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D. Fennell



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    MO09 - Mesothelioma I (ID 120)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track:
    • Presentations: 1
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      MO09.02 - A Randomised Phase II trial of Pegylated Arginine Deiminase in patients with Malignant Pleural Mesothelioma (ID 1355)

      16:15 - 17:45  |  Author(s): D. Fennell

      • Abstract
      • Presentation
      • Slides

      Background
      Preclinically, arginine deprivation has shown activity as a novel antimetabolite strategy for MPM patients who are deficient for the rate-limiting enzyme in arginine biosynthesis argininosuccinate synthetase (ASS1). Here, we examine the efficacy and safety of the arginine-lowering agent ADI-PEG20 (Polaris Group, San Diego, US) among patients with MPM.

      Methods
      We performed a multicentre randomised phase II clinical trial, based on patients with good performance status (0 or 1), non-resectable disease, ASS1-deficient MPM, and measurable disease. Patients were randomized 1:2 to receive best supportive care (BSC) or BSC+ADI-PEG20, stratified by: gender, histology (sarcomatoid versus non-sarcomatoid), prior treatment (chemonaive or previous platinum combination therapy), and centre. The primary endpoint, progression-free survival (PFS), is assessed by modified RECIST, and secondary endpoints include overall survival, tumor response rate, and toxicity. Translational endpoints included measurement of plasma arginine, citrulline and ADI-PEG20 antibody levels, assessment of metabolic response by [18F]Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and ASS1 methylation status using Illumina’s 450K DNA methylation array. The target sample size was estimated to detect a PFS hazard ratio of 0.60. [Trial funded by Cancer Research UK].

      Results
      ASS1 deficiency was detected in 98 of 214 patients (46%) of which 68 were randomized on the trial (44 ADI-PEG20+BSC and 24 BSC alone). 66 patients have progressed so far (42 ADI-PEG20+BSC vs. 24 BSC alone), and 32 patients were alive (23 ADI-PEG20+BSC vs. 9 BSC alone). The hazard ratio for PFS was 0.53 (95%, CI 0.31 to 0.90, p=0.02) with a median PFS of 98 days for patients randomized to ADI-PEG20+BSC compared with 59 days for patients receiving BSC alone. ADI-PEG20 toxicity in patients with MPM has been consistent with previous trials of ADI-PEG20 in melanoma and liver cancer: commonly skin injection site reactions (grade 1-2), infrequent episodes of neutropenia (range: grade 1-4), anaphylactoid reactions (2 patients with grade 3 episodes) and serum sickness (1 patient). The best response by modified RECIST was stable disease. Metabolic responses (in 39 evaluable ADI-treated patients) were as follows: 46% with partial response (18/39), 31% with stable disease (12/39), 15% progressive metabolic disease (6/39) and 8% mixed metabolic response (3/39) by FDG-PET assessment. There was a significant difference between IHC assessed ASS1-negative and ASS1-positive patients and the methylation status of the ASS1 gene (p=0.025).

      Conclusion
      ADI-PEG20 is generally well tolerated and shows evidence of clinically significant activity in patients selected for arginine-dependent MPM demonstrating differential methylation of ASS1. Arginine deprivation may have a role in the future management of MPM either alone or in combination with selected therapies.

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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.02 - Association between Gene Expression Profiles and Clinical Outcome of Pemetrexed-Based Treatment in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer: Exploratory Results from a Phase II Study (ID 185)

      10:30 - 12:00  |  Author(s): D. Fennell

      • Abstract
      • Presentation
      • Slides

      Background
      We report exploratory gene expression profiling data from a prospective single-arm Phase-II-study in patients with non-squamous non-small cell lung cancer (nsNSCLC) treated with pemetrexed. Main results indicated a significant association of low thymidylate-synthase (TS) expression with longer PFS and OS [1].

      Methods
      Treatment-naive nsNSCLC patients (Stage IIIB/IV) received 4 cycles of first-line pemetrexed/cisplatin; non-progressing patients continued on pemetrexed maintenance [1]. Diagnostic tissue samples were used to assess TS expression (nucleus/cytoplasm) by immunohistochemistry (IHC, H scores), and to extract total mRNA for expression-array profiling (expression of 1,030 genes summarized from 60,000 transcripts). Cox proportional-hazard models were applied to explore the association between each gene and PFS/OS, mRNA gene expression was used both as continuous and binary (cutpoint: median) variable. Unadjusted p-values (significance level =0.01) and false discovery rates (FDR) were calculated. Genes significantly correlated with PFS/OS were further correlated with TS-protein expression (Spearman rank test). Finally, unsupervised clustering was applied to all samples with mRNA expression (n=51) for all 1,030 selected array genes and an overlapping 870-gene subset associated with adenocarcinoma (ADC, n=47) previously described [2].

      Results
      51/70 (72.9%) biopsies were evaluable; 9 of 1,030 genes were significantly associated with PFS/OS (unadjusted p<0.01). 8/9 genes were negatively correlated with nuclear TS expression; the test was statistically significant for 5/8 genes (unadjusted p<0.01, Table 1). None of these genes has a known relationship to folate metabolism. Cluster analysis of all 51 samples based on 1,030 genes revealed no clear trend regarding PFS/OS. Cluster-analysis of 47 ADC samples identified 3 groups (n=21, 11 and 15 patients, respectively) with median (95%CI) PFS and OS of 8.1 (6.9, not estimable [NE]) and 20.3 (17.5, N.E) months; 2.4 (1.2, NE) and 4.3 (1.4, NE) months; and 4.4 (1.2, NE) and 8.3 (3.9, NE) months, respectively. Figure 1

      Conclusion
      This exploratory analysis provides insights on key genes potentially linked to low TS expression. Nine genes were significantly associated with PFS/OS; however such association cannot be differentiated as prognostic or predictive since this study is single arm. Further research would be needed to understand the relationship of these markers with clinical outcomes. [1] Nicolson et al, J Thorac Oncol 2013, May 29 [Epub]. [2] Wilkerson et al, PLoS One 2012;7(5):e36530.

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    O03 - NSCLC - Targeted Therapies I (ID 113)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O03.01 - GALAXY-1: Randomized phase II study of docetaxel with or without ganetespib in advanced lung adenocarcinoma: Results in biomarker sub-groups and all adenocarcinoma patients. (ID 1715)

      10:30 - 12:00  |  Author(s): D. Fennell

      • Abstract
      • Presentation
      • Slides

      Background
      Ganetespib (G) is a highly potent 2[nd]-generation Hsp90 inhibitor showing synergistic activity with docetaxel (D) in NSCLC xenografts. G has a favorable clinical safety profile and has shown single-agent clinical activity in NSCLC patients with tumors harboring EML4-ALK translocations and KRAS mutations (mKRAS).

      Methods
      We conducted a randomized, international open-label Phase 2 study of D with or without G in patients with advanced lung adenocarcinoma, one prior systemic therapy, and ECOG PS 0/1. D was given at 75 mg/m[2] on Day 1 of a three-week cycle in both arms. In the combination arm, G was given at 150 mg/m[2] on Days 1 and 15. The co-primary endpoints were PFS in patients with elevated LDH (eLDH) levels, or tumors harboring KRAS mutation. Key secondary endpoints were OS and PFS in all adenocarcinoma patients. Target enrollment was 240 adenocarcinoma patients, including 120 eLDH and 80 mKRAS patients. The study was initiated in all NSCLC patients and amended to include only those with adenocarcinoma histology.

      Results
      Enrollment of 252 adenocarcinoma patients completed in November 2012; enrollment of eLDH (total N=112) and mKRAS (total N= 86) patients completed in May 2013. In all adenocarcinoma patients (N=252), baseline characteristics were balanced between the two arms (median age 60 years, males 56%, PS 0 41% and never-smokers 25%). Median numbers of cycles delivered were 6 and 4 for D+G and D, respectively. Grade 3/4 adverse events for the D+G and D alone arms were: neutropenia 37% vs. 38%; fatigue 6% vs. 3%; anemia 8% vs. 2%; diarrhea 3% vs. 0; fever with neutropenia 11% vs. 2%. A pre-specified analysis was conducted in May 2013. PFS HR for eLDH population (N=76) was 0.88 (90% CI: 0.57, 1.36, p=0.310); OS HR was 0.63 (90% CI: 0.40, 0.99, p=0.046). PFS HR for mKRAS population (N=63) was 0.83 (90% CI: 0.51, 1.37, p=0.271); and OS HR was 0.85 (90% CI: 0.48, 1.50, p=0.313). OS HR in the all adenocarcinoma population was 0.82 (90% CI: 0.62, 1.09, p=0.082), and the PFS HR was 0.84 (90% CI: 0.65, 1.07, p=0.038). For patients that were enrolled >6 months after diagnosis of advanced NSCLC (N=176), a pre-specified stratification factor, the OS HR was 0.61 (90% CI: 0.43, 0.87, p=0.0093), and the PFS HR was 0.61 (90% CI: 0.45, 0.83, p=0.0041). Final data analysis is expected by end of September 2013. Updated PFS and OS results for all populations will be presented at the meeting.

      Conclusion
      Survival improvement was noted in all adenocarcinoma patients with the addition of ganetespib to docetaxel. The maximal benefit was achieved in patients with eLDH and those diagnosed with advanced NSCLC >6 months prior to study entry.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-055 - The RON (MST1R)/MSP pathway is a potential therapeutic target in malignant plural mesothelioma (ID 3250)

      09:30 - 16:30  |  Author(s): D. Fennell

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer. Treatment options are limited and drug resistance is common. Thus, there is a need to identify novel therapeutic targets in this disease in order to improve treatment options and survival times. Macrophage stimulating protein (MSP) is the only ligand recognised to bind to the RON receptor (MST1R). RON is a member of the MET proto-oncogene family. The MSP-RON signalling pathway has been implicated in a variety of cellular functions such as macrophage morphogenesis and phagocytosis. De-regulation of this pathway has been linked to tumour progression and metastasis in a number of cancers. We have previously identified RON as frequently activated in MPM and high positivity for RON by IHC was an independent predictor of favourable prognosis.

      Methods
      A panel of mesothelioma cell lines were screened for the expression of MSP and RON at the mRNA (RT-PCR) and protein (Western blot) level. The effect of MSP, IMC-RON8 (a humanised IgG1 monoclonal antibody), LCRF004 (a small molecule inhibitor) and NRWHE (a small peptide) was examined in the H226 cell line using proliferation (BrdU ELISA), apoptosis (Multi-parameter apoptosis assay) and migration assays (xCELLigence). A phospho-kinase proteome profiler array was utilised to detect the downstream signalling pathways activated upon MSP stimulation. The expression of MSP and the macrophage marker, CD-68, was examined by IHC using MPM TMAs. Studies are ongoing to determine the effect of the LCRF004 compound in vivo using a xenograft murine model with the H226 cells.

      Results
      The mRNA and protein levels of RON and MSP were differentially expressed in a panel of MPM cell lines. Treatment with LCRF004 resulted in significantly decreased proliferation and increased apoptosis in the H226 cells. MSP was unable to rescue the cells from the effects of LCRF004. NRWHE and RON8 had little effect on either proliferation or apoptosis. All of the compounds examined inhibited the migration capacity of the H226 cells. The combination of LCRF004 and MSP produced a synergistic effect, showing greater inhibition of migration than either compound alone. However, MSP treatment resulted in the up-regulation of a number of phosphor-kinases including Akt, ERK and the Src family. Currently, a number of proteins identified in the array studies are undergoing validation. Results of an in vivo H226 murine model using the LCRF004 compound will be presented at the meeting.

      Conclusion
      From previous work performed in this laboratory, we have determined that high expression of RON in MPM is an independent predictor of favourable prognosis. IHC was performed on a TMA of MPM patient samples and high expression levels of MSP correlated with better survival. There was no association between CD68 staining and MSP, nor correlation of CD68 expression with survival. Targeting the RTK domain of the RON receptor with a small molecule inhibitor is an effective interventional strategy in MPM. The seemingly counter intuitive results obtained from the MPM TMA studies and the in vitro experimental data, may be RON isoform dependant. Additional studies are ongoing to further delineate the RON-MSP axis in MPM.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-013 - A randomised phase II trial of Olaparib maintenance versus placebo monotherapy in patients with chemosensitive advanced non-small cell lung cancer (NSCLC) (ID 1375)

      09:30 - 16:30  |  Author(s): D. Fennell

      • Abstract

      Background
      In the UK approximately 35,000 people die from lung cancer annually, the majority from NSCLC. Chemotherapy is one of the main treatments for advanced NSCLC but those treated will still only live for an average of 9 or 10 months after diagnosis. Chemotherapy damages tumour cell DNA, and NSCLC tumours that respond to chemotherapy are less able to repair this damage. Olaparib blocks the Poly (ADP-ribose) polymerase (PARP) enzyme which is essential for DNA repair. It is hypothesized that if DNA repair is prevented then this will cause cancer cell death. The UK National Cancer Research Institute Lung Clinical Studies Group, as part of the National Cancer Research Network/AstraZeneca initiative, have developed this clinical trial to investigate whether or not giving Olaparib following chemotherapy will benefit patients with NSCLC who have responded to initial chemotherapy treatment by prolonging the time before the tumour re-grows. The study is funded by a research grant from Cancer Research UK (C16728/A14917) and an investigator sponsored grant and free drug from AstraZeneca. The trial is sponsored by Velindre NHS Trust, and coordinated by the Wales Cancer Trials Unit, Cardiff, UK.

      Methods
      A UK multicentre randomised phase II trial. Eligible patients include histological diagnosis of stage IIIB/IV squamous/non-squamous non small cell lung cancer, ECOG PS0-1, age>=18, chemonaive and having given informed consent. Figure 1 Patients are initially registered before induction chemotherapy after which if there is evidence of radiological response (partial or complete) they will be randomised to either Olaparib (300mg po bd q21) until disease progression, or placebo. Those with stable disease or progression will not be eligible for the main trial and will receive local standard treatment. The primary endpoint of the randomised trial is progression-free survival based on RECIST v1.1 with secondary endpoints of safety, tolerability, feasibility of use, response, overall survival and tumour volume reduction. The median PFS for patients with CR/PR after 3 – 4 cycles of induction chemotherapy treatment is expected to be 3 months. With 90% power and a one-sided α of 0.2, 114 participants are required to demonstrate statistical significance between the arms if the true hazard ratio for Olaparib compared to placebo is 0.65, based on the logrank test. We therefore aim to recruit 57 participants into each arm, over a 12 month accrual period, with minimum participant follow-up of at least 6 months. The primary analysis of data will be performed after 98 PFS events.

      Results
      Not applicable

      Conclusion
      Not applicable

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    P2.14 - Poster Session 2 - Mesothelioma (ID 196)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 2
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      P2.14-011 - MesobanK: A UK based bioresource for malignant pleural mesothelioma (ID 1314)

      09:30 - 16:30  |  Author(s): D. Fennell

      • Abstract

      Background
      Availability of quality assured, fully annotated mesothelioma tissue collected to rigorous standard operating procedures will facilitate better understanding of mesothelioma biology. Currently, few bioresources of mesothelioma tissue exist, the largest being the National Mesothelioma Virtual Bank hosted by the University of Pittsburgh (http://www.mesotissue.org/). A few other clinical/research groups hold fresh tissue from small numbers of mesothelioma patients but these collections are not formally linked and often do not involve collection of tissue and data to Standard Operating Procedures. The British Lung Foundation/Mick Knighton Mesothelioma Research Fund has recently funded MesobanK, a UK based bioresource of malignant mesothelioma tissue samples.

      Methods
      Tissue Microarray: MesobanK will construct a tissue microarray (circa 1000 cases) using historical formalin fixed paraffin embedded blocks of tissue taken at thoracoscopy/surgical resection. Inclusion criteria requires sufficient tissue to permit multiple 0.5 mm cores (to allow for tumour heterogeneity) and a clinical minimum data set. Fresh tissue: Fresh frozen mesothelioma tissue (300 cases over 3 years) will be collected prospectively from multiple centres across the UK together with parallel pleural fluid, whole blood, serum and plasma. Each case will have a detailed anonymised linked clinical data set with follow up data. Cell lines: MesobanK plans to create 20 new fully annotated mesothelioma primary cell lines. The bioresource will be supported by a web-based IT infrastructure for annotating and searching the collection. Clinical data will be collected on each case and supplemented by laboratory and pathology results, Hospital Episode Statistics data and UK Cancer Registry data in order to achieve as complete a data set as possible. MesobanK will follow the Guiding Principles laid out by the NCRI Confederation of Cancer Biobanks and the UK Medical Research Council Operational and Ethical Guidelines on Human Tissue and Biological Materials for Use in Research. It will also be managed within the scope of all relevant regulatory frameworks and quality management/quality assurance systems. In addition, we share the aim of the US National Cancer Institute (NCI) National Biospecimen Network Blueprint: to create a comprehensive framework for sharing and comparing research results through a robust, flexible, scalable and secure bioinformatics system that supports the collection, processing, storage, annotation and distribution of biospecimens and data using standard operating procedures based on best practices. A steering committee will have overall control of MesobanK. An independent scientific advisory board will review applications for samples and advise the steering committee. Prioritisation for access to samples will be based solely on scientific merit. All researchers, whether in the UK National Health Service, universities, charities, government agencies or commercial companies, and whether based in the UK or abroad will be subject to the same application process and approval criteria.

      Results
      Not applicable

      Conclusion
      It is anticipated that initial tissue (TMA and cell lines) will be available in 2014.

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      P2.14-013 - A randomised phase II trial of oral vinorelbine as second-line therapy for patients with malignant pleural mesothelioma (MPM) expressing BRAC1 - VIM trial (ID 1937)

      09:30 - 16:30  |  Author(s): D. Fennell

      • Abstract

      Background
      Mesothelioma is increasing worldwide. However there is no approved therapy in the second-line setting. Vinorelbine exhibits promising activity, however there has been no randomised evaluation or validation of biomarkers to support patient stratification. We have recently reported that BRCA-1 is an essential regulator of mesothelioma sensitivity to vinorelbine, and its expression is lost in approximately 38%. The UK National Cancer Research Institute Lung Clinical Studies Group have therefore developed this clinical trial to investigate whether or not giving second-line vinorelbine in addition to active symptom control (ASC) will benefit patients in terms of overall survival. The study is funded by a research grant from Cancer Research UK (CRUK/12/056) and free vinorelbine, labeling and distribution from Pierre Fabre Ltd. The trial is sponsored by Leicester University, and coordinated by the Wales Cancer Trials Unit, Cardiff, UK.

      Methods
      A UK multicentre open-label randomised phase II trial. Eligible patients include histological diagnosis of mesothelioma, received at least one line standard platinum doublet based chemotherapy, age >=18 years, measurable lesions by modified RECIST, radiological evidence of disease progression and informed consent. Patients will be randomised to either control of active symptom control (ASC) or ASC plus vinorelbine using a 1:2 allocation ratio. ASC will be administered as per local practice, continuing follow-up until evidence of radiological progression. Vinorelbine will administered at a dose of 60mg/m[2 ]po od on day 1 (equivalent to 25mg/m[2 ]iv day 1) weekly for 3 weeks for the first cycle, incrementing to 80mg/m[2 ]weekly (equivalent to 30mg/m[2 ]iv) in the absence of haematological toxicity for subsequent cycles. Patients will continue chemotherapy until evidence of radiological progression (or unacceptable toxicity or patient withdrawal). The primary endpoint of the trial is overall survival with secondary endpoints of tolerability, response rate, change in tumour volume and progression-free survival. BRCA1 expression IHC will be evaluated as a stratification factor. The median OS for patients in the control arm is expected to be 1.5 months. With 90% power and a one-sided α of 0.2, 114 participants are required (76 in the vinorelbine arm and 38 in the control arm) to detect a hazard ratio of 0.65, based on the logrank test. The primary analysis of data will be analysed after 111 OS events.

      Results
      not applicable

      Conclusion
      not applicable