Showing papers by "Jonathan A. Ledermann published in 2015"

Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial.

Abstract: Summary Background The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer with the addition of bevacizumab to standard chemotherapy, with the greatest effect in patients at high risk of disease progression. We report the final overall survival results of the trial. Methods ICON7 was an international, phase 3, open-label, randomised trial undertaken at 263 centres in 11 countries across Europe, Canada, Australia and New Zealand. Eligible adult women with newly diagnosed ovarian cancer that was either high-risk early-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage I–IIa, grade 3 or clear cell histology) or more advanced disease (FIGO stage IIb–IV), with an Eastern Cooperative Oncology Group performance status of 0–2, were enrolled and randomly assigned in a 1:1 ratio to standard chemotherapy (six 3-weekly cycles of intravenous carboplatin [AUC 5 or 6] and paclitaxel 175 mg/m 2 of body surface area) or the same chemotherapy regimen plus bevacizumab 7·5 mg per kg bodyweight intravenously every 3 weeks, given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy. Randomisation was done by a minimisation algorithm stratified by FIGO stage, residual disease, interval between surgery and chemotherapy, and Gynecologic Cancer InterGroup group. The primary endpoint was progression-free survival; the study was also powered to detect a difference in overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN91273375. Findings Between Dec 18, 2006, and Feb 16, 2009, 1528 women were enrolled and randomly assigned to receive chemotherapy (n=764) or chemotherapy plus bevacizumab (n=764). Median follow-up at the end of the trial on March 31, 2013, was 48·9 months (IQR 26·6–56·2), at which point 714 patients had died (352 in the chemotherapy group and 362 in the bevacizumab group). Our results showed evidence of non-proportional hazards, so we used the difference in restricted mean survival time as the primary estimate of effect. No overall survival benefit of bevacizumab was recorded (restricted mean survival time 44·6 months [95% CI 43·2–45·9] in the standard chemotherapy group vs 45·5 months [44·2–46·7] in the bevacizumab group; log-rank p=0·85). In an exploratory analysis of a predefined subgroup of 502 patients with poor prognosis disease, 332 (66%) died (174 in the standard chemotherapy group and 158 in the bevacizumab group), and a significant difference in overall survival was noted between women who received bevacizumab plus chemotherapy and those who received chemotherapy alone (restricted mean survival time 34·5 months [95% CI 32·0–37·0] with standard chemotherapy vs 39·3 months [37·0–41·7] with bevacizumab; log-rank p=0·03). However, in non-high-risk patients, the restricted mean survival time did not differ significantly between the two treatment groups (49·7 months [95% CI 48·3–51·1]) in the standard chemotherapy group vs 48·4 months [47·0–49·9] in the bevacizumab group; p=0·20). An updated analysis of progression-free survival showed no difference between treatment groups. During extended follow-up, one further treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated patient), three grade 2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated patients), and one grade 1 treatment-related event (vaginal haemorrhage, in a patient treated with standard chemotherapy) were reported. Interpretation Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, which is concordant with the progression-free survival results from ICON7 and GOG-218, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer. Funding The National Institute for Health Research through the UK National Cancer Research Network, the Medical Research Council, and Roche.

Intermediate clinical endpoints: a bridge between progression-free survival and overall survival in ovarian cancer trials.

Abstract: Ovarian cancer patients are usually diagnosed at an advanced stage, experience recurrence after platinum-based chemotherapy, and eventually develop resistance to chemotherapy. Overall survival (OS), which has improved in recent years as more active treatments have been incorporated into patient care, is regarded as the most clinically relevant endpoint in ovarian cancer trials. However, although there remains a significant need for new treatments that prolong OS further without compromising quality of life, it has become increasingly difficult to detect an OS benefit for investigational treatments because of the use of multiple lines of chemotherapy to treat ovarian cancer. Progression-free survival (PFS), which measures the time to disease progression or death, is unaffected by postprogression therapies but does not evaluate the long-term impact of investigational treatments on tumor biology and responses to future therapies. Recent clinical trials of targeted agents in relapsed ovarian cancer have shown improvements in PFS but not OS, and this is possibly reflective of the long postprogression survival (PPS) period associated with this disease. Intermediate endpoints such as the time to second disease progression or death and the time to second subsequent therapy or death may provide supportive evidence for clinically meaningful PFS improvements and may be used to determine whether these improvements persist beyond the first disease progression and throughout subsequent lines of therapy. For clinical trials that have settings with a long PPS duration and/or involve multiple rounds of postprogression therapy, a primary endpoint of PFS supported by intermediate clinical endpoints and OS may provide a more comprehensive approach for evaluating efficacy.

PARP inhibitors in ovarian cancer: Clinical evidence for informed treatment decisions.

Abstract: Ovarian cancer is the fifth leading cause of female cancer deaths in the Western world. Significant progress has been made in the treatment of patients with ovarian cancer, however, the majority of patients experience disease recurrence and new therapies are being sought for such patients. Clinical investigation of poly(ADP-ribose) polymerase (PARP) inhibitors for ovarian cancer treatment has demonstrated promising activity in this disease. Here, we review the development of PARP inhibitors and their future role in the treatment of patients with ovarian cancer. Studies of olaparib, the first PARP inhibitor to be approved in Europe and the USA, in patients with recurrent ovarian cancer have demonstrated clinical efficacy with improvements in progression-free survival. In maintenance therapy of platinum-sensitive ovarian cancer there is supporting evidence of clinical benefit from exploratory endpoints that include time to first subsequent treatment and time to second subsequent treatment. Adverse events that should be monitored following treatment with PARP inhibitors include nausea, vomiting, fatigue and anaemia. Based on the evidence presented, patients who will receive the greatest benefit from PARP inhibition are those with platinum-sensitive relapsed ovarian cancer and a BRCA mutation.

Multicentre trial of carboplatin/paclitaxel versus oxaliplatin/capecitabine, each with/without bevacizumab, as first line chemotherapy for patients with mucinous epithelial ovarian cancer (mEOC).

Abstract: 5528 Background: Advanced mEOC responds poorly to standard therapy. It comprises < 8% pts in ovarian cancer trials, so it is difficult to examine treatment effects in this subgroup. We conducted th...

European Network of Gynaecological Oncological Trial Groups' Requirements for Trials Between Academic Groups and Industry Partners--First Update 2015.

Abstract: The first version of ENGOT’s Requirements for Trials Between Academic Groups and Industry Partners in Europe was published 2010. This first update integrates the experiences made by the ENGOT network and the cooperative group studies while performing, analyzing, and publishing -among others - three large phase III trials. Furthermore, progress in European legislation and its impact on clinical studies in Europe have been considered in this update process.

An overview of early investigational therapies for chemoresistant ovarian cancer

Abstract: Introduction: Epithelial ovarian cancer (EOC) is the fourth commonest cause of female cancer death in the developed world. Although progress in treatment has improved survival, ∼ 80% of patients with advanced EOC will experience a recurrence and eventually will become resistant to chemotherapy. The aim of treatment for chemoresistant EOC has traditionally been limited to palliation of symptoms but the recent introduction of new therapies targeting molecular pathways is beginning to demonstrate improvements in disease control.Areas covered: This review provides an overview of early investigational drugs for the treatment of ‘platinum-resistant’ EOC. The article is based on English peer-reviewed articles located on MEDLINE and related abstracts presented at major international meetings.Expert opinion: Drugs targeting several pathways are increasingly used to treat ‘platinum-resistant’ EOC. Currently, drugs targeting the angiogenesis pathway have been shown to significantly improve patient outcome. Studies a...

Correction to Lancet Oncol 2014; 15: 856. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial.

Abstract: Topp MS, Göckbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multi-centre, singlearm, phase 2 study. Lancet Oncol 2015; 16: 57–66—In table 2 of this Article, the “MRD response during fi rst two cycles in patients with CR or CRh” row should not have been indented, and should have been the last row in the table. The data in the “Patients” row for “100-day mortality from day of HSCT” should read “··”. In the fourth paragraph of the Results section, the third sentence should read “The overall 100-day mortality after allogeneic HSCT (counting from the day of HSCT after blinatumomab-induced response was 11% (95% CI 0–23)”. These corrections have been made to the online version as of March 30, 2015. Correction to Lancet Oncol 2014; 15: 856

Frequency, severity and timing of common adverse events (AEs) with maintenance olaparib in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR SOC).

Abstract: 5550 Background: Maintenance monotherapy with the PARP inhibitor olaparib prolongs progression-free survival in PSR SOC pts with no adverse impact on HRQoL. BRCAm pts derive greater benefit. Nausea...

New clinical research strategies for rare gynecologic malignancies.

Abstract: Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. PURPOSE OF REVIEW: More than 50% of all gynecologic cancers can be classified as rare tumors (defined as an incidence of < 6 per 100 000) and as such represent a major challenge for clinicians. RECENT FINDINGS: The rapidly increasing number of targeted therapies provides a unique opportunity to improve treatment options of rare gynecologic cancers; however, their low frequency makes it difficult to test these new agents. Harmonization of medical practices and novel trial designs are needed to identify and develop new treatments for rare gynecologic tumors. SUMMARY: This requires international partnerships, harmonization of treatment recommendations, and international collaborations to overcome existing regulatory barriers in international trials. Whereas randomized trials may be possible in some rare tumor types, there are others for which conducting even single arm studies may be challenging. For these very rare tumors, robust collection of data through national registries could lead to improvements in treatment.

Exploratory outcome analyses according to stage and residual disease in the ICON7 trial of front-line carboplatin/paclitaxel (CP) ± bevacizumab (BEV) for ovarian cancer (OC).

Abstract: 5548 Background: In ICON7, progression-free survival (PFS) was significantly improved in patients (pts) receiving BEV with front-line CP and continued as a single agent [Perren 2011] but no overall...

Do Cell-Cycle Phase-Specific Markers Predict Disease Grade, Stage, and Outcome in Cervical Carcinoma?

Abstract: Aims Multiparameter analysis of cell cycle markers has shown a strong relationship between cell cycle progression and tumor grade, stage, and clinical outcome in penile, renal, ovarian, and breast cancers. We sought to link expression of cell cycle phase–specific markers in cervical cancer to tumor grade, stage, and clinical outcome to investigate their potential use as prognostic and predictive markers. Methods Pretreatment biopsy material was obtained from 35 patients with cervical cancer (stage IB2-IVA) and 12 normal cervix control cases. Each patient was treated with neoadjuvant chemotherapy followed by chemoradiation. Immunohistochemical staining was performed using a panel of cell cycle phase markers: replication licensing factors: Mcm2 (minichromosome maintenance 2) and geminin, and the standard proliferation marker Ki67 (clone MIB-1). Results The expression levels of each cell cycle biomarker were very high in all cases of squamous cell carcinoma of the cervix regardless of grade or stage of disease. In our cohort, all cases displayed an aggressive, so-called actively cycling phenotype. Univariate analysis showed that none of the cell cycle biomarkers predicted grade, stage, or clinical outcome. Conclusions Cell cycle phase–specific markers do not appear to predict disease grade, stage, or outcome in our sample of patients with cervical cancer. This is not surprising, given that the expression of each cell cycle biomarker was very high in all cases. Indeed, all the cases of squamous cell carcinoma of the cervix (n = 28) and all but 1 of the adenocarcinomas (n = 7) in this study displayed an aggressive “actively cycling” phenotype. This predominance of actively cycling tumors is unusual and may reflect the viral etiology underlying the disease. These preliminary findings raise many interesting questions including the prognostic value of disease grade and markers of proliferation in cervical tumors as reliable prognostic indicators. Further work on a larger cohort of patients is warranted.

Abstract 611: Exploratory analyses suggest ovarian tumors with somatic or germline loss of function mutations inBRCA1orBRCA2are biologically similar and sensitive to PARP inhibition

Abstract: Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA The PARP inhibitor olaparib (LynparzaTM) elicits responses in ovarian cancer patients with inherited (germline) loss of function mutations in the BRCA1 or BRCA2 genes (gBRCAm). In the tumors of such patients the unmutated (wt) copy of the relevant BRCA gene is usually lost. Many patients are aware of their BRCA mutation status due to the wide availability of blood testing. However, in around a third of ovarian tumors with BRCA mutations the mutation has not been inherited but is tumor-specific (sBRCAm). Given the difference in origin of mutation, it is important to determine whether there are genotypic and phenotypic differences between sBRCAm and gBRCAm ovarian tumors. In a randomized, Phase II trial of 265 patients with platinum-sensitive relapsed serous ovarian cancer ([NCT00753545][1]; Study 19), maintenance treatment with olaparib (400 mg bid; capsules) led to a significant increase in progression-free survival (PFS) vs placebo in patients with a BRCA mutation (HR 0.18; 95% CI 0.10-0.31; P<0.00001). Diagnostic tumor samples from the study were sequenced by Foundation Medicine. After filtering for common polymorphisms, BRCA gene variants were classified using American College of Medical Genetics standards as mutant, wild type or variant of unknown significance (VUS). VUS were further classified on the basis of information from the Breast Information Core database. Mutation origin (g vs s) and zygosity were determined by tumor allele frequency analysis and/or by comparison to germline sequencing, and heterogeneity was determined using the Foundation Medicine SGZ algorithm, which compares allele frequency to model expectations, taking into account tumor purity, ploidy and local copy number. BRCA mutations were found in 53% of the 209 samples with data available. Known germline BRCA mutations were correctly classified as germline by the SGZ algorithm. Tumor BRCA mutations were identified in 40 patients without confirmation of a mutation in a blood sample. Twenty of these patients were classified as sBRCAm (12 BRCA1 and 8 BRCA2) by the algorithm. Only one case was called without loss of the wt BRCA allele. It has been hypothesized that TP53 mutation is an early event and was found to be consistent between tumors and precursor lesions. Allele frequencies/clonality for BRCA and TP53 mutations were comparable and there was no evidence of systematic subclonality in the sBRCAm cases. An exploratory analysis of PFS and overall survival (OS) was performed on the 20 patients (10 received treatment and 10 placebo). Consistent with results from the gBRCAm population, a trend in event rate in favor of treatment over placebo was observed (3/10 vs 8/10 events for PFS and 3/10 vs 7/10 for OS). Although from a small number of patients, data are consistent with sBRCA mutation as an early event in tumorigenesis and support phenotypic similarity of gBRCA and sBRCA mutated tumors. Citation Format: Brian Dougherty, Zhongwu Lai, Jonathan A. Ledermann, Jane D. Robertson, Tony W. Ho, Wenting Wu, Darren R. Hodgson, Maria C M Orr, Mark J. O'Connor, Matthew J. Hawryluk, Timothy A. Brennan, Roman Yelensky, James X. Sun, J Carl Barrett. Exploratory analyses suggest ovarian tumors with somatic or germline loss of function mutations in BRCA1 or BRCA2 are biologically similar and sensitive to PARP inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 611. doi:10.1158/1538-7445.AM2015-611 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00753545&atom=%2Fcanres%2F75%2F15_Supplement%2F611.atom

Genomic characterization of long-term responders to olaparib.

Abstract: 5566 Background: BRCA1/2 mutations (BRCAm) predict benefit from olaparib (vs placebo) in platinum sensitive high grade serous ovarian cancer (HGSOC). However not all patients (pts) with BRCAm respo...

Adjuvant chemotherapy and radiation therapy (RT) versus RT alone for women with high-risk endometrial cancer : Toxicity and quality-of-life results of the randomized PORTEC-3 trial.

Abstract: 5501 Background: PORTEC-3 is an intergroup trial investigating survival improvement with adjuvant chemotherapy given during and after pelvic RT (CTRT) versus RT alone (RT) for women with high-risk ...