Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer.

Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer.

Baseline Results of the West London lung cancer screening pilot study - Impact of mobile scanners and dual risk model utilisation.

Objectives: The West London lung screening pilot aimed to identify early-stage lung cancer by targeting low-dose CT (LDCT) to high risk participants. Successful implementation of screening requires maximising participant uptake and identifying those at highest risk. As well as reporting pre-specified baseline screening metrics, additional objectives were to 1) compare participant uptake between a mobile and hospital-based CT scanner and 2) evaluate the impact on cancer detection using two lung cancer risk models.

Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours.

Background: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]).

Patients And Methods: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry.

Multidisciplinary interventions in a specialist Drug Development Unit to improve family history documentation and onward referral of patients with advanced cancer to cancer genetics services.

Background: Molecular aberrations in cancer may represent therapeutic targets, and, if arising from the germline, may impact further cancer risk management in patients and their blood relatives. Annually, 600-700 patients are referred for consideration of experimental drug trials in the Drug Development Unit (DDU) in our institution. A proportion of patients may merit germline genetic testing because of suspicious personal/family history or findings of tumour-based testing.

Clinical outcomes of adolescents and young adults with advanced solid tumours participating in phase I trials.

Background: Adolescent and young adult (AYA) patients with advanced solid tumours are often considered for phase I clinical trials with novel agents. The outcome of AYAs in these trials have not been described before.

Aim: To study the outcome of AYA patients in phase I clinical trials.

The role of genomic profiling in adolescents and young adults (AYAs) with advanced cancer participating in phase I clinical trials.

Introduction: Adolescents and young adults (AYAs) diagnosed with cancer between ages 15-39 years may harbour germline variants associated with cancer predisposition. Such variants represent putative therapeutic targets, as may somatic variants in the tumour. Germline and tumour molecular profiling is increasingly utilised to facilitate personalisation of cancer treatment in such individuals.

High frequency of radiological differential responses with poly(ADP-Ribose) polymerase (PARP) inhibitor therapy.

Despite impressive clinical activity in patients with germline and mutant cancers, antitumor responses to poly(ADP-Ribose) polymerase (PARP) inhibitors are variable. We set out to assess the rate of intrapatient radiological differential responses (RDR) to PARP inhibitors, its correlation with patient outcomes, and the identification of factors associated with RDR. We retrospectively reviewed all patients with advanced cancers from five early phase PARP inhibitor monotherapy trials.

Phase I clinical trials in patients with advanced non-small cell lung cancer treated within a Drug Development Unit: What have we learnt?

Objectives: Despite advances in novel drug development for patients with advanced non-small cell lung cancer (NSCLC), there are still only a limited number of approved treatments. We therefore evaluated the clinical outcomes of patients with advanced NSCLC referred to a dedicated phase I clinical trials unit assessed baseline clinical factors associated with successful enrollment onto phase I trials.

Material And Methods: We conducted a retrospective study involving patients with advanced NSCLC referred to the Drug Development Unit at the RMH between January 2005 and December 2013.

Baseline clinical predictors of antitumor response to the PARP inhibitor olaparib in germline BRCA1/2 mutated patients with advanced ovarian cancer.

Background: The PARP inhibitor olaparib was recently granted Food and Drug Administration (FDA) accelerated approval in patients with advanced BRCA1/2 mutation ovarian cancer. However, antitumor responses are observed in only approximately 40% of patients and the impact of baseline clinical factors on response to treatment remains unclear. Although platinum sensitivity has been suggested as a marker of response to PARP inhibitors, patients with platinum-resistant disease still respond to olaparib.

Clinical factors of response in patients with advanced ovarian cancer participating in early phase clinical trials.

Drug resistance to conventional anticancer therapies is almost inevitable in patients with advanced ovarian cancer (AOC), limiting their available treatment options. Novel phase I trial therapies within a dedicated drug development unit may represent a viable alternative; however, there is currently little evidence for patient outcomes in such patients. To address this, we undertook a retrospective review of patients with AOC allocated to phase I trials in the Drug Development Unit at Royal Marsden Hospital (RMH) between June 1998 and October 2010.

Trabectedin as a chemotherapy option for patients with BRCA deficiency.

Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin has a unique multi-faceted mechanism of action that involves transcription regulation and DNA repair systems, including transcription-coupled nucleotide excision repair and homologous recombination repair (HRR) as the main hallmarks of its antiproliferative activity.

Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation.

PI3K plays a key role in cellular metabolism and cancer. Using a mass spectrometry-based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines, and phosphatidylcholines, were decreased in mice bearing PTEN-deficient tumors compared with non-tumor-bearing controls and in addition were increased following dosing with class I PI3K inhibitor pictilisib (GDC-0941). These candidate metabolomics biomarkers were evaluated in a phase I dose-escalation clinical trial of pictilisib.

Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial.

Background: Angiogenesis is a validated clinical target in advanced epithelial ovarian cancer. Cediranib is an oral antiangiogenic vascular endothelial growth factor receptor 1-3 inhibitor that has shown antitumour activity in recurrent ovarian cancer. We assessed efficacy and safety of cediranib in combination with platinum-based chemotherapy and as continued maintenance treatment in patients with first relapse of platinum-sensitive ovarian cancer.

A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies.

Background: The kinase activity of mTOR involves 2 multiprotein complexes, (mTORC1-mTORC2). Targeting mTORC1 with rapalogues induces compensatory feedback loops resulting in AKT/ERK activation, which may be abrogated by mTORC2 inhibition. A first-in-human trial evaluating tolerability, pharmacokinetics and pharmacodynamics of the dual TORC1/TORC2 inhibitor OSI-027 was conducted.

Venous thromboembolism at time of diagnosis of ovarian cancer: Survival differs in symptomatic and asymptomatic cases.

Objectives: To determine the impact on survival of symptomatic and asymptomatic venous thromboembolism (VTE) at time of diagnosis of primary ovarian malignancy.

Materials And Methods: The clinical records of 397 consecutive cases of primary ovarian malignancy were studied. Clinical, pathological and survival data were obtained.

First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.

Purpose: This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K).

Patients And Methods: Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue.

Dose-response relationship in phase i clinical trials: a European Drug Development Network (EDDN) Collaboration Study.

Introduction: Because a dose-response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.

Phase I study of intermittent oral dosing of the insulin-like growth factor-1 and insulin receptors inhibitor OSI-906 in patients with advanced solid tumors.

Purpose: We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors.

Experimental Design: This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 [schedule (S) 1, days 1-3 every 14 days; S2, days 1-5 every 14 days; S3, days 1-7 every 14 days]. A fed-fasting expansion cohort was included in the study.

Defining dose-limiting toxicity for phase 1 trials of molecularly targeted agents: results of a DLT-TARGETT international survey.

Introduction: It is increasingly clear that definitions of dose-limiting toxicity (DLT) established for phase 1 trials of cytotoxic agents are not suitable for molecularly targeted agents because of specific toxicity profiles. An international survey collected expertise on the definition of DLT, as part of an initiative aimed at presenting new guidelines for phase 1 trials of targeted agents.

Methods: A 15-question survey was sent to corresponding authors of phase 1 reports.

Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents--dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies, an European Organisation for Research and Treatment of Cancer-led study.

Introduction: Traditional dose-limiting toxicity (DLT) definition, which uses grade (G) 3-4 toxicity data from cycle 1 (C1) only, may not be appropriate for molecularly targeted agents (MTAs) of prolonged administration, for which late or lower grade toxicities also deserve attention.

Patients And Methods: In collaboration with pharmaceutical companies and academia, an European Organisation for Research and Treatment of Cancer (EORTC)-led initiative, Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies (DLT-TARGETT), collected data from completed phase 1 trials evaluating MTAs as monotherapy. All toxicities at least possibly related to the study drugs that occurred during C1-6, their type, grade (CTCAEv3.

Phase I trials in patients with relapsed, advanced upper gastrointestinal carcinomas: experience in a specialist unit.

Background: Conventional therapeutic options for patients with advanced upper gastrointestinal cancers (UGIC) are limited. Following first-line treatments, some patients are offered experimental therapies, including participation in Phase I trials. This study aims to describe the experience of UGIC patients treated in a dedicated Phase I unit.

Efficacy of chemotherapy in BRCA1/2 mutation carrier ovarian cancer in the setting of PARP inhibitor resistance: a multi-institutional study.

Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.

Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more.

The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial.

Background: Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib.

Meeting the challenge of ascites in ovarian cancer: new avenues for therapy and research.

Malignant ascites presents a considerable clinical challenge to the management of ovarian cancer, but also provides a wealth of opportunities for translational research. The accessibility of ascitic fluid and its cellular components make it an excellent source of tumour tissue for the investigation of prognostic and predictive biomarkers, pharmacodynamic markers and for molecular profiling analysis. In this Opinion article, we discuss recent advances in our understanding of its pathophysiology, the development of new methods to characterize its molecular features and how these findings can be used to improve the treatment of malignant ascites, particularly in the context of ovarian cancer.