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G. Griffiths



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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 - 09:30  |  Author(s): G. Griffiths

      • 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: 1
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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 - 09:30  |  Author(s): G. Griffiths

      • 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

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    P2.24 - Poster Session 2 - Supportive Care (ID 157)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P2.24-025 - Applying the results of the FRAGMATIC trial to real life: longitudinal qualitative study exploring the experiences of patients partcipating in a randomised Phase III clinical trial investigating the effect of FRAGMin Added To standard therapy In lung Cancer (ID 1581)

      09:30 - 09:30  |  Author(s): G. Griffiths

      • Abstract

      Background
      Clinical data suggests low molecular weight heparin (LMWH) may produce a survival benefit when given to cancer patients. Several studies are being conducted in different cancer primaries to explore this hypothesis including FRAGMATIC, which will be presented at the World Lung Conference. The FRAGMATIC trial is an open label multi-centre Phase III randomised controlled trial in patients with lung cancer comparing anticancer treatment according to local practice plus dalteparin (Fragmin®), with anticancer treatment according to local practice alone. The primary outcome measure is overall survival and the secondary outcome measures include; toxicity, VTE-free survival, metastasis-free survival, quality of life, patient experience and cost utility. 2202 patients have been recruited in order to detect an advantage of 5% in overall survival at 1 year (to 30%). Fragmin is given as a daily subcutaneous injection for six months by the patients themselves or a willing partner/ carer. This may raise practical challenges regarding how applicable the results of the main trial will be to clinical practice especially with regard to quality of life and thus compliance. We conducted a longitudinal quality of life study to explore the experiences of patients participating in the FRAGMATIC trial to better inform the patient journey and practicalities of applying results to clinical practice.

      Methods
      Semi-structured interviews were held at up to three time points, with two groups of patients recruited from the intervention (n=4) and control (n=6) arms of the FRAGMATIC trial.A total of twenty interviews were analysed using Interpretative Phenomenological Analysis to identify emergent themes that reflect participants' lived experience. We report data focusing on participant views and experiences of self injection for six months.

      Results
      No discernable difference in quality of life was identified between patients in the control or intervention arm who reported similar experiences of the cancer journey and its treatments. Patients on the intervention arm found daily Fragmin injections to be acceptable and a small consequence of having additional treatment as they saw it. Patients developed processes in order to administer Fragmin at similar times and described adaptive techniques to reduce discomfort and bruising. Minimal training was required to be able to inject Fragmin and few side effects were reported. The most common side effect was stinging which was short lived and bruising around injection sites. Patients reported these events did not impact upon quality of life. Overall, Fragmin was found to be an acceptable intervention, which did not pose any compliance problems.

      Conclusion
      The FRAGMATIC trail will report the impact of daily subcutaneous LMWH on overall survival in lung cancer. In this trial 1100 patients self injected Fragmin or had it administered to them. Based on qualitative interview data, Fragmin injections were well tolerated and the experiences of patients suggest that it would be relatively simple to introduce self-injecting into standard lung cancer therapy should the results of the FRAGMATIC study demonstrate a survival benefit.

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    P3.04 - Poster Session 3 - Tumor Immunology (ID 155)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.04-002 - A phase II trial to assess the safety and immunological activity of Trovax plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma - SKOPOS trial (ID 1837)

      09:30 - 09:30  |  Author(s): G. Griffiths

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) is an incurable and fatal malignancy of the pleural membranes. MPM has a poor prognosis and patients have a median survival of 9-13 months in clinical studies, with above 1,500 cases in the UK per year. No surgical approach has been shown to prolong survival and pemetrexed-cisplatin is now seen as the chemotherapy standard of care in the UK. However it is clear that new therapeutic strategies are urgently needed for MPM. Immunotherapy is potential new treatment approach to be considered in MPM, as the disease has been shown to respond to various immunotherapeutic strategies tested in animal models and early phase clinical trials. TroVax® consists of a highly attenuated vaccinia virus containing the human TAA 5T4 glycoprotein gene under regulatory control of a modified VV promoter, mH5. Velindre NHS Trust and the Wales Cancer Trials Unit (WCTU) have developed the SKOPOS trial to evaluate whether TroVax® is active in the treatment of MPM. SKOPOS is funded by the June Hancock Mesothelioma Research Fund, and the Velindre Cancer Centre Stepping Stones Appeal. Oxford BioMedica (UK) Ltd. is providing TroVax® vaccine free of charge, and also labeling and distribution costs. The trial is sponsored by Velindre NHS Trust, and coordinated by the WCTU.

      Methods
      A UK single centre, single arm, phase II trial. Eligible patients include locally advanced or metastatic, histologically or cytologically proven MPM, WHO performance status 0-1, life expectancy > 6months, at least four weeks since any previous therapy (surgery, radiotherapy). Enrolled patients will be treated with: TroVax® - intramuscular injection, dose 1 x 10[9] TCID ~50~/ml in 1ml, given on Day 1 of weeks 1, 3, 6, 9, 12, 15, 18, 21, 24. Folic Acid - 400μg oral daily from Day 2 of week 3 to Day 2 of week 16 B12 Vitamin – 1000μg intramuscular, Day 2 of weeks 3 and 12 Dexamethasone –4mg BD, Days 2-6 of weeks 4, 7, 10, 13 Pemetrexed - 500 mg/m[2] over 10 min, given on day 3 of weeks 4, 7, 10, 13 Cisplatin - 75mg/m[2] over 1h, given on day 3 of weeks 4, 7, 10, 13 The co-primary endpoints of the trial are i) cellular response to 5T4 and MVA antigens measured by intracellular cytokine staining (ICCS); and ii) antibody response to 5T4 and MVA antigens as measured by ELISA. Secondary outcome measures include safety, progression free survival, objective response rate and overall survival. The sample size was determined using Fleming’s single arm design. The outcome measure is the immune response to the 5T4 antigen. A success in this trial is defined as an increased response (at least a doubling in the 5T4 antibody or T-cell response) from that measured at baseline at any of the six follow-up time points. If an increased response is seen in at least 64% of patients then we will research the vaccine further in this group of patients. Using Fleming’s single-stage design, p1=0.40 and p2=0.64, setting alpha=0.05 (1-sided) and 80% power, 26 participants are required.

      Results
      Not Applicable

      Conclusion
      Not applicable

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    P3.08 - Poster Session 3 - Radiotherapy (ID 199)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P3.08-012 - I-START Trial: A UK phase I/II trial of isotoxic accelerated radiotherapy in locally advanced non-small cell lung cancer (ID 1575)

      09:30 - 09:30  |  Author(s): G. Griffiths

      • Abstract

      Background
      Approximately 35,000 people die from lung cancer each year in the UK, the majority from non-small cell lung cancer (NSCLC). Patients with locally advanced (LA) NSCLC are often not suitable for chemotherapy or combined chemo-radiotherapy treatment because of patient or tumour factors. In these cases radical radiotherapy alone is used. Increased radiation dose may improve both local tumour control and survival. The radiotherapy dose is limited by surrounding organs, which include the lungs, heart, spinal cord and oesophagus. The maximum radiotherapy dose that can safely be delivered to the oesophagus is not known. The I-START trial was therefore developed, on behalf of the UK National Cancer Research Institute Lung Clinical Studies Group, to establish oesophageal radiation dose limits and to investigate the feasibility and effectiveness of a novel approach to dose escalation in LA-NSCLC. The study is funded by Cancer Research UK (C25518/A11535), sponsored by Velindre NHS Trust and coordinated by the Wales Cancer Trials Unit.

      Methods
      Patients with histologically or cytologically confirmed stage II to IIIb NSCLC, suitable for radical radiotherapy, are eligible for the trial. Enrolled patients will receive 20 fractions of radiotherapy over 4 weeks. The trial is split into two phases: Phase I: To establish the maximum tolerated (MTD) dose of radiotherapy to the oesophagus in patients where the oesophagus overlaps with the planning target volume (PTV). Phase I patients will be split into 2 groups depending on the length of the oesophagus lying within the PTV (Group 1A is where the overlap ≤6.5cm and Group 1B is where the overlap >6.5cm). Cohorts of 6 or 12 patients are recruited to both groups at sequentially increasing dose levels (58, 61, 63, 65Gy). Progression to the next oesophageal dose level will depend on the number of patients in a cohort with grade 3 or 4 acute oesophagitis, or other grade 3 or 4 toxicity, occurring up to 2 months after radiotherapy. Once the MTD to the oesophagus is established for each group, all participants will follow the Phase II protocol with the determined oesophageal dose limit. Phase II: Patients will receive a maximum of 65Gy in 20 fractions and the dose prescribed will be the highest dose achievable without exceeding defined safe dose limits for organs at risk. Where the oesophagus does not overlap with the PTV, patients can immediately be treated in Phase II, whereas patients whose oesophagus overlaps with the PTV can only be entered into Phase II once Phase I is complete, i.e. the MTD to the oesophagus has been established. The primary outcome of Phase II is the toxicity rate (grade 3 or 4) at 3 months. The I-START trial will determine whether this novel method of increasing the radiotherapy dose in patients with NSCLC patients is tolerable, safe and effective. If the results are positive, then this new treatment may be compared against the best currently available standard treatment in a future larger randomised (Phase III) trial.

      Results
      Not applicable.

      Conclusion
      Not applicable.