itraconazole resulted in a statistically significant increase in the relative bioavailability of olaparib: CExposure to olaparib was significantly increased when co-administered with the potent CYP3A4 inhibitor itraconazole, and significantly decreased when co-administered with the potent CYP3A4 inducer rifampin, compared with olaparib alone. Potent CYP3A4 enzyme inhibitors and inducers should be avoided during olaparib treatment. ClinicalTrials.gov identifiers: NCT01900028 (Study 7) and NCT01929603 (Study 8).
Langley R.E.,MRC Clinical Trials Unit |
Stephens R.J.,MRC Clinical Trials Unit |
Nankivell M.,MRC Clinical Trials Unit |
Pugh C.,MRC Clinical Trials Unit |
And 7 more authors.
Clinical Oncology | Year: 2013
Aims: Over 30% of patients with non-small cell lung cancer (NSCLC) develop brain metastases. If inoperable, optimal supportive care (OSC), including steroids, and whole brain radiotherapy (WBRT) are generally considered to be standard care, although there is no randomised evidence demonstrating that the addition of WBRT to OSC improves survival or quality of life. Materials and methods: QUARTZ is a randomised, non-inferiority, phase III trial comparing OSC + WBRT versus OSC in patients with inoperable brain metastases from NSCLC. The primary outcome measure is quality-adjusted life years (QALYs). QUARTZ was threatened with both loss of funding and early closure due to poor accrual. A lack of preliminary randomised data supporting the trial's hypotheses was thought to underlie the poor accrual, so, with no knowledge of the data, the independent trial steering committee agreed to the unusual step of releasing interim data. Results: Between March 2007 and April 2010, 151 (of the planned 534) patients were randomised (75 OSC + WBRT, 76 OSC). Participants' baseline demographics included median age 67 years (interquartile range 62-73), 60% male, 50% with a Karnofsky performance status <70; steroid usage was similar in the two groups; 64/75 (85%) received WBRT (20 Gy in five fractions). Median survival was: OSC + WBRT 49 days (95% confidence interval 39-61), OSC 51 days (95% confidence interval 27-57) - hazard ratio 1.11 (95% confidence interval 0.80-1.53) in favour of WBRT. Quality of life assessed using EQ-5D showed no evidence of a difference. The estimated mean QALYs was: OSC + WBRT 31 days and OSC 30 days, difference -1 day (95% confidence interval -12.0 to +13.2 days). Conclusion: These interim data indicate no early evidence of detriment to quality of life, overall survival or QALYs for patients allocated to OSC alone. They provide key information for discussing the trial with patients and strengthen the argument for continuing QUARTZ to definitively answer this important clinical question. © 2012 The Royal College of Radiologists.
Plummer R.,Northern Center for Cancer Care |
Stephens P.,Northern Center for Cancer Care |
Aissat-Daudigny L.,Teva Laboratories France |
Cambois A.,Cephalon France |
And 3 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2014
Purpose: Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme important in DNA repair. PARP-1 activation at points of DNA strand break results in poly(ADP-ribose) polymer formation, opening the DNA structure, and allowing access of other repair enzymes. CEP-9722 inhibits PARP-1 and PARP-2 and is designed to potentiate DNA-damaging chemotherapies. Methods: This dose-escalating phase 1 study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics/pharmacodynamics of CEP-9722 plus temozolomide in adults with solid tumors. Tumor response was also assessed. Participants received a 14-day cycle of CEP-9722 (days 1 and 3-5 or days 1-5), followed by 28-day cycles of CEP-9722 plus temozolomide 150 mg/m2 on days 1-5. The initial CEP-9722 dose (cohort 1) was 150 mg/day; dose escalation followed a modified Fibonnaci sequence. Results: Twenty-six patients received CEP-9722 150-1,000 mg/day combined with temozolomide. Dose-limiting toxicities of asthenia and persistent weight loss at 1,000 mg/day resulted in 750 mg/day being defined as the MTD and recommended dose for further study. Overall, 24 (92 %) patients had treatment-related adverse events (TRAEs), mostly grade 1 or 2, with nausea, vomiting, and diarrhea having the strongest relation to CEP-9722. Four patients had grade 3 TRAEs (asthenia, myositis, diarrhea, and fatigue). Systemic exposure generally increased with dosage, with high inter- and intra-patient variability at all doses. Pharmacodynamic assessment confirmed PARP inhibition although no dose response was apparent. One patient with melanoma achieved a partial response (1,000 mg/day). Conclusions: CEP-9722 was adequately tolerated with temozolomide; the MTD was 750 mg/day. Only limited clinical activity was observed. © 2014 The Author(s).
Waddell T.,Royal Marsden NHS Foundation Trust |
Chau I.,Royal Marsden NHS Foundation Trust |
Cunningham D.,Royal Marsden NHS Foundation Trust |
Gonzalez D.,Royal Marsden NHS Foundation Trust |
And 17 more authors.
The Lancet Oncology | Year: 2013
Background: EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. Methods: In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 and capecitabine 1250 mg/m2 per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m2 and oxaliplatin 100 mg/m2 on day 1, capecitabine 1000 mg/m2 per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. Findings: Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11·3 months (95% CI 9·6-13·0) compared with 8·8 months (7·7-9·8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1·37, 95% CI 1·07-1·76; p=0·013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥3 neutropenia 35 [13%] vs 74 [28%]). Interpretation: Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. Funding: Amgen, UK National Institute for Health Research Biomedical Research Centre. © 2013 Elsevier Ltd.
Mahadevan D.,Arizona Cancer Center |
Plummer R.,Northern Center for Cancer Care |
Squires M.S.,Astex |
Rensvold D.,Arizona Cancer Center |
And 8 more authors.
Annals of Oncology | Year: 2011
Background: AT7519 is an inhibitor of multiple cyclin-dependent kinases (CDKs). Based on potent antitumor activity in preclinical models, a first-in-human clinical trial in refractory solid tumors investigated its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD). Patients and methods: AT7519 was administered in a '3 + 3' dose- escalation scheme on 5 consecutive days every 3 weeks to patients with advanced, refractory solid tumors. Samples to monitor AT7519 PK and PD were obtained. Results: Twenty-eight patients were treated at seven dose levels (1.8-40 mg/m 2/day). At 40 mg/m 2/day, one patient developed hypotension and ST segment elevation. At 34 mg/m 2/day, dose-limiting toxic effects (DLTs) were QTc prolongation with one death (grade 5), fatigue (grade 4) and mucositis (grade 3). Electrocardiogram review suggested a dose-dependent increase in QTc and recruitment was discontinued without establishing a maximum tolerated dose. Four patients exhibited stable disease for >6 months and one had a prolonged partial response. PK profile revealed modest interpatient variation with linear exposure at increasing doses. Inhibition of markers of CDK activity was observed across the dose range and manifested in antiproliferative activity at a dose of 28 mg/m 2. Conclusion: AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
Patterson J.M.,Northumbria University |
McColl E.,Northumbria University |
Carding P.N.,Freeman Hospital |
Hildreth A.J.,Northumbria University |
And 2 more authors.
Head and Neck | Year: 2014
Background. This prospective study evaluated swallowing outcomes prechemoradiotherapy (pre-CRT) up to 1 year post-CRT, in a substantial cohort of patients with head and neck cancer and explored factors predicting outcome. Methods. One hundred twelve patients were assessed pretreatment and at 3, 6, and 12 months posttreatment using a questionnaire, endoscopic assessment, water swallow test, and diet score. Results. Seventy-one patients were retained, the majority had oropharyngeal (53%) or hypopharyngeal cancer (20%). A marked deterioration occurred between pretreatment and 3 months posttreatment (p ≤.01). Significant improvement between 3 and 12 months was found on 2 swallowing measures, but not self reported. Three of the 4 pretreatment assessments predicted outcomes at 1 year. Conclusion. CRT results in a marked deterioration on different paradigms of swallowing measurements. Improvement occurs on some clinical measures, but limited change is observed in patients' perceptions. Pretreatment measures are important indicators of long-term dysphagia. Swallowing recovery is complex, taking different courses between clinical tests and perspectives. © 2013 Wiley Periodicals, Inc.
Loo H.W.,Northern Center for Cancer Care |
Locks S.M.,Northern Center for Cancer Care
British Journal of Radiology | Year: 2010
We report a case of congenital abnormality of bicornuate bicollis uterus in a patient who developed FIGO (International Federation of Gynecology and Obstetrics) stage IIB invasive carcinoma of the cervix in 2006. She was managed with radical concurrent chemoradiotherapy using an external photon beam of 50 Gy in 25 fractions and a weekly infusion of cisplatin, followed by low dose rate intracavity brachytherapy of 18 Gy to Manchester point A over two fractions. Intra-uterine afterloading brachytherapy catheters were inserted into both uterine cavities. Treatment was well tolerated with manageable acute toxicities. Complete response was achieved with therapy. The patient remains well on follow up with no clinical evidence of disease recurrence two years after initial treatment. © 2010 The British Institute of Radiology.