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D.A. Fennell

Moderator of

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    MS 17 - Immunotherapy for Mesothelioma (ID 35)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 4
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      MS17.01 - Overview: Immunotherapy in Mesothelioma (ID 1922)

      14:15 - 15:45  |  Author(s): A.K. Nowak

      • Abstract
      • Presentation

      Abstract:
      Immunotherapy has recently confirmed its place as an important treatment strategy for a number of solid tumors, including melanoma and non-small cell lung cancer. Checkpoint blockade, in particular, has emerged as an ‘off-the-shelf’ immunotherapy which does not rely on known tumor antigens, costly and time-consuming individualised preparation of autologous tumor, or viral vectors. This overview will cover the history of immunotherapy in mesothelioma, recent reported clinical trials, trials in progress, and current cutting edge research with the potential for translation. Although mesothelioma is not classically considered immunogenic, there is abundant evidence that it is recognised by the immune system. Earlier studies described the relationship between tumour infiltrating lymphocytes and prognosis, occasional spontaneous remissions are seen, and there have been reports of low rates of responsiveness to a range of immunotherapies over the past 30 years. There is also a body of work demonstrating impaired immune responsiveness in people with mesothelioma and an immunosuppressive intratumoral milieu. Specifically, NK cell activity is reduced, CD4+ lymphocyte numbers are reduced, and dendritic cell function is impaired (Cornwall S, unpublished data), amongst other changes. Regulatory T cells and inhibitory cytokines within the tumour may contribute to an immunosuppressive milieu [1]. The presence of CD8+ infiltration within the tumour is a predictor of more favourable outcomes [2]. More recently, mesothelioma, in particular sarcomatoid subtype, was shown to overexpress PD-L1 and to predict poor prognosis [3] Historically, response rates below 20% have been seen in clinical trials of systemic and intrapleural interferons, generally accompanied by high toxicity [4]. Similarly, other cytokines such as Interleukin-2 or GM-CSF have shown either poor response rates, low feasibility, or excessive toxicity [5]. Gene therapy approaches have similarly shown very low response rates and are technically demanding [6]. More recent trials have focussed on antigen-specific approaches using the known tumor antigens mesothelin and WT-1, and the use of checkpoint blockade. Immunological checkpoints are inbuilt mechanisms that negatively regulate the size and duration of an immune response, both during induction of the T cell response and during the effector phase of the response, in tumor tissue. Their normal function is to prevent excessive and ongoing T cell activation which may lead to overwhelming autoimmunity. Many tumors, including mesothelioma, express ligands for these checkpoint molecules, allowing tumors to negatively regulate the anti-tumor immune response and thus evade elimination [3]. The expression of checkpoint molecules including Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and PD-1 on T cells, and the expression of ligands such as PD-L1 and PD-L2 on tumors, has allowed the development of antibody blockade which can prevent downregulation of the anti-tumor response by inhibitory signals, hence ‘taking off the brakes’ and facilitating a more effective host response to tumor. CTLA4 is expressed on T cells after activation, and counter-regulates the T cell activation which normally occurs when the co-stimulatory receptor CD28 is engaged. Whilst ligation of CTLA4 normally restricts ongoing T cell co-stimulation and activation, abrogating anti-tumour immunity[7], CTLA4 blockade using monoclonal antibody inhibitors can allow the endogenous anti-tumour response to proceed unopposed. The first report of a clinical trial of this drug class in mesothelioma was published by Calabro and colleagues in 2013 [8], with results showing some similarities to the first trials of CTLA4 blocking antibodies in melanoma. Durable partial responses were seen in two patients, with a further seven of 29 patients experiencing prolonged stable disease. The disease control rate was 31%, median progression free survival was 6·1 months, and almost 40% of participants were alive at two years. The phenomenon of early progression followed by a lengthy partial response was seen in one patient. The authors noted that the progression free survival and two year survival results were better than expected for this population, and although partial responses were uncommon they were long lasting. This study provided the rationale for the subsequent testing of tremelimumab in a large randomised phase II study in mesothelioma which has recently completed recruitment (NCT01843374). A recent presentation at the American Association for Cancer Research (AACR) reported on results from the mesothelioma cohort enrolled in the KEYNOTE-028 study. This trial used PD1 axis blockade with pembrolizumab in patients with mesothelioma selected to express the PD-L1 ligand. Of 25 patients treated, partial response was observed in 7 (28%) and stable disease in 12 (48%), giving a disease control rate of 76% with a tolerable toxicity profile. Many of the responses seen were profound and durable[9], highlighting the enormous potential of this approach in mesothelioma. Finally, mesothelin is highly expressed on mesothelioma cells, predominantly of the epithelioid subtype. A number of methods of targeting mesothelin are under development and clinical testing. The anti-mesothelin immunotoxin SS1P has been administered together with lymphodepletion using cyclophosphamide and pentostatin. Major responses were observed in a subset of patients in a small clinical trial (n=10), notably with some reports of immune pseudoprogression before eventual treatment response. Other treatments using mesothelin as a target include CRS-207, a live attenuated listeria monocytogenes strain which expresses mesothelin, and MORAb-009, a monoclonal antibody that targets mesothelin. Immunotherapy in mesothelioma remains very immature. Results of PD1 and/or PD-L1 blockade in larger numbers of treated patients are needed, and phase III studies will be important to define any benefits. Combinations of checkpoint blockade have shown outstanding efficacy in other cancer types and must be tested in mesothelioma. Underpinning these trials must be the search for biomarkers of treatment efficacy. Technologies such as tumor sequencing also have the potential to identify neoantigens with immunological reactivity in individual patients, an approach that could lead to the development of personalised vaccines, potentially in combination with other immunotherapies. References 1. Hegmans, J.P.J.J., et al., Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. European Respiratory Journal, 2006. 27(6): p. 1086-95. 2. Yamada, N., et al., CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother, 2010. 59(10): p. 1543-9. 3. Mansfield, A.S., et al., B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis. J Thorac Oncol, 2014. 9(7): p. 1036-40. 4. Boutin, C., et al., Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma. Cancer, 1994. 74(9): p. 2460-7. 5. Astoul, P., et al., Intrapleural recombinant IL-2 in passive immunotherapy for malignant pleural effusion. Chest, 1993. 103(1): p. 209-13. 6. Schwarzenberger, P., et al., Antitumor activity with the HSV-tk-gene-modified cell line PA-1-STK in malignant mesothelioma. Am J Respir Cell Mol Biol, 1998. 19(2): p. 333-7. 7. Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews. Cancer, 2012. 12(4): p. 252-64. 8. Calabro, L., et al., Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol, 2013. 14(11): p. 1104-11. 9. Alley, E.W., et al., Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028, in Proc Am Assoc Cancer Res. 2015.

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      MS17.02 - Immunotoxins and Mesothelin Antibody (ID 1923)

      14:15 - 15:45  |  Author(s): R. Hassan

      • Abstract
      • Presentation

      Abstract:
      Mesothelin is a tumor differentiation antigen that is highly expressed in several cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. The limited expression of mesothelin on normal human tissue and its high expression in many solid tumors make it an attractive candidate for cancer therapy. Several drugs targeting mesothelin, including immunotoxins (SS1P, RO6927005), a chimeric monoclonal antibody (Amatuximab), an antibody drug conjugate (Anetumab Ravtansine), and a tumor vaccine (CRS-207), are in various stages of development to treat patients with mesothelin-expressing tumors. The first anti-mesothelin therapeutic agent to enter the clinic was the immunotoxin SS1P and it demonstrated that mesothelin could be successfully exploited as a target for cancer therapy and has led to a broad interest in developing different approaches for mesothelin immunotherapy treatment of solid tumors including malignant mesothelioma. Immunotoxins are targeted anti-cancer therapeutics that kill cancer cells by inhibition of protein synthesis using a cytotoxic bacterial toxin payload. In a phase I clinical trial SS1P had limited anti-tumor activity because it was immunogenic and patients develop antibodies to the drug limiting treatment efficacy. However, we have recently shown that co-administration of SS1P with a lymphocyte depleting regimen of pentostatin and cyclophosphamide can delay anti-drug antibody formation, increasing the number of treatment cycles that patients can receive and resulting in durable responses in heavily pre-treated mesothelioma patients. In addition, a new generation of immunotoxin molecules with reduced immunogenicity and non-specific toxicity have been developed through protein engineering techniques. RO6927005 is a next generation anti-mesothelin PE-fusion protein that has been protein-engineered to maximally reduce its immunogenicity so that patients can receive multiple cycles of the drug. In pre-clinical studies RO6927005 has increased activity compared to SS1P against mesothelioma tumor cells directly obtained from patients as well as activity in mesothelioma tumor models either alone or in combination with chemotherapy. A phase I clinical trial of RO6927005 has just been initiated for patients with mesothelin expressing cancers including malignant mesothelioma. There are other antibody based therapeutics in advanced clinical development for treatment of malignant mesothelioma including amatuximab and anetumab ravtansine. In a phase II single arm trial of unresectable, chemotherapy naïve patients with pleural mesothelioma, amatuximab with pemetrexed and cisplatin was well tolerated with objective tumor response or stable disease rate of 90% by independent radiologic review. Based on these results a registration front-line study of amatuximab with pemetrexed and cisplatin versus pemetrexed and cisplatin alone has been initiated for treatment of newly diagnosed patients with pleural mesothelioma. Anetumab Ravtansine (BAY 94-9343) is an antibody-drug conjugate in which a human anti-mesothelin monoclonal antibody is conjugated to the maytansinoid tublin inhibitor DM4. In preclinical studies it showed significant anti-tumor activity against mesothelioma cell lines as well as mesothelioma patient derived xenografts. Anetumab Ravtansine is currently being evaluated in patients with mesothelin expressing cancers who have failed standard therapies and represents a potential therapeutic option for treatment of patients with mesothelioma given the high and uniform expression of mesothelin in this tumor. Hopefully, these different approaches to exploit mesothelin for immunotherapy of malignant mesothelioma will result in new treatment options for these patients.

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      MS17.03 - DC Vaccination (ID 1924)

      14:15 - 15:45  |  Author(s): J.G. Aerts

      • Abstract
      • Presentation
      • Slides

      Abstract:
      In recent years immunotherapy has become a new standard in the treatment of malignant diseases. Most clinical evaluated treatments like anti-PD1 aim to reactivate the cytotoxic T-cell response directed against the tumor (CTL-t ). A requirement for this treatment to be effective is the presence of CTL-t within the tumor as reviewed by us recently [Aerts, 2013]. CTL-t formation is dependent on a number of factors which are inhibited by tumor-derived factors and tumor-induced immune suppressive cells, precluding patients to respond to the PD-1 checkpoint blockade pathway. Knowing and bypassing these inhibition pathways of the tumor increases the number of responding patients. For instance, in melanoma it has been shown that combination treatment of anti-PD-1 and anti-CTLA-4 almost doubles the patients benefitting from checkpoint blockade inhibitors. However the number of inhibition pathways is diverse and also changeable according to the act – react principle. The blockade of one inhibitory pathway of the tumor may ultimately lead to the upregulation of another inhibitory pathway. This complex interplay inhibits the formation of new CTL-t and an exhaustion of the CTL-t present in the tumor. That is why cell based therapy, either with ex-vivo generated T-cells or stimulated dendritic cells (DC), precluding a number of inhibitory mechanisms in the patient is an alternative to increase the number of responding patients and thus the efficacy of immunotherapy. Mesothelioma is an aggressive neoplasm, with highly specific growth features making it a distinctive malignant tumor from other cancer types. One of the key immunological features in mesothelioma is the abundant immunosuppressive environment it is creating. There is a large infiltration of regulatory T-cells, immunosuppressive macrophages and myeloid derived suppressor cells (MDSC). Furthermore, the tumor milieu negatively influences immune activation for instance by the presence of hypoxic areas. , tumor metabolites (e.g. arachidonic acid), and suppressive cytokines and chemokines negatively influence the immune activation. Some early phase studies showed a possible clinical effect of immunotherapy in mesothelioma. For instance, checkpoint inhibition with anti-CTLA-4 and anti PD-1 in a subgroup of patients showed some benefit which is now further evaluated in larger studies in second and further line treatment [Calabro 2013, NCT01843374 results pending, NCT02399371 amongst others] . Although it can be questioned whether that is the right setting to determine clinical benefit in placebo controlled trials. Anti mesothelin antibodies also did show clinical efficacy which is now investigated further [Hassan 2010]. Cell based therapy may increase efficacy of immunotherapy also in mesothelioma. The choice of the tumor associated antigens (TAA) to induce a CTL-t is critical, considering the diverse and changing repertoire of TAA. Genetically altered T-cells, directed against mesothelin or Wilms tumour-1 (WT-1) have been developed and are tested in the clinic [NCT02414269 amongst others]. Also DC therapy, being the most powerful initiator of an immune response, is also tested. An advantage of DC, apart from the induction of a natural CTL-t activation, is the ability to load the DC with a pluripotent antigen mixture. DC therapy with an autologous tumor cell lysate demonstrated promosing results [Hegmans 2010] and an allogeneic tumor cell lysate is now tested as tumor associated antigen source in the clinic [NCT2395679]. In the patient stimulation of DC seems an attractive option and has been investigated but may be hampered by the immunosuppressive environment created by the tumor [Powell, 2006]. A new concept with in vivo activation of DC with mesothelin loaded listeria bacteria is now investigated in mesothelioma [NCT01675765]. DC treatment can also be optimized with the addition of different checkpoint activators or inhibitors [Lievense WCLC 2015] Apart from the immune activation strategies, investigations should focus on how to diminish the highly immunosuppressive effect of mesothelioma. Results of our trial on combination treatment with ex vivo matured DC loaded with autologous tumor cell lysate and regulatory T cell (Treg) depletion showed a reduction in circulation Treg [data submitted for publication]. We are in the field of a whole new changing treatment paradigm for mesothelioma. Immunotherapy will be one of the new treatment options. Much effort has to be invested to determine the optimal combination treatment for particular patients. Dendritic cell-based therapy seems an attractive option to generate a more robust immune response that can serve as a backbone for combination treatment.

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      MS17.04 - CTLA4 and PD-1 (ID 1925)

      14:15 - 15:45  |  Author(s): H.L. Kindler

      • Abstract
      • Presentation

      Abstract not provided

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Author of

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    MINI 38 - Biology and Prognosis (ID 167)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      MINI38.04 - BRCA1/OCT1/MAD2L1 Axis Regulates a Bifurcating Apoptotic Pathway Induced by Vinorelbine in Mesothelioma (ID 2675)

      18:30 - 20:00  |  Author(s): D.A. Fennell

      • Abstract
      • Slides

      Background:
      There is currently no licenced second line therapy for mesothelioma patients upon relapse after pemetrexed cisplatin. The vinca alkaloid spindle poison, vinorelbine, exhibits useful activity in mesothelioma, warranting evaluation in a new UK randomised clinical trial, VIM. However the molecular determinants of efficacy are unclear. We have reported that BRCA1 is an essential regulator of vinorelbine-induced apoptosis, and loss of detectable BRCA1 occurs in 39% of mesotheliomas. However the mechanisms governing BRCA1 dependent lethality has been lacking. We have utilized a functional genetic approach to uncover critical genes required for vinorelbine efficacy.

      Methods:
      Apoptosis was analysed by PARP cleavage and caspase 3/7 activity assay. Focused RNAi targeting Caspase 8, BAX and BAK was conducted to delineate critical death activators. Mouse embryonic fibroblasts (MEFs) wild type (WT) or double knockout (DKO) for BAX/BAK cells were also used. MAD2L1 expression was studied by western blot and qRT-PCR. Tumour explants were derived from 10 MPM patients.

      Results:
      Mitochondrial and caspase-8 dependent apoptosis pathways were shown by triple knockdown of BAX, BAK and Caspase 8 to be required to rescue completely from vinorelbine-induced apoptosis. Loss of BRCA1 recapitulated this apoptosis block and was associated with loss of Oct1 dependent MAD2L1 associated transcriptional upregulation. RNAi mediated silencing of MAD2L12 phenocopied BRCA1 loss. In cells selected for resistance to vinorelbine, MAD2L1 failed to upregulate, secondly to constitutive downregulation of BRCA1. Using mesothelioma explants derived at extrapleural decortication, exhibited either marked resistance or sensitivity to vinorelbine induced apoptosis; correlation with regulation of BRCA1/Oct1/MAD2L is ongoing and will be presented.

      Conclusion:
      BRCA1 functions through an Oct1/MAD2L1-dependent activation of both mitochondria dependent and independent pathways to induce apoptosis. This implicates a requirement for a functional spindle assembly checkpoint, with implications for expanding the biomarker repertoire governing vinorelbine efficacy in mesothelioma

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    ORAL 11 - Clinical Trials 1 (ID 100)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      ORAL11.04 - Discussant for ORAL11.01, ORAL11.02, ORAL11.03 (ID 3317)

      10:45 - 12:15  |  Author(s): D.A. Fennell

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    ORAL 14 - Biology 2 (ID 112)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      ORAL14.06 - MesobanK - an International Mesothelioma Tissue Bioresource - Now Open for Tissue Requests (ID 988)

      16:45 - 18:15  |  Author(s): D.A. Fennell

      • Abstract
      • Presentation
      • Slides

      Background:
      Availability of quality assured, fully annotated mesothelioma tissue collected to rigorous standard operating procedures (SOPs) to facilitate basic and translational research is very limited. MesobanK, funded by the British Lung Foundation and the Mick Knighton Mesothelioma Research Fund, is a UK based bioresource to collect fresh tissue, blood, pleural fluid and anonymised linked clinical data to strict SOPs from patients with malignant pleural mesothelioma.

      Methods:
      1) To construct a tissue microarray (TMA) from 1000 cases of formalin fixed paraffin embedded pleural mesothelioma tissue linked to a clinical data set. Each case will have several cores taken to allow for tumour heterogeneity. 2) To collect 300 cases of fresh pleural mesothelioma tissue (5 samples per case), blood (whole blood, serum, plasma and buffy coat) and pleural fluid (supernatant and cell pellet) linked to a clinical data set. Longer term follow up and survival data will be provided by the UK National Cancer Registration Service. 3) To develop at least 20 new fully characterised and annotated mesothelioma cell lines. Governance MesobanK abides by all relevant UK and EU legislation regarding the collection of tissue and data. Mesobank is a member of the UK Confederation of Cancer Biobanks. Prioritisation for access to samples will be based solely on scientific merit. The project is managed by a dedicated project manager and overseen by a Steering Committee; an independent Scientific Advisory Board reviews anonymised applications for samples.

      Results:
      All required ethical permissions have been obtained. A secure, web-based multi-user database has been constructed for data collection. As of April 2015, 730 of the 1000 cases for the TMA have been acquired from UK pathology departments and the first part of the TMA construction is underway at the Cancer Research UK Cambridge Institute. In the first year of operation, 100 prospective cases have been banked and quality control to assess tumour percentage and necrosis in each sample is underway. Figure 1 shows weight of sample versus tumour percentage from the QC of the first 144 samples. Twenty six new cell lines have been developed and are currently being characterised. Figure 1



      Conclusion:
      Procurement of formalin fixed tissue for the TMA and fresh biospecimens is progressing well and MesobanK is now open for investigators to apply for tissue samples. Enquiries about tissue availability should be directed to mesobankadmin@papworth.nhs.uk. An application form is available at www.mesobank.com. A cost contribution model has been developed to support on-going funding of MesobanK.

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    P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P1.08-014 - The Small Molecule Inhibitor, LCRF004, Is Effective in Targeting the RON/MST1R Pathway in Malignant Pleural Mesothelioma (ID 1311)

      09:30 - 17:00  |  Author(s): D.A. Fennell

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer. We have previously identified RON as frequently activated in MPM patient samples and cell lines. RON is a member of the MET proto-oncogene family and is bound by macrophage stimulating protein (MSP). High positivity for total RON by IHC was an independent predictor of favourable prognosis. Additionally, elevated expression levels of MSP correlated with better survival. The aim of this study was to further examine the MSP-RON signalling axis in MPM using a RON inhibitor, LCRF004.

      Methods:
      MPM cell lines and a normal mesothelial cell line were screened for the expression of RON and MSP at the protein (Western) and mRNA (RT-PCR) level. Downstream mediators affected by MSP stimulation and LCRF004 were identified using a proteome profiler array. The effect of LCRF004 and MSP were examined using proliferation (BrdU ELISA), viability (High Content Analysis), migration (xCELLigence), apoptosis and cell cycle (HCA) assays. A xenograft study was also completed.

      Results:
      Treatment with LCRF004 resulted in a significant decrease in proliferation, viability and migration in vitro and reduced tumour growth in vivo (p<0.05, compared with vehicle control). In addition, LCRF004 significantly increased apoptosis. In terms of cell cycle, drug treatment decreased cells in 2n, whilst increasing cells in the G0/G1 phase. Experiments are on going to further characterise the mechanism of action of LCRF004.

      Conclusion:
      The in vivo and in vitro data generated in this study, indicates that the MSP-RON signalling axis is a potential target in MPM. Targeting the RTK domain of the RON receptor with a small molecule inhibitor is an effective interventional strategy in MPM.

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    P2.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 225)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P2.08-008 - A Phase 1 Dose Escalation Study of VS-5584, a PI3K/MTOR Inhibitor, Administered with VS-6063, a Focal Adhesion Kinase Inhibitor, in Mesothelioma (ID 2812)

      09:30 - 17:00  |  Author(s): D.A. Fennell

      • Abstract

      Background:
      Malignant mesothelioma is a rare, but aggressive pleural or peritoneal tumor which is highly invasive and progresses rapidly. The median survival of patients with mesothelioma is between 9 and 13 months, and survival has not been significantly affected by most currently available therapeutic interventions. There are no approved therapies following first line treatment. VS-6063 is an oral inhibitor of focal adhesion kinase (FAK) currently being evaluated in a randomized phase 2 study in patients with malignant pleural mesothelioma who have stable disease or better after front line chemotherapy. VS-5584 is an oral dual inhibitor of PI3K/mTOR currently undergoing phase I testing in solid tumors. Previously reported literature has shown that dual PI3K/mTOR inhibitors have activity in patients with relapsed mesothelioma. In preclinical models, the combination of VS-6063 and VS-5584 have demonstrated synergy in tumor models of malignant mesothelioma supporting the potential exploration of this combination clinically.

      Methods:
      This is a multi-center, open-label, phase 1 trial in subjects with relapsed malignant mesothelioma. The study is comprised of two sequential parts: Part 1 (Dose Escalation of VS-5584 with a fixed dose of VS-6063) and Part 2 (Expansion). Patients receive VS-5584 orally on an intermittent dosing schedule and VS-6063 400 mg orally BID. Primary endpoints are to determine the maximum tolerated dose, recommended Phase 2 dose/schedule and to assess safety and tolerability of the combination in this patient population. Secondary endpoints include assessing the pharmacokinetics of VS-5584 and VS-6063 when co-administered. Exploratory endpoints include response rate and biomarker correlation with response and PD. The study is currently enrolling across 4 sites in the United States and United Kingdom. Clinical trial: NCT02372227.

      Results:
      Not applicable

      Conclusion:
      Not applicable

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    P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P3.08-014 - COMMAND: A Phase 2 Randomized, Double-Blind, Study of Defactinib (VS-6063) as Maintenance Therapy in Malignant Pleural Mesothelioma (ID 2847)

      09:30 - 17:00  |  Author(s): D.A. Fennell

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung. Median OS with frontline chemotherapy of pemetrexed/cisplatin (pem/cis) is ~12 months. There is no established second line therapy. Pem/cis has been shown to enrich cancer stem cells (CSCs) in tumors. Focal adhesion kinase (FAK) inhibitors have been found to decrease CSCs in mesothelioma models. The use of a FAK inhibitor in a maintenance setting after frontline chemotherapy may therefore extend survival of MPM patients. Furthermore, approximately 40% of MPM tumors exhibit disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Mesothelioma cell lines that lack merlin are more sensitive to FAK inhibitors than those with wild type merlin. This Phase 2 study will determine if defactinib (VS-6063), an oral inhibitor of FAK, provides superior clinical benefit compared with placebo as maintenance treatment in patients with MPM following frontline pem/platinum therapy.

      Methods:
      COMMAND is a multinational, randomized, double-blind, placebo-controlled trial. Approximately 370 patients with PR or SD following ≥4 cycles of frontline pem/platinum therapy will be enrolled. Patients will receive defactinib 400 mg BID or matched placebo. Randomization will be stratified by merlin status, as determined by immunohistochemistry. Primary endpoints include OS and PFS. An adaptive enrichment design at the interim analysis (projected to occur in Q2 2015) may restrict patients to those with low merlin protein expression if greater benefit is observed among this subpopulation. Secondary endpoints include patient-reported outcomes, objective response and safety and tolerability. The study is currently enrolling across 15 countries. Clinical trial: NCT01870609.

      Results:
      Not applicable

      Conclusion:
      Not applicable