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 Cook1,2,3
1Division 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, UK
Phase 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 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. 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. 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.
Rothwell DG, Ayub M, Cook N, et al. Utility of ctDNA to support patient selection for early phase clinical trials: The TARGET study. Nat Med 2019;25:738–43.
Middleton G, Crack LR, Popat S, et al. The national lung matrix trial: Translating the biology of stratification in advanced non-small-cell lung cancer. Ann Oncol 2015;26:2464–9.
Sharma RA, Plummer R, Stock JK, et al. Clinical development of new drug-radiotherapy combinations. Nat Rev Clin Oncol 2016;13:627–42.
Abstract No 1: SPIRE: A Phase Ib/Randomized IIa Open Label Clinical Trial Combining Guadecitabine with Cisplatin and Gemcitabine Chemotherapy for Solid Malignancies Including Bladder Cancer
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. Griffths1
1Southampton 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, UK
Objectives: 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.
Abstract No 2: A Phase 1b Study of Oraxol in Combination with Ramucirumab in Patients with Gastric or Esophageal Cancers Who Failed Previous Chemotherapy
Yee Chao1, Laura Tenner2, Noelyn Anne Hung3, David Cutler4, Douglas Kramer4, Rudolf Kwan4, Cheung-Tak Hung5, Wing Kai Chan4
1Department 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 Zealand
Background: 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.
Abstract No 3: Phase 1 Trial Summary of Encequidar, a Novel P-Glycoprotein Inhibitor to Enhance Oral Bioavailability of Chemotherapies
Wing-Kai Chan1, David Cutler2, Rudolf Kwan1, Jay Zhi2
1Athenex Pharmaceuticals, Taiwan, 2Athenex Pharmaceuticals, USA
Background: 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.
Abstract No 4: A Pilot Study of Oral Paclitaxel and Encequidar in Patients with Cutaneous Angiosarcomas (KX-ORAX-010)
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 Ravi5
1Department 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, USA
Background: 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.
Abstract No 5: Oral Paclitaxel for the Treatment of Metastatic Breast Cancer 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 Chan7
1Department 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 Zealand
Background: 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.
Abstract No 6: Developing Nuclear Factor Erythroid 2-Related Factor 2 Inhibitors for Cancer Therapy: Clobetasol Propionate and Beyond
Eun-Ji Choi1, Soo-Youl Kim2, Sang-Min Jeon1
1Institute 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 Korea
The 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.
Abstract No 7: Automated Extraction and Visualization of Data from the TARGET (Tumor chARacterisation to Guide Experimental Targeted Therapy) Trial to Support Interim Analysis
Katherine Dempsey1, Paul O'Regan1, Julie-Anne Stevenson1, Dónal Landers1, Matthew G. Krebs2,3
1Digital 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, UK
Objective: 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 generate and customize visualizations of large, multi-dimensional data sets.
Abstract No 8: eTARGET: A Digital Science Solution to Integrate Clinical and Genomic Data for the Manchester Molecular Tumor Board
Julie-Anne Stevenson1, Mahmood Ayub1, Sarah Dransfield2, Anja Le Blanc3, Richard Hoskins3, Elwyn Shing2, Derek Barley4, Mike Westaway5, Paul Fitzpatrick1, Dónal Landers1, Matthew G. Krebs2,6
1Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK, 2The Christie NHS Foundation Trust, Manchester, UK, 3Research IT, The University of Manchester, Manchester, UK, 4Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK, 5Microsoft Limited, Customer Success Unit, UK, 6Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester,UK
Objective: Manchester Cancer Research Centre has established an MTB to facilitate precision medicine decision-making within the TARGET trial (Tumor chARacterisation to Guide Experimental Targeted therapy). The MTB meets monthly to review clinical data and next generation sequencing (NGS) results from tumor tissue and circulating tumor DNA for patients being considered for early phase clinical trials. Initially the MTB relied on multiple paper reports. Here we present eTARGET, a digital solution which integrates clinical and genomic NGS data to facilitate data review and decision-making by the MTB. Methods: eTARGET was developed in Microsoft Azure, a secure cloud computing platform. Components included encrypted storage for data upload from different sources, a database for storing and integrating the data and a web application, developed with clinical input, to view the data. The solution enabled automated extraction of individual pseudonymized clinical and genomic data. Results: eTARGET has been utilized at 14 MTB meetings since October 2017 and 172 patient cases have been captured. eTARGET has enabled the MTB to review individual patient data in a single portal, capture real-time decisions regarding significant variants and trial options, and upload the meeting outcome to the electronic patient record. The portal can be viewed remotely where all attendees see the same view, thus supporting virtual MTBs. Recent enhancements have included a search function to identify patients with genomic alterations of interest, the integration of NGS data from Foundation Medicine and the ability to view serial changes in NGS profiles on treatment. Conclusion: eTARGET has overcome the challenge of integrating data from disparate sources in different organizations by presenting a single view of patient clinical and genomic data. We have shown the utility of eTARGET in a hospital setting to support decision-making for an MTB. The eTARGET project opens the possibility of wider MTB participation including cross-center collaboration.
Abstract No 9: Clinical Trials Going Digital: Technology, Research and Patient Engagement
Jennifer Royle1, Elaine Blowers2, Paul Fitzpatrick1,3, Andrew Hughes1,4, Laura Stephenson1, Julie Stevenson1, Jennifer Bradford1, Dónal Landers1,5
1Digital Experimental Cancer Medicine Team, CRUK Manchester Institute, The University of Manchester, Manchester, UK, 2The Christie NHS Foundation Trust, Manchester, UK, 3PF Data Innovations, UK, 4Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK, 5Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK
Objective: Advances in technology are altering everyday life and set to transform healthcare. Technology has the potential to change how we do clinical trials. New ways of working need to be developed and tested in technology trials through clinical development involving patients. The aim of this research was to investigate the feasibility of establishing a technology clinical trial capability within a clinical trials unit. Methods: 6-month assessment: 1) Creation of a Patient Design Lab within the clinical research facility at The Christie NHS Foundation Trust. 2) Review of the European/UK regulatory landscape and University of Manchester and NHS research processes. 3) Development of a secure and flexible cloud infrastructure for digital solutions. Results: 1) Design lab consultations resulted in 123 interactions (68 patients, 11 carers, 44 staff) to assess co-creation. Co-creation of project strategy, process approach, user interfaces, and system acceptability were all successful, particularly for hypothesis development. 2) Developed a framework and guidance document for conducting technology trials and the first digital trial started. 3) Secure technology infrastructure established to support digital clinical trials. Conclusion: A digital-trial capability has been established in an early phase clinical trials unit. Digital clinical trials require a more interactive approach than standard clinical trials, with active patient-collaboration and a central role for research nurses. A new set-up and approval process are required to be able to deliver digital clinical trials.
Abstract No 10: REal-time Analytics for Clinical Trials (REACT): Supporting Decision-Making for Early Cancer Trials
J. A. Bradford1, F. Butt1, R. Hoskins2, J. Stevenson1, L. Stephenson1, D. Landers1
1Digital Experimental Medicine Team, Clinical and Experimental Pharmacology, Cancer Research UK Manchester Institute, Manchester, UK, 2Research IT, The University of Manchester, Manchester, UK
Objectives: Phase 1, first-in-human clinical trials are amongst the most complex and challenging during drug development and involve the organization, gathering and interpretation of large amounts of data (~10,000 data points per patient). Moreover, adaptive changes to these trials are often needed; for example, to the dose, schedule, patient population, drug combination and the deployment of potential predictive biomarkers. This drives the need for near real-time access to emerging trial data to support timely and effective decisions. Methods: REACT is a digital science platform providing clinical trial teams and investigators with an integrated, intuitive suite of visualizations which support multiple domains of clinical data including efficacy, safety and tolerability. Results: REACT has the potential to enable the sponsor to detect signals in the data and understand the benefit-risk profile for new cancer treatments earlier compared with the standard programmed output approach. It also avoids the need for manual extraction and visualization of data. REACT, originally developed alongside clinicians at AstraZeneca, has been delivered to other sponsors and investigators by the digital Experimental Cancer Medicine Team (ECMT). More recently the digital ECMT have further enhanced REACT by integrating clinical and genomic data, which has enabled investigation of genetic alterations across the patient population in a genomic profile visualization and tracking of genetic changes in the tumor using bespoke circulating tumor DNA visualizations. Furthermore, REACT has been linked to cBioPortal, an open source tool which enables in-depth genomic analysis for patients of interest. Conclusion: REACT enables near real-time access to the trial data to those involved in ongoing early clinical trials, both from the sponsor organization and care-giving site thus allowing focus on earlier data interpretation and decision-making rather than data gathering. REACT supports both the individual patient management by the caregiver and drug development decisions made by the trial sponsor.
Abstract No 11: Clinical Trials in the Home: Renal Monitoring for Cancer Patients – A Decentralized, Patient–Focused Approach
Leanne Ogden1, Dónal Landers1, Jenny Royle1, Laura Stephenson1, Laura Hutchinson1
1Digital Experimental Cancer Medicine Team, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Manchester, UK
Objectives: Recruitment to cancer clinical trials is challenging and usually limited to patients with preserved kidney function. The current fixed renal function cut-off is arbitrary and not a risk-based approach driven by current clinical science in nephrology. Due to increased survival rates for both conditions, there is now a significant population who have cancer and reduced kidney function. The aim of this research was to assess whether new technological advances in point of care (POC) creatinine meters and digital science could provide personalized risk-based monitoring and ultimately give more patients the opportunity to take part in early oncology trials. We created an approach that explored the potential and acceptability of using a POC device, data capture via a smartphone, and risk-categorization through an Acute Kidney Injury (AKI) algorithm, to enable decision-making and the first step in challenging traditional eligibility criteria and clinical trial design. Methods: Three POC devices were evaluated for usability, size and complexity. A smart phone app was developed, capturing device data and sending securely to a Cloud environment. Creatinine testing, calibration and patient acceptability was assessed over a 2-week period with 17 interactions (patient/carer/nurse) and with a focus group. Results: The Nova Biomedical StatSensor® was chosen due to good end user feedback and stable performance characteristics. The smartphone app user interface design was acceptable with patients based on patient acceptability testing, producing near-real time creatinine readings which could be reviewed by the medical team. Conclusion: This initial proof of concept successfully demonstrated that creatinine can be measured by a POC device, the data captured via an app and reported in near-real time. A digital clinical trial has been designed and is awaiting ethical approval to assess potential clinical benefits of this digital solution to alert medical teams to impending AKI amongst the cancer population.
Abstract No 12: Lessons from a Clinical Research Facility Floor Pilot of a Digital Data Capture Tool
Gemma Wickert1, Joanna Clarke1, Leanna Goodwin1, Carla Timmins1, Dilshad Chang1, Alison Walker1, Amanda Rees1,2, Andrew M. Hughes2,3, Jennifer Bradford3, Donna M. Graham1,2
1Experimental Cancer Medicine Team, The Christie NHS Foundation Trust, Manchester, UK, 2Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK, 3Digital ECMT – Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Manchester, UK
Objective: A digital transformation in healthcare is underway with the NHS encouraging improved integration of technology into daily clinical practice. There exists an opportunity to improve data collection in early phase clinical trials using a digital solution. This project assessed the use of a portable digital data collection tool for routine use in an early phase clinical trials facility (CRF). Methods: A bespoke digital trial data collection template was developed and a pilot performed to assess use of portable devices for collection of data on the day-case CRF. Medical and nursing staff trialed devices, simulating real-time review, assessment and treatment of virtual patients. Full use of the day-case NIHR Manchester CRF was granted, in addition to dedicated time from nursing and medical CRF staff. This facilitated a realistic experience of portable device use on the clinic floor. Results: The use of portable digital devices to collect data resulted in timely and accurate collection of data. Interactions with patients differed when using an electronic device in place of paper documentation. Practical concerns about method of transporting the device and maintaining good infection control practices need addressing. Conclusion: Integration of technology into routine clinical practice in a CRF presents unique advantages and challenges. Therefore, modification of current practice may be required. This pilot positions this group as a potential exemplar in the area of digital data collection for early phase clinical trials.
Abstract No 13: A Review of Software Availability for Adaptive Phase I Clinical Trials
Graham Wheeler1, Michael Grayling2
1CRUK and UCL Cancer Trials Centre, University College London, London, UK, 2Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK
Objective: The increasing expense of drug development has seen interest in using adaptive trial designs grow substantially. Research on identifying barriers to using adaptive designs has found the availability of user-friendly software is an important factor in making adaptive designs easier to implement. Here, we present the current state of software availability for adaptive trial designs, specifically for phase I and phase I/II dose-finding studies. Methods: We reviewed articles from 31 journals published between 2013–2017 on methodology for adaptive phase I and phase I/II dose-finding trials, to see how often software to implement novel methods is made available at the time of publication. We contrasted our findings against these journals current policies on code distribution. Secondly, we conducted additional searches of popular code repositories (e.g. CRAN, GitHub) to identify further existing user-contributed software for adaptive designs for phase I trials. Results: We obtained 4,123 articles, of which 81 articles across 21 journals were considered eligible. Overall, 56/81 (69%) articles did not make code available, nor provide details of existing packages used. For four journals that required code used in any research to be submitted with manuscripts, code was not available for 25/35 (71%) published articles. Our software review identified 31 packages (30 for R, 1 for Stata) for various phase I trial adaptations. However, software for complex outcomes (both toxicity and efficacy) and longitudinal adaptations to dose-finding designs is lacking. Conclusion: There is much room for improvement in the provision of software alongside adaptive design publications in phase I trials. Though several packages are available, well-established software for more complex trial adaptations remains sparsely available.
Abstract No 14: Patient Centered, Physician Investigator Friendly, Pragmatic Phase I/II Trial Designs: The 4P Model
David C. Norris1, Shiraj Sen2, Roman Groisberg3, Vivek Subbiah4
1Precision Methodologies, LLC, Seattle, WA, USA, 2Sarah Cannon Research Institute at HealthONE, Denver, CO, USA, 3Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA, 4MD Anderson Cancer Center, Houston, TX, USA
Objective: Patients enrolling on Phase I/II trials, together with their oncology investigators, face decision-problems neglected by current trial designs. Hitherto, early-phase oncology trial designs have privileged statistical formalism and algorithmic rigidity, abstracting clinical judgment exercise away from investigators. ‘Achieving’ such abstraction apparently requires dichotomizing complex toxicities and responses, and ignoring optimal-dose heterogeneity. The recent advent of pragmatic phase 1 dose-titration designs, however, facilitates restoring primacy to clinical judgment and the individual patient. Herein, we generalize one such design to incorporate measures of therapeutic response, exemplifying a ‘4P’ concept of Patient centered, Physician Investigator friendly Pragmatic Phase I/II trial design. Methods: We start from crucial questions early-phase trial participants ask their oncologists during on-trial follow-up, and treat these as defining ‘use cases’ for a synoptic graphical ‘dashboard’ . Building upon a previously described visualization, we prototype a data graphic fulfilling these use cases. Results: Three characteristic questions arise: (1) Have you found signs my cancer is or isn’ t responding to the study drug? (2) How does my experience compare with other patients in this trial? (3) Should I keep taking the drug at my current dose, or should we change the dose—or stop it? Questions (1–2) constitute use cases for a ‘swimmer plot’ linked to the dose-titration diagram. Question 3 underscores the imperative to maintain an up-to-date titration heuristic, incorporating any emerging evidence linking drug-exposure measures (including on-target toxicities) with clinical response. This latter consideration prompts addition of response-vs-exposure plots in which both absolute dose and grade of on-target toxicity appear as covariates. Conclusion: Our clinically realistic dashboard illuminates a ‘4P’ concept that restores patient-centered decision making to its rightful status in early-phase oncology trials. By accentuating crucial decision-problems faced by early-phase cancer trial participants and their oncologists, this model should help methodologists to propose useful adjunctive formal decision supports.
Abstract No 15: Costing “the” Maximum Tolerated Dose: What is the Economic and Human Cost of 1–Size–Fits–All Dose Finding in Oncology?
David C. Norris1
1Precision Methodologies, LLC, Seattle, WA, USA
Objectives: Dose Titration Algorithm Tuning (DTAT) renders individualized dose-finding feasible in Phase 1 oncology studies, supplanting ‘the’ maximum tolerated dose (‘the’ MTD) with an ‘MTDi’ concept. Against the criterion of individualized dosing, how great a cost does our current 1-size-fits-all dosing constraint impose on society? Methods: Dose titration is carried out for 1000 simulated subjects from a population pharmacokinetic-pharmacodynamic (PKPD) model, yielding an empirical MTDi distribution to which a gamma density is fitted. Individual-level efficacy, in terms of the probability of achieving remission, is assumed to be an Emax-type function of dose relative to MTDi, scaled (arbitrarily) to identify MTDi with the LD50of the individual’ s tumor. (Thus, a criterion 50% of the population achieve remission under individualized dosing.) Current practice is modeled such that all patients receive a first-cycle dose at ‘the’ MTD, and those for whom MTDi<MTDthe experience a ‘dose-limiting toxicity’ (DLT) aborting subsequent cycles. Therapy thus terminated is assumed to confer no benefit. Individuals for whom MTDi⩾MTDthe tolerate a full treatment course, and achieve remission with probability determined by the Emax curve. A closed-form expression is obtained for the population remission rate, and optimized numerically over MTDthe as a free parameter. Results: Simulated MTDi follow a gamma distribution with shape parameter α≈1.75. The population remission rate under 1-size-fits-all dosing at optimized MTDthe proves to be a function of the shape parameter—and thus the coefficient of variation (CV)—of the gamma distribution of MTDi [Figure 1].
Conclusions: The CV of MTDi determines the efficacy lost under one-size-fits-all dosing at ‘the’ MTD. Within plausible ranges for this CV, failure to individualize dosing can waste fully half of a drug’ s efficacy. This underscores the importance to all stakeholders of pursuing dose individualization in early-phase oncology studies, since these losses accrue to patients, investors and society as a whole.
Abstract No 16: Precision Medicine in Oncology: Where Are We Now?
John F. G. Bobo1, Srinivasan Vijayakumar2, Vani Vijayakumar3
1University of Mississippi Medical Center, School of Medicine, Jackson, Mississippi, USA, 2Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, Mississippi, USA, 3Department of Radiology, University of Mississippi Medical Center, Jackson, Mississippi, USA
Our objective is to show that the definition of precision medicine (PM) is multifaceted and broadening. As clinicians advocating for PM in the digital era, it is essential to remind ourselves that PM is more than just genomic medicine. Among other things, it includes genomic medicine, big data, electronic health record, and adaptive clinical trials. The following table illustrates the current developments in each sector. Healthcare is one of the last industries to participate in the digital era though it arguably has the most to gain. Table 1 illustrates the potential to advance healthcare when personalized medicine, real data, and human ingenuity are encouraged.
Abstract No 17: Prognostic Significance of Circulating Markers of Host Inflammation in Immunotherapy Treated Phase 1 Patients
K. Taylor1, O. Espin-Garcia1, D. V. Araujo1, R. Saleh1, Y. Kanjanapan1, M. O. Butler1, A. Spreafico1, A. R. Hansen1, A. R. A. Razak1, L. L. Siu1, P. L. Bedard1
1Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
Objective: Inflammation is a hallmark of cancer. Circulating markers of host inflammation, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR) are readily available. This study set out to evaluate the prognostic utility of these markers in patients (pts) enrolled in early phase clinical trials with immunotherapy (IO). Methods: Advanced solid tumor pts enrolled in IO phase 1 trials at Princess Margaret Cancer Centre between August 2012 and 2018 were identified from the institutional database. Previously validated PM-IPI (ECOG ≥1, Albumin <LLN and number of metastatic sites >2), NLR, PLR and MLR were calculated pre-treatment and correlated with clinical-pathological variables and survival. NLR, PLR and MLR were dichotomized with cutoffs 4, 185, and 0.3, respectively, based on existing literature. Results: Of the 493 pts analyzed, 274 were male, median age was 59 (range 19–86) and 156/337 had ECOG PS 0/1. Thirty-six immune-checkpoint inhibitor trials were included, 290 pts received single-agent therapy and 203 combination. The most common tumor types were gastrointestinal (19%), gynecological (17%) and skin (16%); median number of metastatic sites 2(1–7), previous lines of treatment 1(0–14) and 19% received prior IO. Median PFS and OS were 2.8 and 10.4 months respectively, with PM-IPI significant for both OS and PFS (p<0.001). Kaplan Meier (KM) analysis revealed differences in OS using NLR and MLR (p<0.001) but not PLR (p=0.051). Increased NLR and MLR were associated with reduced OS in a multivariate analysis (adjusting for age, sex, smoking, ECOG, metastatic sites and prior treatment/IO), with HRs of 1.57 (1.26–1.97, p<0.001) and 1.7 (1.19–2.44, p=0.037). KM analysis for PFS showed similar results as OS, however, only MLR was significantly associated with PFS in a multi-variable model (HR 1.38, 1.02–1.86, p=0.038). Conclusion: Increased NLR and MLR are associated with poorer survival in pts enrolled in IO Phase 1 trials.
Abstract No 18: Pick-Seq®: A Novel Technology for Microscopic RNA Biomarker Discovery
Nolan Ericson1, Rebecca Podyminogin1, Jennifer Chow1, Jia-Ren Lin2, Yu-An Chen2, Zoltan Maliga2, Peter Sorger2, Kyla Teplitz1, Eric Kaldjian1, Tad George1
1RareCyte, Inc., Seattle, WA, USA, 2Harvard Medical School, Boston, MA, USA
Objective: Pick-Seq combines high-resolution multi-parameter tissue imaging with micro-region retrieval for RNA sequencing. This study investigates the feasibility of Pick-Seq for RNA-level biomarker identification. Methods: Formalin-fixed, paraffin-embedded tonsil sections were stained with immunofluorescence (IF) for cytokeratin and B and T cell markers. Slides were imaged with CyteFinder® Imaging System and selected 40 μm diameter micro-regions of T and B cell areas were retrieved with the integrated CytePicker® Retrieval Module. RNA was isolated and whole transcriptome amplified (SMART-seq v4), followed by Nextera XT library preparation, sequencing on Illumina MiSeq, and gene expression analysis. Differentially expressed genes were selected to create a Pick-Seq-informed IF staining panel to confirm RNA expression results. Cell compositions of each micro-region were deconvolved with CIBERSORT. Results: Tonsil micro-regions from one T cell zone and two adjacent follicles were retrieved for RNA sequencing. Transcriptomic analysis confirmed increased expression of B cell markers in follicles and T cell markers in the T cell zone. CIBERSORT confirmed expected enrichment of T cells and B cells in the picked regions. Principle component analysis of gene expression found that micro-regions picked from the two follicles clustered independently from each other, and from the T cell zone micro-regions. Fragments per kilobase million (FPKM) analysis revealed differential expression of genes, particularly CD19 and CD21, between the adjacent follicles. IF staining confirmed differential protein expression, indicating that only one follicle contained a germinal center within the plane of section. Conclusions: We have demonstrated high-resolution multi-parameter imaging of FFPE sections for retrieval of micro-regions for transcriptomic analysis using Pick-Seq. RNA expression analysis differentiated follicle and T cell areas in tonsil and uncovered differences between adjacent follicles that were confirmed by IF imaging. These data demonstrate the power of Pick-Seq as a tool for biomarker discovery.
Abstract No 19: Nano-Omics Enrichment Tools for Cancer Biomarker Discovery
Hadjidemetriou1, Lana Papafilippou1, Richard D. Unwin2, Jane Rogan3, Andrew Clamp4, Kostas Kostarelos1
1Nanomedicine Lab, Faculty of Biology, Medicine and Health, AV Hill Building, The University of Manchester, Manchester, UK, 2Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK, 3Manchester Cancer Research Centre Biobank, The Christie NHS Foundation Trust, CRUK Manchester Institute, Manchester, UK, 4Manchester Cancer Research Centre, Institute of Cancer Sciences, The Christie NHS Foundation Trust, University of Manchester, Manchester, UK
Objectives: The development and implementation of cancer biomarker-based screening tools require novel analytical platforms to enable the discovery of biomarker panels that will overcome the limitations associated with the clinically used biomarkers. The systematic discovery of protein biomarkers directly from human plasma using proteomics remains extremely challenging, due to the wide concentration range of plasma proteins. Here, we describe the use of lipid-based nanoparticles as an ‘omics’ enrichment tool to amplify cancer signals in the blood and to uncover disease specific signatures. Methods: We aimed to exploit the spontaneous interaction of clinically-used liposomes with plasma proteins, also known as ’ protein corona’ formation, in order to facilitate the discovery of previously unreported biomarker molecules for cancer diagnostics. Liposomes were incubated with plasma samples obtained from ovarian carcinoma patients and healthy donors and corona-coated liposomes were subsequently recovered and analyzed. Results: Comprehensive comparison between ‘healthy’ and ‘diseased’ corona samples by label-free proteomics revealed 413 differentially abundant potential biomarker proteins. Moreover, immunoassay-based validation of selected proteins demonstrated the potential of the nanoparticle-platform proposed to discover novel biomarkers with greater specificity and sensitivity than the clinically used biomarkers. Conclusions: Our results suggest that nanoparticles dispersed in biological fluids have the potential to be used as an enrichment ‘omics’ platform for biomarker discovery. This work is thought to pave the way for many more studies needed to allow the clinical exploitation of protein corona fingerprinting as a novel tool to track tumors over time and discover panels of novel biomarkers for early and accurate disease diagnosis.
Abstract No 20: Personalized Ovarian Cancer Models for Target Discovery and Precision Medicine
Goldie Y. L. Lui1, Kay E. Gurley1, Elizabeth M. Swisher2, Carla Grandori3, Christopher J. Kemp1
1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 2Division of Gynecologic Oncology, University of Washington, Seattle, WA, USA, 3SEngine Precision Medicine, Seattle, WA, USA
Objective: Ovarian cancer is a highly heterogeneous disease, with a complex genomic landscape and multiple histopathologic subtypes. Chemotherapy remains the standard of care for most ovarian cancer patients, with clinically approved targeted agents only available to small subsets of patients. Our studies address two of the greatest unmet needs in the field: (1) the need for more targeted therapies tailored to tumor-specific genetic alterations; and (2) the need for better models during preclinical and clinical testing that accurately reflect the complex biology of patient’ s tumors. Methods: Using multiple high-throughput RNAi and drug screens, we have identified novel drug targets and combinations specific for different subsets of ovarian cancer. These include new therapies for MYC-driven ovarian cancer, ARID1A-mutant clear cell carcinoma, and chemotherapy-resistant ovarian tumors. Preclinical validation of these therapies is being supported by patient-derived ovarian organoid cultures that we have demonstrated to retain the pathologic and molecular characteristics of their original tumors. Results: Functional results from validation studies are being integrated with subtype, genomic, and drug sensitivity analyses to determine whether there are secondary biomarkers of response to facilitate clinical development of these novel targets. Further, we have demonstrated the feasibility, diagnostic utility, and immediate clinical relevance of high-throughput functional screening of patient-derived ovarian organoids to identify immediate and clinically actionable results for patients. This has enabled patients to be treated with effective targeted agents that are otherwise not approved for ovarian cancer. Conclusion: We have optimized a drug development pipeline utilizing patient-derived ovarian organoid cultures and high-throughput screening. Collectively, these studies bridge bench and bedside to enable functional precision medicine for ovarian cancer patients.
Abstract No 21: The Biomarker Validation Pipeline for Precision Radiotherapy in Prostate Cancer
Niluja Thiruthaneeswaran1,2, Becky Bibby1, Ronnie Pereira1,3, Robert Bristow1,3, Ananya Choudhury1, Catharine West1
1Division of Cancer Sciences, University of Manchester, Manchester, UK, 2Sydney Medical School, University of Sydney, Sydney, Australia, 3Manchester Cancer Research Centre, The Oglesby Cancer Research Building, Manchester, UK,
Objective: There is increasing interest in personalizing radiotherapy in this era of genomic profiling and improved sequencing technologies. Biomarker development requires validation in multiple cohorts, which involves using formalin-fixed paraffin-embedded (FFPE) tissue. The latter is challenging due to nucleic acid degradation, which increases with sample age. Using needle core (NC) biopsies is particularly challenging because of low tissue volumes and potential sampling errors. Recent clinical trials using tissue NC biopsies to measure biomarkers have reported ~40% sample attrition rate. There is a need to optimize methods for nucleic acid extraction and select the best platform for generating transcriptome data. A 28-gene hypoxia-associated signature was derived for prostate cancer. The signature was validated for prognostic significance in in silico cohorts. The aim was to identify the best approach for nucleic acid extraction and platform for signature generation prior to further validation. Methods: FFPE prostate NC samples were available from 422 patients treated between 2009 and 2014. To compare the effect of age, prospective samples were collected from 24 patients biopsied in 2018. Whole sections (20 μm) were taken to determine the optimal nucleic acid product for downstream applications comparing two commercial RNA extraction kits. To assess downstream usability, the 28-gene prostate-specific hypoxia signature was measured using an established qPCR based biomarker platform TaqManTM low-density array (TLDA), QuantiGene multiplex assay and gene expression analysis platform (ClariomTM S). Results: There was no difference in RNA concentration (24.5ng/μl Roche vs. 27 ng/μl Norgen) and total yield (679 vs. 540 ng). The only RNA quality parameter that was significant was DV200 with the Roche extraction kit having a significantly higher percentage of RNA fragments with ≥200 base pairs (55.3 vs. 36.9 %, p < 0.0001). The prospective cohort had an average RNA concentration of 60.8 ng/μl and a DV200 of 48.6% using the Roche extraction kit with a median 18s qPCR Ct of 20.7 vs 27.4 for the retrospective samples (p < 0.0001). All FFPE NC samples passed the QC metrics on the ClariomTM S platform with all 28 genes expressed compared to no samples expressing all 28 genes on the QuantiGene and TLDA platform despite the addition of a pre-amplification step. Conclusion: The RNA extraction kit most suitable for prostate FFPE NC biopsies is the Roche High Pure FFPET RNA kit. The Clariom S gene expression platform was superior to TLDA and Quantigene for validation of a prostate hypoxia gene signature in retrospective cohorts with the added advantage of providing whole transcriptomic data for future studies.
Abstract No 22: Fundamental Approach to Screening for the Breast Cancer Radiomics Study
Bhavesh Pratap1, Eric Aboagye1
1Imperial College London, London, UK
Objective: Using retrospective routine NHS scans already available within the Trust, we aim to develop a prognostic vector that is sufficiently powerful to enable management of patients with breast cancer. The perspective is that patients having a routine NHS CT scan could have their primary tumor radiomics analyzed immediately to determine their prognosis and if possible predict an alternative treatment course which would lead to better Phase-I trial options. Although the idea makes this study special, there are initial challenges faced in order to acquire suitable subjects. Retrospective imaging based studies require full access to the NHS Imaging database (PACS in NHS trust) of CT scans. A list of all the subjects who had had a clinician requested CT scan was acquired. The historic dataset of patients with positive diagnosis from the Somerset database was also acquired. These two databases were compared. Methods: PACS and Somerset databases were used for the screening process to determine the eligibility for each subject. Results: 5146 subjects were screened for study eligibility - 2723 subjects were screened through the PACS list and 2423 subjects through Somerset list. The number of suitable subjects identified through the Somerset was more than that of PACS (1.2:1 or 358:292 Somerset:PACS). The time taken to screen subjects for eligibility was almost half that of the Somerset list. Data are being assessed for radiomics. Conclusion: Compared to previous studies (screening done on lung and ovarian cancer), this method of acquiring already-available dataset of patients with positive diagnosis proved to be time-effective. Databases with historic datasets would lead us to optimal selection of patient groups in future.
Abstract No 23: Assessing Patient Referrals for Early Phase Clinical Trials
James Molloy1, Natalie Cook1,2, Fiona Thistlethwaite1,2, Matt Krebs1,2, Louise Carter1,2, Donna Graham1,2
1Division of Cancer Sciences, University of Manchester, Manchester, UK, 2The Christie NHS Foundation Trust, Manchester, UK
Objective: to review the demographic and clinical characteristics of cancer patients referred to the Experimental Cancer Medicine Team (ECMT) at the Christie Hospital for consideration of early phase clinical trials (EPCT). Methods: Data was retrospectively collected on 106 patients referred to the ECMT over 10 weeks in 2018. Data was extracted from electronic case records including demographic data, socioeconomic data, cancer and medical history and referral outcomes. Results: Patients aged <75 years comprised 94.3% of referrals, representing a marked overrepresentation compared with the overall cancer patient population. The majority of patients referred were women (58.5%) and 5.6% were from ethnic minorities. Utilizing the index of multiple deprivation (a comparative measure of deprivation measured at postcode level) it was noted that 24.5% of patients referred lived in areas from the 4 more deprived deciles compared to 40% if there was even distribution (p=0.004). This figure is particularly marked when considering the high number of deprived areas within Greater Manchester. The most common type of primary malignancy in the referral population was colorectal, followed by lung and urological. Patients had received a median of 3 lines of systemic therapy prior to referral (range 0–10). Of the patients referred, 35% were deemed ineligible for EPCT, with the commonest reasons being current medications and other comorbidities. From the 69 patients deemed eligible for clinical trials 48% were consented to molecular profiling studies and 32% were enrolled onto EPCT. Conclusion: As another potential treatment option for patients with advanced cancer, providing equity of access to ECPT is important. From the population reviewed in this study, older patients and those from ethnic minorities and more socioeconomically deprived areas were underrepresented. Investigating the causes for these disparities and developing methods to overcome them represent important areas for future studies.
Abstract No 24: An Audit of Screen Failures in Early Phase Cancer Clinical Trials: A Single Institution Experience
Sreeja Aruketty1, Joanna Clarke1, Daniel Lovelle Gomez1, Dilshad Chang1, Alison White1, Matthew Krebs1,2, Louise Carter1,2, Donna Graham1,2, Shaun Villa1,2, Fiona Thistlethwaite1,2, Amanda Rees1, Natalie Cook1,2
1Experimental Cancer Medicine Team, The Christie NHS Foundation Trust, Manchester, UK, 2Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
Objective: Successful enrolment of patients to early phase clinical cancer trials (EPT) requires adherence to strict inclusion/exclusion criteria assessed during the trial screening period. Patients who consent but then do not meet these criteria are considered screen failed patients (SFP). A 2016 audit carried out at The Christie NHS Foundation Trust (The Christie) revealed a high (32%) screen failure rate in an EPT patient population, including an avoidable failure rate of 16%. Following this audit, practice changes were implemented to reduce avoidable failures. The aim of this re-audit was to re-evaluate the SFP using 2018 data. Method: Patients were identified from a database of all patients consented to an EPT. Retrospective data was collected from 155 patients consented to EPT between 01/01/2018 – 31/12/2018. Reasons for screen failure were explored using EPT workbooks and patient’ s electronic records and medical notes. Results: Patients were consented to one of 35 EPT. SFPs constituted 23/155 (15%) patients. Median age of SFPs was 61yrs (42–72yrs), M: F 1:1.3. In the SFP population the most common cancer types were lung (11, 48%) and GU (4, 18%). Reasons for screen failure included abnormal baseline imaging in 5 (22%) patients, including 3 patients with a new diagnosis of brain metastasis. Abnormal blood tests, rapid disease progression and co-morbidities each occurred in 3 (13%) of SFPs. Unexpected death (disease-related), biopsy failures, cardiac issues and unexpected trial closure each occurred in 2 (9%) of SFPs. Decisions to screen fail were made by Principal Investigators in 18 (78%) cases and by sponsor in 5 (22%). Avoidable failures were present in 1 (4%) case. Conclusion: SFP rate decreased to 15% in the current audit, compared to 32% in 2016. This reduction demonstrates the positive impact of implementing practice changes. The audit will be repeated on a regular basis for quality assurance.
Abstract No 25: A Qualitative Study to Explore Patients' Views on Palliative Care in the Context of a Phase I Clinical Trial
Sarah Bellhouse1, Lucy Galvin1,2,3, Lorraine Turner1, Sally Taylor1, Michelle Davies1, Matthew Krebs1,4, Janelle Yorke1,5
1The Christie NHS Foundation Trust, Manchester, UK, 2Central Manchester Child and Adolescent Mental Health Services, Manchester University NHS Foundation Trust, Manchester, UK, 3School of Natural Sciences and Psychology, Liverpool John Moores University, Liverpool, UK, 4Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK, 5Division of Nursing, Midwifery and Social Work, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
Objective: The definition and role of palliative care is evolving from a traditional model of end of life care to one of earlier intervention. In recent years, a simultaneous care model for advanced cancer patients has been recommended meaning that palliative care services are offered throughout their cancer journey. To inform the successful adoption of this model in a phase I trial context, the study aimed to explore patients’ care needs and their perceptions of specialist palliative care. Methods: Purposeful sampling was used to recruit advanced cancer patients who had been referred to the phase I clinical trial team. Semi-structured interviews were conducted and transcripts were analyzed using thematic analysis with a framework approach to data organization. Results: Ten people (60% male, 47–68 years) participated. Participants expressed considerable physical and psychological impacts from cancer and cancer treatment. Despite this, participants did not recognize a need for specialist palliative care support. Understanding of the role of specialist palliative care was poor and largely limited to care provided at end of life. There was perceived conflict between considering a phase I trial and receiving specialist palliative care; a phase I trial offers hope for the future which was at odds with receiving care associated with end of life. Participants felt that specialist palliative care should be introduced earlier and educational resources developed to increase patient acceptability of palliative care services and improve engagement. Conclusion: Patients with advanced cancer referred for phase I trials are likely to benefit from specialist palliative care. However, this study suggests that patients may not recognize a need for support nor accept this support due to misperceptions about the role of palliative care. Developing a specific educational resource about specialist palliative care for this population would help overcome barriers to engaging with a simultaneous care model.
Abstract No 26: Update on the Patient Reported Experience Measure for Experimental Cancer Medicine
C. Sawyer1,2, R. Lee1,2, J. Taylor3, G. Punnett1,2, E. Blowers1, A. Wardley1,4, L. Carter1,4, J. Yorke1,2,4
1The Christie NHS Foundation Trust, Manchester, UK, 2Christie Patient Centred Research, The Christie NHS Foundation Trust, Manchester, UK, 3Patient Representative, 4Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
Objective: There is currently no published validated questionnaire to capture the experience of patient involvement in clinical trials. Our objective is to develop the Patient Reported Experience Measure for Experimental Cancer Medicine (PREM-ECM). Methods: Four stage, mixed-methods study that follows the FDA guidelines for the development and validation of Patient Reported Outcomes: Stage I: item generation using interviews and focus groups (n=25); Stage II: item refining and questionnaire layout using cognitive interviewing techniques (n=5); Stage III: cross-sectional study (n=150) to administer the ‘draft item-list’ . Advanced psychometric analysis will be conducted (Rasch modelling) to identify items with the best measurement properties for final inclusion. Preliminary reliability and validity testing will be applied; Stage IV: pilot test the final PREM-ECM in 20–25 patients. Results: Stages I and II have been completed, including 25 interview/focus group participants (Phase I = 2; Phase 1 = 12; Phase 2 = 11), and 5 cognitive interviews.
Study participants recommended the development of two questionnaires: 1) covers experiences of trial introduction/screening/consenting and 2) covers ongoing trial experience. Both draft questionnaires will be administered in stage III. Each includes the following themes: hope; informed about other treatment options; confident to decline participation or come-off trial; shared decision making; being kept informed; trial burden; fear of side-effects and symptoms; emotional support for self/family/friends. Conclusion: The PREM-ECM will be the first validated experience measure for cancer clinical trials. We anticipate study completion end 2019. Based on patient/carer feedback we have started the process of developing an experience measure for carers/family/friends.
Abstract No 27: Making Early Phase Clinical Research Accessible: Behind the Scenes of Early Phase Research: A Patient and Public Engagement Event Hosted by the Christie NHS Foundation Trust
E. Darlington1, S. Villa1, A. Rees1,2, D. Graham1,2, J. Halliwell1, C. Dickinson3, K. Cresswell4.5
1The Experimental Cancer Medicine Team, The Christie NHS Foundation Trust, Manchester, UK, 2Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK, 3Cancer Research UK, Manchester, UK, 4NIHR Manchester Biomedical Research Centre, Manchester, UK, 5Public Programmes Team, Manchester University NHS Foundation Trust, Manchester, UK
Objective: To host a patient and public engagement (PPE) event with defined aims to; engage patients/the public with early phase cancer research (EPCR) and precision medicine (PM), improve staff knowledge of public perceptions of EPCR/PM, and improve public understanding of, and participation in, EPCR. Methods: The event was held on Saturday 2nd February 2019, to coincide with World Cancer Day. The day included; educational presentations, guided tours of the NIHR Clinical Research Facility (CRF) and interactive informational stalls followed by an informal networking lunch. The event was advertised via The Christie, local hospitals and social media. Feedback was collated using structured forms, video recordings and free-text post-it notes/email. Results: Information collected from attendees at the start of the event demonstrated misconceptions and a lack of understanding about EPCR/PM. Event feedback revealed that 86% of attendees felt more comfortable to approach their GP/referring physician about the option of an early phase trial as a result of attending the event. 93% of attendees felt they understood the difference between early and late phase trials, and 100% understood the term ‘precision medicine’ following attendance at the event. Perceptions expressed by the attendees were collated and disseminated to early phase researchers for information and understanding. The event facilitated a mutual understanding between researchers and the public. Conclusion: Engagement events for EPCR and PM are important to challenge perceptions. This event has demonstrated a shift away from the original misconceptions, through improved understanding about the terms and concepts involved. Sharing lessons learned from such events has potential to improve perceptions of EPCR and, subsequently, recruitment to early phase clinical trials.
Abstract No 28: Introducing an Education Programme to Ensure CRF Readiness for Advance Therapy Medicinal Products Clinical Trials
Laura McNab1, Alexandra Marrinan1, Michelle Davies1
1NIHR Manchester Clinical Research Facility, The Christie NHS Foundation Trust, Manchester, UK
Objectives: The Christie Hospital is the lead organization for one of three Advanced Therapy Treatment Centers (ATTCs) funded by Innovate UK. The iMATCH (Innovate Manchester Advanced Therapy Centre Hub) consortium aims to facilitate the scale up of delivery of Advance Therapy Medicinal Products (ATMPs) by making complex ATMP trials as easy to deliver as standard drug trials. Staff education and training form an integral part of achieving these objectives. Methods: The Christie Clinical Research Facility has some early experience in delivering ATMP studies, however activity was sporadic therefore maintaining staff competence was challenging. With a growing ATMP trial portfolio, the appointment of an ATMP senior practice educator was seen as critical. This has facilitated the development of a comprehensive education programme which includes didactic and experiential learning. Implementation has been over 4 months, releasing 2–3 nursing staff every week for a series of lectures. Moreover, the programme includes specialist clinical placements with specific learning objectives and competencies using a self-directed workbook. Results: Improvements to clinical and theoretical knowledge are evident from staff feedback. Specifically, initiating Patient Group Directions for IV antibiotics, blood products, emergency training and in-depth awareness of ATMP toxicities have improved staff confidence levels. Conclusion: While the ATMP education programme is in its infancy, early feedback indicates staff feel supported in the management of this complex group of patients. Evaluation is ongoing at weekly management meetings and through formal audit. The programme and results are shared monthly through the consortium to other Clinical Research Facility establishments and at national ATMP meetings.
Abstract No 29: Developing an National Institute for Health Research Clinical Research Facility for the Safe Delivery of Oncology Advanced Therapy Medicinal Product Trials
M. Davies1, E. Dolan2, L. Hope2, S. Abraham1, S. Cliffe2, F. Thistlethwaite2,3
1Manchester NIHR Clinical Research Facility, The Christie NHS Foundation Trust, Manchester, UK, 2The Christie NHS Foundation Trust, Manchester, UK, 3Division of Cancer Sciences, The University of Manchester, Manchester, UK
Objective: Oncology Advanced Therapy Medicinal Product (ATMP) trials are predicted to grow exponentially. This is partly due to the success of the recently licensed CD19 Chimeric Antigen Receptor T cells (CAR-T). These complex trials are challenging to deliver and can be associated with severe toxicities. In order to facilitate the growing portfolio of ATMP trials, the Christie National Institute for Health Research (NIHR), Clinical Research Facility (CRF) has undergone an intensive period or reorganization and training. This redevelopment has been facilitated by iMATCH (Innovate Manchester Advanced Therapy Centre Hub), a Manchester based consortium awarded funding from Innovate UK with the objective of scaling up delivery of ATMPs. Methods: Process mapping of the patient pathway alongside a gap analysis using a set of international quality standards (JACIE) has provided a framework to underpin the development of the CRF with a focus on: Developing a unique governance structure; Formation of the Advanced Immune and Cell Therapy Research Team; Implementing a bespoke education programme; Recruitment of a JACIE quality manager; Implementing an ATMP operational readiness plan. Results: Recruitment of ATMP specialist staff is complete, an education programme has been implemented and key relationships with essential specialties are well established. A small but growing portfolio of ATMP studies are open to recruitment. The ATTC network has facilitated UK wide information sharing and other CRFs have benefited from the Christie CRF ATMP operational plans. Conclusions: The Christie is the lead organization in an Innovate UK funded ATMP consortium. iMATCH was established to scale up delivery of ATMPs and form a national network of Advanced Therapy Treatment Centres (ATTCs). The CRF plays a central role in delivering iMATCH milestones while benefiting from funding for key new posts central to ensuring the CRF has operational capability for ATMP trial delivery.
Abstract No 30: Advanced Clinical Practitioners: The Innovation behind the Role and How They Can Support Clinical Research Practice
L. Turner1, L. Cooper2, S. Subin3, M. Davies4
1Manchester Experimental Cancer Medicine Centre, The Christie NHS Foundation Trust, Manchester, UK, 2Birmingham Women's and Children's NHS Foundation Trust, WT NIHR Clinical Research Facility, Birmingham, UK, 3NIHR Manchester Clinical Research Facility, The Manchester Royal Infirmary, Manchester, UK, 4Manchester NIHR Clinical Research Facility, The Christie NHS Foundation Trust, Manchester, UK
Objective: Advanced Clinical Practice (ACP) is a level of practice characterized by a high degree of autonomy and complex decision making, underpinned by a master’ s level award that encompasses the four pillars of advanced practice (The multi-professional framework for advanced clinical practice in England, 2017). Throughout the United Kingdom (UK), the ACP roles remain underutilized in UK clinical research settings. Advanced Nurse Practitioner (ANP) roles in clinical research provide significant scope to utilize research resources more efficiently while offering a high level of specialized holistic care. However, the development of this role continues to be challenging due to historical issues relating to interpretation of good clinical practice (GCP) guidelines. Methods: Following a scoping exercise of ANPs in the UK, a National Forum of ANPs in Clinical Research was established in 2018. The forum aims to raise the awareness of the role locally, nationally and internationally; offer support to CRFs developing ACP roles and address common challenges. Results: Since its inception the forum has achieved recognition and adoption by the UK Clinical Research Facility (UKCRF) Network. Similarly, the National Institute for Health Research (NIHR) have also initiated discussions about supporting these innovative roles. Furthermore, there is increasing interest, appreciation and support of the ANP role from individual Clinical Research Facilities across the UK, acknowledging the importance of innovation and creativity of roles. Conclusion: The UK ANP clinical research forum will endeavor to: continue to grow ANP forum with the appropriate key stakeholders; professional promotion of the role e.g. parallel session, conferences, publications; disseminate the unique worth of the role across research boundaries; address the historic challenges which result from the subjective language currently used in GCP guidance.
Abstract No 31: Investigating the American Model of Advanced Practice Providers in Clinical Research: A Travel Bursary Award Report
M. Davies1, L. Turner2
1Manchester NIHR Clinical Research Facility, The Christie NHS Foundation Trust, Manchester, UK, 2Manchester Experimental Cancer Medicine Centre, The Christie NHS Foundation Trust, Manchester, UK
Objective: Advanced Practice Providers (APPs) is the term used in the United States (US) to collectively describe nurse practitioners and physician assistants. APPs have been an established part of the US healthcare workforce for many years and a recent survey established that there are currently between 5350 and 7000 APPs practicing in Oncology alone. APPs are often an integral part of US clinical research teams and often contribute significantly to clinical trial participant’ s care by having duties delegated as a sub-investigator. Conversely, advanced practice roles within clinical research in the United Kingdom (UK) is still underutilized. Reason for the slow uptake of these roles in clinical research teams is multifaceted but likely related to interpretation of Good Clinical Practice (GCP) guidelines by key stakeholders. Methods: A successful travel bursary award allowed the authors to travel to two internationally renowned cancer research centers in the US to explore how these roles have been successfully developed and integrated: The MD Anderson Cancer Centre and The Fred Hutchinson Cancer Research Centre. Results: APPs are a fundamental part of the US healthcare workforce and the Advanced Practice qualification is widely acknowledged & registered. APP’ s are considered an Integral part of clinical research teams in both institutions. APPs contribute to the clinical management of trial participant’ s and are delegated as sub-investigators. However, there are variations across states regarding APP legislation. Conclusion: The Christie Hospital Manchester Clinical Research Facility (CRF) was the first in the UK to employ a qualified ANP in 2012 and has continued to champion the role. The experiential learning and ongoing collaborations achieved by visiting international centers with established APPs in clinical research is invaluable and will contribute to the authors’ ongoing national work to support other CRFs to develop advanced practice roles.