Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

Abstract

Donna M. Graham1,2,3, Louise Carter1,2,3, Matthew G. Krebs1,2,3, Duncan Jodrell4, Anne Armstrong2,3, Elaine Kilgour1,2,5, Tim Illidge1,2,3, Joseph Clarke,2 Rachel Chown2, Kaye Williams1,2, Caroline Dive1,2,5, Janelle Yorke1,2, Clare Dickinson2,3, Andrew Hughes1,2,5, Fiona Thistlethwaite1,2,3, Rob Bristow,1,2,3 Natalie Cook1,2,31Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK, 2Manchester Cancer Research Centre, Manchester, UK, 3The Christie NHS Foundation Trust, Manchester, UK, 4Cancer Research UK Cambridge Institute (CRUK), University of Cambridge, Cambridge, UK, 5CRUK Manchester Institute, Manchester, UKPhase I clinical trials are the gateway to establishing new treatments for cancer patients by translating preclinical scientific advances to the clinic. The traditional Phase I design has involved small groups of patients, investigating toxicity and patient safety, and the pharmacodynamic and pharmacokinetic activities of novel treatments. Recent years have seen a rapid evolution in the scope and conduct of Phase I trials.The “Phase I: Where Science Becomes Medicine” conference, was held between the 14th and 16th of July 2019 in Manchester, UK with a dedicated focus on Phase I cancer trials and an overview of the dynamic landscape of the field. Global experts presented and discussed the key issues facing Phase I clinical triallists in a city with a long history of drug development and translational cancer research.Discussions were held across 10 sessions on a range of interlinked topics related to Phase I clinical trials. These included: novel drug targets and their impact on trial design, biomarkers and precision medicine, immunooncology, radiotherapy combinations, advanced therapies and trial methodology. The conference involved a mixture of plenary lectures, keynote speaker sessions, debates, poster presentations, a parallel nursing workshop, and exhibitions from various organizations.Over 220 delegates attended the conference with global representation. Delegates had diverse backgrounds spanning academia, industry and International professional healthcare bodies. Each session of the conference commenced with a video featuring patients’ and caregivers’ voices. These detailed first-hand accounts of how cancer and clinical trials affect participating patients and their families and provided a reminder of the importance of these trials and a focus for each session. In addition, 31 abstracts were accepted to be presented as posters and are included in the conference proceedings. Prizes were awarded to the top five posters (abstract numbers 7, 8, 18, 20 and 26).The meeting was opened by Professor Robert Bristow and Dr Natalie Cook who described the vision for the Phase I program in Manchester and the changes in cancer treatments over recent years. This included the increasing use of personalised therapies and genomic profiling, incorporation of novel combination therapies and the use of radiotherapy within a real-world evidence clinical database.Professor Lillian Siu, Chair of the Drug Development Program at Princess Margaret Cancer Centre in Toronto, delivered the first keynote of the conference, presenting “Phase I: Past and present”. She gave a fascinating overview of the evolution of Phase I clinical trials with novel designs, increasing patient numbers, incorporation of biomarkers and the emergence of immunotherapy as areas of change over recent years. Alongside these changes, Phase I trialists are also carrying the responsibilities of Phase II and III triallists due to the evolution of trial design. Despite this, the critical endpoints of safety and establishing recommended Phase II dose remain. Professor Siu highlighted a shift in trial design, where patients play an increasingly important role in both the development of and participation in Phase I trials.Dr Howard (Skip) Burris, Chief Medical Officer and Head of the Drug Development Programme of the Sarah Cannon Research Institute and 2019 President of the American Society of Clinical Oncology (ASCO) detailed the “Next steps for Phase I”. He highlighted the prominence of Phase I trials at the recent ASCO annual meeting and reiterated critical themes of biomarkers for drug selection and expansion of patient numbers. He also emphasized the role of real-world data for potential patient benefit and issued the challenge to the Phase I community to consider how eligibility criteria for trials can be broadened to allow access for a greater proportion of the patient population to provide greater possibility of benefit and to expedite the drug approval process.Genomics and biomarkers were the focus of the debate session, where the question: “Every cancer patient should have comprehensive genomic profiling prior to each experimental therapy” was debated by Dr Timothy Yap who argued for, and Professor Jeff Evans who argued against the motion. Rebuttals were delivered from Dr Donna Graham and Dr Matthew Krebs. Debate around this question centered around health economics and equity of access, lack of available drug targets, the emergence of circulating tumor DNA (ctDNA) as a potentially more cost effective, quicker and for some patients, a more feasible alternative to tumor profiling, matching rates to targeted therapy clinical trials, and associated response rates. The house voted in favor of comprehensive genomic profiling prior to each experimental therapy.The panel session on novel targets and the impact on trial designs offered insightful commentary on the future of Phase I trials. Professor Ruth Plummer started the discussion with an evaluation of how low prevalence targets have affected the goal and conduct of clinical trials. Professor Sarah Blagden then focused on some of the challenges and opportunities we currently face in the UK around complex trial designs. Dr Alan Jordan concluded the session by talking about the drug development pipeline. He stressed the vital approach of coordination and collaboration between research clinicians, chemists developing new drugs and scientists to design better drugs which meet the criteria patients consider important for quality of life. The three speakers concluded that collaboration and patient insight is needed throughout the drug development and discovery processes, and stressed the importance of pharmacodynamics and predictive biomarkers in designing appropriate clinical trials.A recurrent focus of the conference was the role of biomarkers for precision medicine. Professor Caroline Dive discussed the Tumour chARacterisation to Guide Experimental Targeted therapy (TARGET) trial[1] which includes a ctDNA profile and the development of the digital platform eTARGET. This is used to capture genomic data and personalize trial selection to the genomic sequence of the patient’s tumor. Professor Gary Middleton highlighted practical considerations in developing studies to match patients to trials citing the MATRIX trial for lung cancer patients.[2] Following this, Professor Steven Jones detailed the potentially transformative role of transcriptomics in providing effective individualized treatment options for patients. A key message of this session was the need for well-validated and clinic ready biomarkers to drive development of new precision medicine strategies.The final session of day two focused on immuno-oncology. Dr Charles Ferté from AstraZeneca provided an overview of the current immunotherapy research and the potential benefits offered by combination approaches. The topic of immunotherapy combinations was further developed by Dr Stefan Symeonides, who highlighted the vast number of immune-oncology-based clinical trials currently recruiting and the scientific rationale that should underpin development of such studies. Dr Santiago Zelenay ended the session by discussing tumor-protective and tumor-promoting inflammation as potential treatment targets for novel drugs. This session laid out the challenge to develop strong rationale for immune-oncology combinations and the role predictive biomarkers must play in combination choice.The final day of the conference started with a discussion around the challenges and opportunities of developing radiotherapy drug combinations in Phase I trials. Professor Kaye Williams outlined how academic investigators had worked closely with the regulatory bodies and pharmaceutical representatives to develop a consensus statement on the clinical development of new drug-radiotherapy combinations.[3] The RaDCom (Radiotherapy-Drug Combinations Consortium) initiative has subsequently brought together the UK experts working across six biological themes including DNA damage response, signaling pathways, tumor microenvironment, tumor metabolism, immunotherapy and biological therapies. Professor Dave Raben elaborated on the role of the US National Clinical Trials Network, that develops and oversees Phase I/II radiotherapy-based studies focused on novel combinations in multiple disease sites and indications. Finally, Professor Anthony Chalmers delivered an insightful talk highlighting exemplars of the translational cycle of developing trials informed by preclinical experimental data investigating the combination of radiotherapy with DNA damage repair inhibitors for the treatment of glioblastomas and lung cancer.The session on Advanced Therapies explored early phase trial development across a range of cellular therapies. Prof Brian Bigger discussed the use of gene modified stem cell therapies for childhood dementia whilst Dr Sophie Papa focused on approaches to the use of CAR-T cells in solid malignancies. Dr Reno Debets described the development of a Phase I trial in Rotterdam using MAGE-C2 engineered TCR T cells for patients with melanoma and head-and–neck cancer. Whilst this session represented a complex and diverse range of approaches, the deepened understanding of methods to manipulate cells in increasingly sophisticated ways to use as ‘ living platforms’ will hold the key to future success in tackling extremely challenging diseases.Running parallel with the main conference proceedings was a Cancer Research UK supported nursing workshop entitled “The Role of Research Nurses in the Development & Delivery of Phase I Trials”. The session was interactive and informative, discussing the changing nature of Phase I trials and the implications these changes may have for clinical practice and their delivery. The workshop hosted international speaker Lindsay Carlsson providing a North-American perspective and showcased research nurses and Advanced Nurse Practitioners within the UK. Dr Allan Jordan also spoke about the drug development process and Professor Janelle Yorke highlighted the role of nurses as researchers and leaders with opportunities for expansion of this field.Concluding the conference were three panel debates, where the house reflected on potentially disruptive changes in Phase I clinical trials. The first, posed the question “Do ‘ rules-based’ designs offer better value than ‘ model-based’ designs?” Professor Percy Ivy argued that pre-defining a simple set of dose-escalation rules enable all centers to participate, and not just those who have access to statistical support. Favoring ‘ model based’ design, Professor Adrian Mander acknowledged that these trial designs do require additional statistical input over ‘ rules-based’ designs, but that this resulted in a better delineation of a dose which was likely to be better tolerated in subsequent phases of drug development. “How can Phase I be brought into the digital age?” was the second question posed to the house. Dr Dónal Landers discussed how innovative technologies can help monitor patients such as a home monitoring of kidney function to broaden patient eligibility and monitoring on Phase I trials. Dr Donna Graham discussed a pilot program for electronic data collection when patients attend the hospital for clinical trial assessments. There was also discussion about the rhetoric of digital technologies, including navigating the challenges of cost and trial integration.To conclude this session, the fundamental question “What is the primary purpose of Phase I?” was posed to the delegates. Professor Udai Banerji argued that the primary focus for Phase I is to define the recommended dose range for Phase II trials as frequently a single dose cannot be recommended from Phase I. In contrast, Professor Glen Clack argued that the focus should be on expediting drug registration through of the use of agile, modular trial designs.Critical Learnings from this session concluded there is no ‘ one-size-fits all’ trial design for Phase I, and designs may be influenced by sponsor requirements to optimize for time, cost or reduction in uncertainty. Modular Phase I clinical trial designs, supported by the Medicines and Healthcare Products Regulatory Agency (MHRA), provide opportunities to move more rapidly between the different studies needed to fully characterize the drug in Phase I. Furthermore, the volume and complexity of Phase I data makes the application of digital capabilities to acquire and interpret per-protocolled assessments a necessity.Professor Andrew Hughes concluded the conference by reinforcing the importance of Phase I trials as the bedrock to improve outcomes for cancer patients. These trials provide the very first signals as to the right dose, the right patients and the right combinations. He highlighted one of the recurrent messages from the patient videos was that Phase I trials represent a source of hope for patients and their families and that delivering on this represents a key responsibility for the entire Phase I community.We thank the Experimental Cancer Medicines Centre (ECMC), The Christie NHS Foundation Trust, National Institute for Health Research (NIHR), Conference Partners. Tim Illidge and Rob Bristow are supported by the NIHR Manchester Biomedical Research Centre.S. J. Crabb1,2, S. J. Danson3,4, D. Dunkley1, A. Whitehead1, N. Downs1, S. Hill1, J. Bennett2, L. Ksiazek2, S. L. Brown3, L. Evans4, M. Serra5, K. Jones6, C. McDowell7, J. W. Catto8, R. Huddart5, G. Griffths11Southampton Clinical Trials Unit, University of Southampton, Sheffield, UK, 2Southampton Experimental Cancer Medicine Centre, University of Southampton, Southampton, Sheffield, UK, 3Sheffield Experimental Cancer Medicine Centre, University of Sheffield, Sheffield, UK, 4Department of Oncology and Metabolism, Weston Park Hospital, Sheffield, UK, 5Division of Radiotherapy and Imaging, Institute of Cancer Research and Royal Marsden, London, UK, 6Bob Champion Unit, Institute of Cancer Research and Royal Marsden Hospital, London, UK, 7Combinations Alliance, Cancer Research UK, London, UK, 8Academic Urology Unit, The Medical School, University of Sheffield, Sheffield, UKObjectives: Cisplatin resistance derives partly through tumor suppressor gene promotor methylation. In Vitro this is reversible through co-administration of DNA hypomethylating agents. Guadecitabine is a DNA methyltransferase inhibitor providing optimized delivery of the active metabolite decitabine. SPIRE is an ECMC (Experimental Cancer Medicine Centre) Combinations Alliance phase Ib/IIa clinical trial to establish a recommended phase II dose and schedule (RP2D) to combine guadecitabine with cisplatin/gemcitabine chemotherapy (GC). We report the phase Ib component. Methods: Patients with incurable metastatic solid cancer, received GC (G: 1000 mg/m2, IV, day (D) 8 + 15; C: 70 mg/m2, IV, D8), and guadecitabine (SC, D1–5) for up to 6 x 21D cycles. Maximum tolerated dose (MTD) was determined through pre-defined dose limiting toxicity (DLT; CTCAE v4.03) criteria in cohorts of 3–6 (rolling 6 design). The RP2D was expanded to include 6 bladder cancer patients. If DLTs occurred due to neutropenia, then subsequent cohorts incorporated GCSF (filgrastim, 300μg SC, D15–21). Primary endpoint: guadecitabine MTD. Secondary endpoints included pharmacodynamic and pharmacokinetic parameters. Results: DLT occurred in 3 of 4 patients in cohort 1 (guadecitabine 20mg/m2 D1–5), in 1 of 8 patients (febrile neutropenia) in cohort 2 (guadecitabine 20mg/m2 D1–5 + GCSF) and 3 of 5 patients (febrile neutropenia; G3 diarrhea and hypokalaemia; G4 neutropenia and thrombocytopenia ≥7 days and G3 tooth infection) in cohort 3 (guadecitabine 30mg/m2 D1–5 + GCSF). Pharmacodynamic endpoints of hemoglobin F levels and serum gene promoter methylation status for LINE-1, LTR12C, D4Z4, SAT2, and NBL2 were consistent with guadecitabine target effect. Pharmacokinetic parameters were consistent with guadecitabine single agent data. Conclusion: Guadecitabine 20mg/m2, day 1–5, with GCSF prophylaxis, is the RP2D in combination with GC. A randomized dose expansion as neoadjuvant treatment for bladder cancer is recruiting.Yee Chao1, Laura Tenner2, Noelyn Anne Hung3, David Cutler4, Douglas Kramer4, Rudolf Kwan4, Cheung-Tak Hung5, Wing Kai Chan41Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, 2Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA, 3University of Otago, Dunedin, New Zealand, 4Athenex Pharmaceuticals, Buffalo, NY, USA, 5Zenith Technology Corporation Limited, Dunedin, New ZealandBackground: Oraxol consists of oral paclitaxel administered with the novel P-glycoprotein inhibitor HM30181A which enables the oral absorption of paclitaxel. Ramucirumab (RAM) + intravenous paclitaxel is FDA approved 2nd line treatment of gastric cancer. Oraxol 200 mg/m2 days 1–3, weekly has similar exposure to weekly paclitaxel 80 mg/m2 intravenously. This study was to determine the maximum tolerated dose (MTD) of Oraxol + RAM. Methods: 17 patients with gastric or esophageal cancers who failed prior fluoropyrimidine or platinum containing chemotherapies were studied. Dose escalation followed the standard 3+3 design: Cohort 1: Oraxol 200 mg/m2 days 1–3, weekly. Cohort 2: Oraxol 250 mg/m2 days 1–3, weekly. Cohort 3: Oraxol 300 mg/m2 days 1–3, weekly. RAM 8 mg/kg IV every 2 weeks was co-administered in all patients. Dose limiting toxicity (DLT) were assessed by week 4. Adverse events (AEs) were assessed per CTCAE (Common Terminology Criteria for Adverse Events) v4.03 and response by RECIST (Response Evaluation Criteria in Solid Tumors) v1.1. Results: Cohort 1: One febrile neutropenia (DLT) occurred in 6 patients. Partial response (PR)=2/6, stable disease (SD)=1/6 and progressive disease (PD)=3/6. Cohort 2: One grade-3 neutropenia with treatment delay (DLT) occurred in 7 pts. PR=3/6 and PD=3/6 in 6 evaluable patients. Cohort 3: Two DLT (febrile neutropenia and grade-3 gastric hemorrhage) occurred in 3 patients. The MTD of Oraxol was 300 mg/m2 days 1–3, weekly in combination with RAM. All patients in this study had complete recovery of their DLT. Oraxol PK did not increase significantly in Cohort-2 and Cohort-3. Conclusions: Based on the lack of significant increase in exposure to Oraxol at higher doses, with similar efficacy and DLT in Cohorts 1 and 2, an extension study using Oraxol 200 mg/m2 Days 1–3, weekly + Ramucirumab 8 mg/kg every 2 weeks as in Cohort-1 is initiated. Clinicaltrials.gov: NCT02970539.Wing-Kai Chan1, David Cutler2, Rudolf Kwan1, Jay Zhi21Athenex Pharmaceuticals, Taiwan, 2Athenex Pharmaceuticals, USABackground: Encequidar is under development for converting iv administration to oral of several important chemotherapeutic agents such as paclitaxel. Phase 1 trial results of encequidar safety/tolerability and pharmacokinetic (PK)/pharmacodynamic (PD) characteristics are summarized. Methods: Three phase 1 trials, conducted in healthy, male, Korean volunteers as a single agent, examined (1) safety/tolerability and PK with doses up to 360 mg daily x 5 d administered under fasting condition, (2) the extent of p-gp inhibition using 16 mg loperamide as probe, with single doses of 15–180 mg, in comparison with 600 mg quinidine, and (3) the duration of p-gp inhibition using loperamide with single doses of 1–60 mg. In the 4th phase 1 trial, patients with solid tumors were treated with oral paclitaxel plus encequidar. Results: A total of 100 volunteers participated in the entry-into-human single- and multiple-dose escalation trial. Encequidar was poorly absorbed and systemic exposure was low, without evidence of systemic p-gp inhibition. All doses tested were well-tolerated - no maximum tolerated dose, dose-limiting toxicity or serious adverse effects. The concentration-QTc modeling proved lack of correlation and thus no QT liability. In 18 volunteers, encequidar enhanced loperamide oral bioavailability by ~ 50%, less than ~120% with quinidine; in 25 volunteers, this enhancement was sustainable 2 weeks post dose of encequidar. In 25 patients with solid tumors, oral paclitaxel at doses of 60–420 mg/m2 with encequidar dosed concomitantly at half paclitaxel doses was well tolerated; effective plasma concentration of paclitaxel was achieved. Through integrated analyses, a dose of 15 mg of encequidar was found optimal and chosen for future studies. Conclusions: Novel p-gp inhibitor encequidar is safe and well tolerated with itself being minimally absorbed. With encequidar as an adjuvant, oral bioavailability of paclitaxel was enhanced to the levels of effective as an oral chemotherapy. A phase 3 trial for oral paclitaxel is ongoing.Herbert H. Loong1, Robert Mennel2, Michael Wagner3, Teresa Tse1, Yat-ming Lau1, Candy Yuen1, Roxanne Moore3, Min-Fun Rudolf Kwan4, David Cutler4, Doug Kramer4, Wing Kai Chan4, Vinod Ravi51Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong SAR, 2Texas Oncology, Dallas, TX, USA, 3University of Washington Seattle Cancer Alliance, Seattle, WA, USA, 4Athenex Inc., Buffalo, NY, USA, 5The University of Texas MD Anderson Cancer Center, Houston, TX, USABackground: Cutaneous angiosarcoma is a rare malignancy which has an aggressive clinical course and there is no approved treatment. It usually occurs in elderly patients who do not tolerate aggressive IV chemotherapy. The novel oral paclitaxel with encequidar (a novel oral Pglycoprotein inhibitor) was granted Orphan Drug Designation by the U.S. FDA for the treatment of angiosarcomas in 2018. Methods: This is a pilot study to investigate the efficacy and tolerability oral paclitaxel (200mg/m2) with encequidar (15 mg) given once daily for three consecutive days every week for the treatment of 25 patents with cutaneous angiosarcomas. Results: Preliminary results from the first 7 evaluable patients studied showed early visible response of the cutaneous angiosarcoma within one or two weeks of treatment. There were 3 complete remission (43%), 1 partial remission (14%) and 3 stable disease (43%). No patients had serious adverse effects, including patients over 80 or 90 years of age. Conclusions: If the current encouraging clinical results are confirmed, this may represent a paradigm shift in the treatment of patients with cutaneous angiosarcoma and to address an unmet medical need in the treatment of angiosarcoma patients.Ming-Shen Dai1, Tsu-Yi Chao2, Tai-Chung Chao2, Chang-Fang Chiu3,4, Yen-Shen Lu5, Her-Shyong Shiah6, Yi-Ying Wu1, David Cutler7, Doug Kramer7, Rudolf Kwan7, Noeline Anne Hung8, Cheung-Tak Hung9, Wing Kai Chan71Department of Hematology/Oncology, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan, 2Division of Hematology-Oncology, Taipei Medical University - Shuang Ho Hospital, Taipei, Taiwan, 3Department of Medical Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, 4Department of Hematology/Oncology, China Medical University Hospital, Tai-Chung, Taiwan, 5Department of Hematology/Oncology, National Taiwan University Hospital, Taipei, Taiwan, 6Department of Hematology/Oncology, Taipei Medical University Hospital, Taipei, Taiwan, 7Athenex Inc., New York, NY, USA, 8University of Otago, Dunedin, New Zealand, 9Zenith Technology Corporation Limited, Dunedin, New ZealandBackground: Intravenous (IV) paclitaxel is an effective treatment for breast cancer. Oral administration paclitaxel is preferable to IV regarding minimizing IV injections, anaphylactic reactions to cremaphor, steroid pre-medications, hospital visits, and relevant costs. However, paclitaxel has poor oral absorption due to active excretion by P-glycoprotein (P-gp) in the intestinal cells. Oraxol (Athenex, USA) consist of HM30181, a novel oral inhibitor of intestinal P-gp combined with oral paclitaxel which enables the oral absorption of paclitaxel. We report the results of an early phase pharmacokinetics (PK) study, including clinical response and tolerability of Oraxol in treatment of metastatic breast cancer patients. Methods: Multicenter, single-arm, open-label, PK study of Oraxol (HM30181A 15mg, plus oral paclitaxel 205 mg/m2) administered orally for 3 consecutive days weekly for 16 weeks. Paclitaxel PK was assessed at week-1 and week-4. Tumor Response was measured at weeks 8 and 16 using RECIST (Response Evaluation Criteria in Solid Tumors) criteria 1.1. Toxicity was assessed using CTCAE (Common Terminology Criteria for Adverse Events) v4.03. Results: Twenty-eight MBC patient were studied. Mean age was 56.6 years (range: 38 – 79). PK results showed that the mean AUC of oral paclitaxel at week-1 was reproducible at week-4 (3050 to 3594ng-hr/mL). Weekly oral paclitaxel can achieve paclitaxel exposure similar to weekly IV paclitaxel (80 mg/m2) reported previously. 26 patients were evaluable for response. All failed previous chemotherapies. There were 11 (42.3%) partial response, 12 (46.2%) stable disease and 3 (11.5%) progressive disease in 26 evaluable patients. Three patients had treatment-related serious adverse effects (grade ≥3 neutropenia) and all patients recovered completely. Conclusions: Oraxol (oral paclitaxel combined with HM30181, a novel oral inhibitor of intestinal P-gp) showed very encouraging anti-cancer activity in MBC patients who failed previous chemotherapies with acceptable toxicity. Oraxol PK is reproducible and can achieve paclitaxel exposure similar to weekly IV paclitaxel (80 mg/m2). Clinicaltrial.gov: NCT03165955.Eun-Ji Choi1, Soo-Youl Kim2, Sang-Min Jeon11Institute of Pharmaceutical Science and Technology, College of Pharmacy, Ajou University, Suwon, Gyeonggi-do, Republic of Korea, 2Cancer Cell and Molecular Biology Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Republic of KoreaThe kelch-like ECH-associated protein 1 (KEAP1) -nuclear factor erythroid 2-related factor 2 (NRF2) pathway plays a central role in cellular antioxidant defense. NRF2 activation due to KEAP1 or NRF2 mutations occurs frequently particularly in lung cancer, suggesting that NRF2 inhibition could be a promising therapeutic strategy. However, no potent NRF2 inhibitors are clinically available to date. To develop potent NRF2 inhibitors for therapeutic purpose, we screened ~4000 clinical compounds and determined clobetasol propionate (CP) as the most potent NRF2 inhibitor. Mechanistically, CP promoted nuclear export and -TrCP-dependent degradation of NRF2 in a glucocorticoid receptor- and a GSK3-dependent manner. As a result, CP induced oxidative stress and strongly suppressed the anchorage-independent growth of tumors with KEAP1 mutation, but not with the wild-type KEAP1. Further, CP alone or in combination with rapamycin strongly inhibited the in vitro and in vivo growth of tumors harboring mutations in KEAP1 or both KEAP1 and LKB1 that are frequently observed in lung cancer. Thus, CP could be a promising repurposed therapeutic agent for cancers with high NRF2 activity. We also proposed that the use CP and rapamycin in combination could be a promising therapeutic strategy for tumors harboring both KEAP1 and LKB1 mutations. Currently, we are further characterizing CP for IND profiling and developing selective NRF2 inhibitors using CP analogues with less steroidal effects.Katherine Dempsey1, Paul O'Regan1, Julie-Anne Stevenson1, Dónal Landers1, Matthew G. Krebs2,31Digital Experimental Cancer Medicine Team, Cancer Research UK Manchester Institute, Manchester, UK, 2The Christie NHS Foundation Trust, Manchester, UK, 3Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UKObjective: The TARGET trial aims to match patients to early phase clinical trials based on their next generation sequencing (NGS) results from tumor tissue and circulating tumor DNA (ctDNA). A high quantity of clinical and sequencing data is generated. Here, we demonstrate the utility of scripted analysis pipelines for the automated extraction and analysis of clinical and genomic data, including the creation of bespoke visualizations of large, complex datasets. Methods: Cancer-associated gene panels were sequenced in ctDNA (N=641 genes) and tumor (N=24 genes) by NGS. The genomic sequencing data were integrated with the clinical data in eTARGET, a cloud-based platform. Data were extracted from the eTARGET database using Structured Query Language queries, processed and visualized using R. Analyses and visualizations were refined based on clinician feedback. Finalized analyses and visualizations were scripted to enable automated reanalysis as new data become available. Results: As of January 2019, data for 172 TARGET patients were included in eTARGET. Clinical questions focused on the frequency of mutations in ctDNA versus tumor, concordance between ctDNA and tumor, and patterns of mutation according to tumor type. Data were visualized in a series of histograms, heat maps and dendrograms. Conclusion: Scripted analysis of data has several key benefits compared with manual, spreadsheet-based approaches. These include: the ability to easily repeat analyses as new data become available; full audit trail from raw data to visualization to support quality control; and the ability to gener