Common Terminology Criteria For Adverse Events V4 Research Articles

Clinical outcome data of anxiety patients treated with cannabis-based medicinal products in the United Kingdom: a cohort study from the UK Medical Cannabis Registry

RationaleCannabis-based medicinal products (CBMPs) have been identified as novel therapeutics for generalised anxiety disorder (GAD) based on pre-clinical models; however, there is a paucity of high-quality evidence on their effectiveness and safety.ObjectivesThis study aimed to evaluate the clinical outcomes of patients with GAD treated with dried flower, oil-based preparations, or a combination of both CBMPs.MethodsA prospective cohort study of patients with GAD (n = 302) enrolled in the UK Medical Cannabis Registry prescribed oil or flower-based CBMPs was performed. Primary outcomes were changes in generalised anxiety disorder-7 (GAD-7) questionnaires at 1, 3, and 6 months compared to baseline. Secondary outcomes were single-item sleep quality scale (SQS) and health-related quality of life index (EQ-5D-5L) questionnaires at the same time points. These changes were assessed by paired t-tests. Adverse events were assessed in line with CTCAE (Common Terminology Criteria for Adverse Events) v4.0.ResultsImprovements in anxiety, sleep quality and quality of life were observed at each time point (p < 0.001). Patients receiving CBMPs had improvements in GAD-7 at all time points (1 month: difference −5.3 (95% CI −4.6 to −6.1), 3 months: difference −5.5 (95% CI −4.7 to −6.4), 6 months: difference −4.5 (95% CI −3.2 to −5.7)). Thirty-nine participants (12.9%) reported 269 adverse events in the follow-up period.ConclusionsPrescription of CBMPs in those with GAD is associated with clinically significant improvements in anxiety with an acceptable safety profile in a real-world setting. Randomised trials are required as a next step to investigate the efficacy of CBMPs.

P01.07.A Neurocognitive outcomes after proton beam therapy for skull base tumours

Abstract Background Evidence suggests that Proton Beam Therapy (PBT) may lessen the risk of neurocognitive decline (NCD) by reducing the dose to the normal brain as compared to conventional photon radiotherapy (XRT). We report the incidence of moderate-severe (Grade ≥3) NCD in adults treated for skull base chordomas and chondrosarcomas within the United Kingdom’s Proton Overseas Programme (POP). Material and Methods Baseline (pre-PBT) and follow-up clinical outcomes data were prospectively collected as part of a national PBT-outcomes registry, which started in 2008 . This registry is curated by a dedicated Proton Clinical Outcomes Unit. Specifically, late toxicities ≥G3 as per CTCAE (Common Terminology Criteria for Adverse Events) v4.0 definition, occurring later than 90 days after treatment completion, were recorded. This study focuses on the incidence of memory impairment (MI) in the adult (≥25 y) cohort. Results Between 2008-2018, 141 adult patients were treated for skull base chordomas (77 patients, 54.6%) and chondrosarcomas (64 patients, 45.4%) via the POP (the majority -62.8%- treated at the University of Florida PBT Institute). Median age at treatment was 51 years (range 26-77). Median prescription dose was 73.8 GyRBE (70-75.6), with a median dose per fraction of 1.8 Gy (1.2-2.1). Of note, the median dose for chondrosarcomas was 70.2 GyRBE (70-75.6), whereas the median dose for chordomas was 73.8 GyRBE (72-75.6). Median follow up was 39 months (0-138). On clinical assessment, 4 patients (2 chordomas, 2 chondrosarcomas) were reported with G3 MI after a median time of 43 months (27-49). None of them had impaired memory at baseline, nor relevant neurological comorbidities. Median age of those who developed G3 MI was 63 y (39-70). Median prescription dose was 72.9 GyRBE (70-73.8). Plans were available for 3 of these 4 patients. Relevant dose statistics to hippocampi and temporal lobes were extracted. Dmean to the omo- and contralateral hippocampi in these 3 patient plans were: patient 1) 33.7 and 11.6 GyRBE; patient 2) 28.1 and 24.4 Gy; patient 3) 8.7 and 8.2 GyRBE, respectively. V20 to the omo- and contralateral temporal lobes in the same patients were: patient 1) 47% and 10%; patient 2) 29% and 28.7%; patient 3) 30% and 28%, respectively. Suggested constraints for these structures are: Dmean &amp;lt; 20 Gy to the hippocampi and V20Gy &amp;lt;10% to the temporal lobes. Conclusion Our results indicate that adult patients undergoing high dose radiation for radioresistant tumours may experience detrimental effects on memory. Neurocognitive baseline and follow-up assessment is not routinely performed in this age group but might be appropriate to explore which domains of cognitive function are mainly affected. Larger cohorts are warranted to establish predictive factors and better understand dose volume effect of brain structures and neurocognitive sequelae.

Concordance of the WHO, RTOG, and CTCAE v4.0 grading scales for the evaluation of oral mucositis associated with chemoradiation therapy for the treatment of oral and oropharyngeal cancers.

The ability to consistently and accurately assess oral mucositis (OM) is critical to descriptions of its incidence and severity and in evaluating the effectiveness of potential interventions. The lack of a single grading scale compounds outcome interpretation. Consequently, we assessed the concordance of three of the most commonly used OM grading criteria (World Health Organization (WHO), Radiation Therapy Oncology Group (RTOG), and the common terminology criteria for adverse events (CTCAE). Data was evaluated from two hundred patients with oropharyngeal or oral cavity cancers who underwent chemoradiation therapy and were enrolled in a double-blind, randomized, placebo-controlled trial in which trained assessors evaluated patients twice weekly. WHO, RTOG, and CTCAE scores were assigned centrally by independent evaluators blinded to the study group. Concordance among the three scales for all OM scores and severe OM scores (score ≥ 3) was defined as the percentage agreement and measured using Cohen's weighted Kappa. Of 3,578 OM assessments, 57% had identical scores for all three scales. When any score was considered, the concordance between WHO and RTOG scales was 71% (kappa 0.58; 95%CI: 0.56-0.60), 62% for the WHO and CTCAE scales (kappa 0.46; 95%CI: 0.44-0.48) and 78% for the CTCAE and RTOG scales (kappa 0.69; 95%CI: 0.68-0.71). When patients had severe OM (WHO score ≥ 3), 99.6% (521/523) of the CTCAE OM assessments had scores of 3 or 4 (kappa 0.98; 95%CI: 0.98-0.999) and 97.7% of the RTOG ones (511/523) had scores of 3 or 4 (kappa 0.69; 95%CI: 0.62-0.75). Among patients who had a WHO score of 4, 31.7% (63/199) and 96.0% (196/199) of patients had RTOG or CTCAE scores of 2 or 3, respectively. Discordance was seen with patients who exhibited mild to moderate OM or most severe OM (grade 4) as described by WHO criteria. Whereas scale selection seems less critical in studies in which general "severe mucositis" is the primary outcome, it is particularly important in accurately describing OM's clinical trajectory and the frequency and impact in its most severe forms.

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

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 &amp; 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

454P - Predictors of severity and comparison of CTCAE V3.0 vs V4.3 in assessing chemotherapy induced extravasation injuries

BackgroundExtravasation is an important Adverse Event in chemotherapy, which is evaluated using CTCAE (Common Terminology Criteria for Adverse Events) grading scale. This study focuses on predicting risk factors and comparing CTCAE v3.0 and 4.3 in assessing chemotherapy-induced extravasation. MethodsAn observational study was conducted in medical oncology wards of a tertiary care hospital among adult patients receiving parenteral chemotherapy. European society of medical oncology – European oncology nursing society (ESMO-EONS) guidelines was used to classify chemotherapeutic agents. Significant risk factors were determined using binary logistic analysis. Spearman’s rank correlation coefficient and Wilcoxon’s sign rank test was applied to evaluate the difference between CTCAE v3.0 and v4.3. ResultsA total of 46 patients were enrolled in the study. According to CTCAE v4.3, amongst the 46 patients who experienced extravasation 30 presented with Grade II and the rest 16 with Grade III severity. Patients aged above 60 years showed significance (OR: 2.236, p = 0.007), and females were prone to severe extravasation injury (OR: 2.713, p = 0.010). Ambulation was found to be a major risk factor (OR: 4.66, p = 0.001). Patients with comorbidities had higher chances of getting severe extravasation (OR: 3.009, p = 0.029) and irritants were found to be predominant in worsening it (OR: 2.24, p = 0.007). The Spearman’s rank correlation coefficient established a good association in EV grades between both versions of CTCAE (rho=0.877, p = 0.000). Wilcoxon’s Rank test revealed a significant difference between the two. (p = 0.0003). ConclusionsThe severity of EV depends on early identification of symptoms, patient related factors and nature of drug. This information is pivotal to work towards a scenario of better-prevented and managed events of EV. The updated versions of CTCAE (v4.3 and v5) are better fit to use for accurate scoring of severity. Legal entity responsible for the studyAll Authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Platinum based chemotherapy in elderly patients with non-small cell lung carcinoma (NSCLC): Experience from an Indian tertiary cancer center.

e20528 Background: Instituting platinum based chemotherapy in elderly population is often associated with poor tolerance and attending toxicities. We present our limited center experience of chemotherapy in the geriatric population group. Methods: This is a retrospective single center experience of all registered patients in lung cancer clinic (LCC) in the department of medical oncology, Dr. B.R.A. IRCH, AIIMS. All histopathologically proven cases of NSCLC with age more than 70 years who received platinum based chemotherapy (single/doublet) with complete patient records were analysed. The study was carried out between November 2016 and August 2018.Data was analysed using STATA v13. Results: The cohort consisted of 25 patients who satisfied the inclusion criteria. Males comprised 84%(n = 21) of the cohort. Median age of study population was 72.7 years years (Range 70-84). 36%(n = 9) of the study population had one comorbidity while 8% (n = 2) had multiple comorbidities. 68% (n = 17) of the cohort were smokers. ECOG(Eastern cooperative oncology group) PS (performance status) 1 was seen in 48% (n = 12) and PS 2 in 32% (n = 8) and PS 3 in 16% (n = 4) respectively of the patients. Histopathologically, 48% (n = 12) of the population constituted squamous cell carcinoma while 40%(n = 10) had adenocarcinoma. 76%(n = 19) patients had Stage 4 NSCLC. Most common chemotherapy regimes used were weekly Paclitaxel carboplatin (n = 11, 44%), three weekly paclitaxel carboplatin (n = 8 , 32%) Pemetrexed carboplatin (n = 5, 20%) and gemcitabine carboplatin (n = 1, 4%). Only 12% (n = 3) could complete more than 4 cycles of chemotherapy and 3 could receive maintenance chemotherapy. Best responses according to RECIST (Response Evaluation Criteria In Solid Tumors) criteria v1.1 achieved were complete response in 12%(n = 3), partial response in 16% (n = 4), stable disease 24%(n = 6) and progressive disease in 48%(n = 12). Most common grade 3 and 4 adverse events according to CTCAE (common terminology criteria for adverse events) v4.03 were mucositis 29.17%(n = 7), diarrhea 12% (n = 3), peripheral neuropathy 12.5 (n = 3) and hematological toxicity 16%(n = 4). Conclusions: The patient number in this study cohort is limited.However, our experience demonstrates that abbreviated therapy in elderly subgroup is fairly well tolerated. Various tools like comprehensive geriatric assessment need to be utilized to provided tailored therapy in the elderly subgroup. A prospective study is required to address the efficacy and toxicity profile of chemotherapy in this select population.

Outcome Definition Influences the Relationship Between Genetic Polymorphisms of ERCC1, ERCC2, SLC22A2 and Cisplatin Nephrotoxicity in Adult Testicular Cancer Patients.

Although previous research identified candidate genetic polymorphisms associated with cisplatin nephrotoxicity, varying outcome definitions potentially contributed to the variability in the effect size and direction of this relationship. We selected genetic variants that have been significantly associated with cisplatin-induced nephrotoxicity in more than one published study (SLC22A2 rs316019; ERCC1 rs11615 and rs3212986; ERCC2 rs1799793 and rs13181) and performed a replication analysis to confirm associations between these genetic polymorphisms and cisplatin nephrotoxicity using various outcome definitions. We included 282 germ cell testicular cancer patients treated with cisplatin from 2009–2014, aged >17 years recruited by the Canadian Pharmacogenomics Network for Drug Safety. Nephrotoxicity was defined using four grading tools: (1) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for acute kidney injury (AKI) or CTCAE-AKI; (2) adjusted cisplatin-induced AKI; (3) elevation of serum creatinine; and (4) reduction in the estimated glomerular filtration rate (eGFR). Significant associations were only found when using the CTCAE v4.03 definition: genotype CA of the ERCC1 rs3212986 was associated with decreased risk of cisplatin nephrotoxicity (ORadj = 0.24; 95% CI: 0.08–0.70; p = 0.009) compared to genotype CC. In contrast, addition of allele A at SLC22A2 rs316019 was associated with increased risk (ORadj = 4.41; 95% CI: 1.96–9.88; p < 0.001) while genotype AC was associated with a higher risk of cisplatin nephrotoxicity (ORadj = 5.06; 95% CI: 1.69–15.16; p = 0.004) compared to genotype CC. Our study showed that different case definitions led to variability in the genetic risk ascertainment of cisplatin nephrotoxicity. Therefore, consensus on a set of clinically relevant outcome definitions that all such studies should follow is needed.

Self-evaluation of duration of adjuvant chemotherapy side effects in breast cancer patients: A prospective study.

BackgroundWe recently reported that self‐evaluation of the incidence and severity of treatment‐related side effects (TSEs) using a National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0‐based questionnaire was feasible and more informative than doctor reports in patients undergoing standard adjuvant chemotherapy for operable breast cancer. Here, we compare self‐ and doctor‐evaluated day of onset and duration of TSEs in the same population.Patients and methodsSix hundred and four patients were enrolled at 11 sites in Italy. CTCAE v4.0 definitions of grade of severity of nausea, vomiting, constipation, anorexia, dysgeusia, diarrhea, fatigue, pain, paresthesia, and dyspnea were translated into Italian and rephrased. Questionnaires were administered after the first and third chemotherapy cycles. At each time‐point, information on TSEs was extracted from the medical charts and compared to patient questionnaires.ResultsA total of 594 and 573 paired patient and doctor questionnaires were collected after cycles one and three, respectively. TSE duration was significantly longer when reported by patients compared to doctors for six and seven of ten items after cycles one and three, respectively. Due to the combined effect of doctor underreporting of TSE incidence and duration, the mean percentages of cycle days with TSEs were significantly higher for all ten items when based on patient reports. Day of onset could not be evaluated because of insufficient numbers of complete records.ConclusionsSelf‐reporting TSE duration is feasible using a CTCAE‐derived questionnaire. As doctors tend to underestimate TSE incidence and duration, patient‐reported outcomes should be incorporated into clinical practice, perhaps using eHealth technologies, to harness their potential to better estimate total TSE burden.

Abstract P2-11-20: Tolerability and outcomes of radiation therapy for breast cancer in older women: A retrospective study in 817 patients

Abstract Background: Breast cancer (BC) management in older women requires an individual approach and is becoming increasingly topical given the aging population. Postoperative radiation therapy (RT) is a standard treatment of BC after breast-conserving-surgery in most patients but its relative benefit may be counteracted by potential side-effects, especially in elderly. The aim of this study was to assess acute and long-term radiation-induced toxicities and the impact of comorbidities on outcomes in the older women treated by RT for non-metastatic breast cancer. Materials and Methods: Women aged ≥ 70 years at diagnosis, who received exclusive or postoperative RT for primary non-metastatic breast cancer, including carcinoma in situ, between 2003 and 2009 were retrieved from the Institut Curie registry. We calculated the Charlson Comorbidity Index (CCI) for each patient and collected the cardiovascular risk factors other than age (hypertension, dyslipidemia, smoking status). We analyzed overall survival (OS), progression free survival (PFS) and acute and late toxicities according to the CTCAE (Common Terminology Criteria for Adverse Events) v3.0. Results: A total of 817 patients was included in this study. Median age at diagnosis was 76.6 years [70 – 93.3]. Most patients had HR+ (hormone-receptor positive) HER2- breast cancer (83.9 %). 517 patients (62.7%) had at least one cardiovascular risk factor. With a median follow-up of 6.7 years [0.5 - 13], OS at 5 years was 86.3% CI95%[83.8 - 88.8], and PFS was 84.5% CI95%[81.9 – 87.1]. OS at 5 years was statistically different according to the Charlson index: 90.2% CI95%[87.2 – 93.3] for a CCI of 0, 84.6 % CI95%[80.5 – 88.8] for a CCI of 1, and 78% CI95%[70.5 – 86.2] for a CCI ≥ 2 (p &amp;lt; 0.001, log-rank test), respectively. Similar results were found for PFS (p &amp;lt; 0.001, log-rank test). 22.6% of patients had no toxicity; of those who experienced toxicity, most was limited to grade I or II. Only five cases (0.6%) of radiation – induced pneumonitis were reported after a median time of 16.4 months (grade I, n = 1; grade II, n = 2). One case (0.1%) of myocardial ischemia was described 14.5 months after RT. Women older than 80 years were less likely to have acute dermatitis (OR = 0.62; CI95%[0.45 - 0.85]), long-term breast pain (OR = 0.31; CI95%[0.14 - 0.62]), and long-term breast deformation (OR = 0.63; CI95%[0.42 - 0.93]) compared to patients younger than 80 years. There was no significant association found between other cardiovascular risk factors and toxicities. Conclusion: Radiation therapy for breast cancer in the older women is well-tolerated. An extended follow-up is planned in order to assess toxicities at a longer time horizon. Further studies could be envisaged to assess the quality-of-life during and after RT for breast cancer in the older patient population. Citation Format: Cao KI, Salviat F, Fourquet A, Falcou M-C, Laki F, Beuzeboc P, Savignoni A, Bazire L, Poortmans P, Kirova YM. Tolerability and outcomes of radiation therapy for breast cancer in older women: A retrospective study in 817 patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-20.

Approach for Classification and Severity Grading of Long-term and Late-Onset Health Events among Childhood Cancer Survivors in the St. Jude Lifetime Cohort.

Characterization of toxicity associated with cancer and its treatment is essential to quantify risk, inform optimization of therapeutic approaches for newly diagnosed patients, and guide health surveillance recommendations for long-term survivors. The NCI Common Terminology Criteria for Adverse Events (CTCAE) provides a common rubric for grading severity of adverse outcomes in cancer patients that is widely used in clinical trials. The CTCAE has also been used to assess late cancer treatment-related morbidity but is not fully representative of the spectrum of events experienced by pediatric and aging adult survivors of childhood cancer. Also, CTCAE characterization does not routinely integrate detailed patient-reported and medical outcomes data available from clinically assessed cohorts. To address these deficiencies, we standardized the severity grading of long-term and late-onset health events applicable to childhood cancer survivors across their lifespan by modifying the existing CTCAE v4.03 criteria and aligning grading rubrics from other sources for chronic conditions not included or optimally addressed in the CTCAE v4.03. This article describes the methods of late toxicity assessment used in the St. Jude Lifetime Cohort Study, a clinically assessed cohort in which data from multiple diagnostic modalities and patient-reported outcomes are ascertained. Cancer Epidemiol Biomarkers Prev; 26(5); 666-74. ©2016 AACR.

Five-year outcomes from a prospective trial of image-guided accelerated hypofractionated proton therapy for prostate cancer

Purpose: To report 5-year outcomes of a prospective trial of image-guided accelerated hypofractionated proton therapy (AHPT) for prostate cancer.Patients and methods: 215 prostate cancer patients accrued to a prospective institutional review board-approved trial of 70Gy(RBE) in 28 fractions for low-risk disease (n = 120) and 72.5Gy(RBE) in 29 fractions for intermediate-risk disease (n = 95). This trial excluded patients with prostate volumes of ≥60 cm3 or International Prostate Symptom Scores (IPSS) of ≥15, patients on anticoagulants or alpha-blockers, and patients in whom dose-constraint goals for organs at risk (OAR) could not be met. Toxicities were graded prospectively according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. This trial can be found on ClinicalTrials.gov (NCT00693238).Results: Median follow-up was 5.2 years. Five-year rates of freedom from biochemical and clinical disease progression were 95.9%, 98.3%, and 92.7% in the overall group and the low- and intermediate-risk subsets, respectively. Actuarial 5-year rates of late radiation-related CTCAE v3.0 grade 3 or higher gastrointestinal and urologic toxicities were 0.5% and 1.7%, respectively. Median IPSS before treatment and at 4+ years after treatment were 6 and 5 for low-risk patients and 4 and 6 for intermediate-risk patients.Conclusions: Image-guided AHPT 5-year outcomes show high efficacy and minimal physician-assessed toxicity in selected patients. These results are comparable to the 5-year results of our prospective trials of standard fractionated proton therapy for patients with low-risk and intermediate-risk prostate cancer. Longer follow-up and a larger cohort are necessary to confirm these findings.

Abstract P5-11-01: Self-evaluation of duration of adjuvant chemotherapy side effects in breast cancer patients: A prospective study

Abstract Background: Collection and analysis of chemotherapy-related side-effects (CSE) is critical in the management of cancer patients (pts) both in experimental trials and in the clinical practice. Usually, most of the available conventional systems like the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) capture CSE severity but not their duration. Recently we observed that self-evaluation of CSE incidence and severity by a CTCAE v4.0-based questionnaire was feasible and potentially more informative than doctor reports in pts undergoing standard adjuvant chemotherapy (ACT) for operable breast cancer (Montemurro et al., JAMA Oncol 2; 445-452, 2016). Our questionnaire had also a section for reporting, for each of the considered CSE, day of onset, duration and whether it was still present at the time of the visit. Here we report the analysis of patient self-evaluation of CSE duration. Methods: The study prospectively enrolled 604 pts receiving ACT for operable breast cancer between January 2011 and October 2013 at 11 sites in Italy. CTCAE v4.0 definitions of grade of severity for nausea, vomiting, constipation, anorexia, dysgeusia, diarrhea, fatigue, pain, paresthesia, and dyspnea were translated into Italian and rephrased. Questionnaires were administered after the first and third cycle of chemotherapy. At each time-point, information on CSE was extracted from the medical charts and compared to patient questionnaires. Results: Overall 1177 questionnaires were collected, 596 after cycle 1 and 581 after cycle 3 of ACT. A median of 82% of the fields was completely filled-in. 594 and 573 pts-questionnaires had a corresponding MD-questionnaire. Comparison of CSE duration after cycle 1 of chemotherapy as self-assessed by pts versus that reported by doctors is summarized in the table. For all CSE, patient reported longer duration than doctors did. Comparisons of reports after cycle 3 were similar.  PatientsDoctors Item (available paried data)Incidence (%)Mean duration* (SD)Incidence 8%)Mean Duration* (SD)P**Nausea (538)673.7 (3.6)401.6 (2.6)&amp;lt;0.01Vomiting (571)221.8 (1.7)111.2 (1.8)&amp;lt;0.01Constipation (546)492.7 (3.4)121.0 (2.9)&amp;lt;0.01Anorexia (563)533.8 (4.2)71.0 (1.9)&amp;lt;0.01Dysgeusia (556)505.0 (5.7)81.0 (4.1)&amp;lt;0.01Diarrhea (568)152.4 (2.8)40.9 (1.8)&amp;lt;0.01Fatigue (533)756.7 (5.2)250.9 (2.5)&amp;lt;0.01Pain (518)323.6 (4.4)100.5 (2.4)&amp;lt;0.01Paresthesia (582)232.9 (5.2)35.2 (0.8)&amp;lt;0.01Dyspnea (574)256.2 (5.6)25.0 (1.8)&amp;lt;0.01 *5% trimmed mean, ** Student T test for paired samples Conclusions: self-reporting of CSE duration is feasible in patients receiving ACT after breast cancer surgery by using a CTCAE-derived questionnaire. Because doctors tend to underestimate both incidence and duration of CSE, patient-reported outcomes should be incorporated into the clinical practice because of the potential to provide a better estimate of the total burden of CSE. Supporte by a grant of the Rete Oncologica Del Piemonte e della Valle d'Aosta. Citation Format: Galizia D, Martinello R, Cagnazzo C, Foresto M, Gallizioli S, Longo V, Berchialla P, Solinas G, Calori A, Volpone C, Parola G, Tealdi G, Ballari A, Montemurro F. Self-evaluation of duration of adjuvant chemotherapy side effects in breast cancer patients: A prospective study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-01.

Refined Hepatic Grading System Improves Risk Stratification of Long-Term Outcomes in the Patients Developing Chronic Gvhd

Background: Chronic GVHD (cGVHD) is a syndrome with diverse clinical features resembling autoimmune disorders. cGVHD affects long-term outcomes of allogeneic HCT, resulting in significant morbidity and mortality. Scoring the severity of cGVHD has been proposed with recent changes in the grading system of cGVHD based on the NIH consensus criteria (NCC) in 2015. Grading of liver GVHD is based on the severity of liver enzyme elevation both in NCC in 2005 and 2015. The cutoff of liver enzyme profiles for liver GVHD grading is arbitrarily determined but never been validated. In this study we attempted to evaluate 3 grading systems of hepatic parameters used in 1) NCC 2005, 2) NCC 2015, and 3) the common terminology criteria for adverse events (CTCAE) version 4.0. We also have adopted binary recursive partitioning (rpart) to define the optimal cut-off that provides the best risk stratification to overall survival (OS) after development of cGVHD.Methods: A retrospective review was conducted to compare the hepatic grading systems using liver enzyme parameters used in NCC 2005, NCC2015 and CTCAE v4.0. We reviewed 336 patients who developed cGVHD after allogeneic HCT performed between 2002 and 2014. Long-term outcomes including OS and non-relapse mortality (NRM) after the occurrence of cGVHD were analyzed using the 3 hepatic grading systems. Using rpart, we determined the optimal value for each component of the liver enzyme profile (i.e. AST, ALT, ALP and bilirubin level) was which could identify the best risk stratification of OS. A refined hepatic grading system was generated based on the cut off of ALP and bilirubin level proposed by rpart method, which divided the patients into three groups: low (bilirubin <14 mmol/L and ALP < 146 IU/L), intermediate (bilirubin level ≥14 mmol/L or ALP ≥ 146 IU/L) and high risk (both) . OS and NRM were also compared according to the refined hepatic grading system.Results: Out of 336 patients, 181 had liver involvement of cGVHD. The 3 year OS rate was 74.9% (66.7-81.3%) in the group developing liver GVHD, while that was 67.0% (57.7-74.7%) in the group without liver GVHD (p=0.629). There is no difference of non-relapse mortality (NRM) between patients with or without liver GVHD (14.4% vs. 17.2%; p= 0.661).In the patients developing liver GVHD, 3 hepatic grading systems were evaluated with respect to OS and NRM after onset of cGVHD. None of the 3 grading systems could stratify the patients statistically according to OS (p=0.211 for NCC 2005; p=0.423 for NCC 2015; p=0.461 for CTCAE4.0) or to NRM (p=0.615 for NCC 2005; p=0.327 for NCC 2015; p=0.941 for CTCAE v4.0). Using rpart, we found that 1) bilirubin level ≥14 mmol/L (p=0.01) and 2) ALP ≥ 146 IU/L (p=0.059) are associated with shorter OS, 2) AST and ALT levels were not associated with OS or NRM.A refined hepatic grading system was generated with assignment of a score to each risk factor. A score of 1 was assigned to bilirubin ≥14 mmol/L and ALP ≥ 146 IU/L, each. Total score was calculated with risk score 0 (n=54, 30.0%), risk score 1 (n=85, 57.2%) and risk score 2 (n=41, 22.8%). This hepatic grading system could stratify the patients according to their OS (p=0.015): 89.6% in low vs. 71.8% in intermediate vs. 58.0% in high risk group after onset of cGVHD.Then, we have applied the refined hepatic grading system into all 336 patients developing cGVHD regardless of organ involvement. As expected, the hepatic grading system can stratify 336 patients according to OS: 79.6% in low vs. 65.4% in intermediate vs. 53.9% in high risk group after onset of cGVHD (p=0.001); according to NRM: 11.9% in low vs. 17.2% in intermediate vs. 26.1% in high risk group after onset of cGVHD (p=0.089).Multivariate analysis was performed including 9 covariates including refined hepatic grading system, liver involvement of cGVHD, cGVHD subtype, cGVHD onset < 5 months, age (by decade), platelet counts, HLA match, gender mismatch, and T cell depletion, and confirmed that the refined hepatic grading system is an independent prognostic factor for OS (p=0.003, HR 0.491) in addition to cGVHD onset <5 months and HLA match.Conclusions: None of hepatic grading systems could stratify the patients according to OS/NRM after development of cGVHD. The refined hepatic grading system using bilirubin ≥14 mmol/L and ALP ≥ 146 IU/L at onset of cGVHD defined by the rpart method, could improve risk stratification of the patients developing cGVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Adverse event grading following CTCAE v3.0 underestimates hypertensive side effects in patients with glioma treated with Bevacizumab.

Anti-VEGF therapy with Bevacizumab (BEV) is widely used in cases of relapsed high-grade glioma (HGG). Arterial hypertension is a known side effect of anti-VEGF therapy. 42 Patients with relapsed HGG were treated with BEV 10mg/kg on days 1 and 15 of 28-day cycles in addition to treatment with 40mg TMZ daily until disease progression, based on magnetic resonance imaging and/or worsening of clinical status. In a retrospective analysis, hypertensive side effects were evaluated as the primary endpoint, while survival information in addition to toxicity was analyzed as secondary endpoint. Grading which employs the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 detected hypertensive events with a significantly higher sensitivity than CTCAE version 3.0. The rate of severe hypertensive events observed as CTCAE≥°3 were 9.5% in version 3.0 and 45.2% in version 4.0. The results presented here indicate that CTCAE version 3.0 may underreport the incidence and grade of BEV-induced hypertension within clinical trials. As hypertension has not only long-term, but also severe short-term side effects, we suggest that arterial hypertension under BEV should be scored according to CTCAE version 4.0 to avoid clinically relevant hypertension-related adverse events in these patients.

Stereotactic Body Radiotherapy for Elderly Patients With Medically Inoperable Pancreatic Cancer.

People over the age of 75 years account for approximately 40% of patients diagnosed with pancreatic cancer, many with comorbidities that may limit their treatment options. This study reports on the use of stereotactic body radiation therapy (SBRT) in this population. Twenty consecutively treated patients over the age of 75 with pathologically proven localized pancreatic cancer were included in this retrospective review. All had been evaluated by a multidisciplinary team as unable to tolerate surgery or combined chemoradiation therapy. Patient outcomes were analyzed to determine the safety and efficacy of SBRT in this elderly cohort. The median age was 83.2 years (minimum 77 y, maximum 90 y). Eighteen patients were treated at time of initial diagnosis, and 2 for recurrence after surgery. Eleven (55%) of the patients had an Adult Comorbidity Evaluation-27 comorbidity index score of 3 (severe) and 6 (30%) had a score of 2 (moderate). Fourteen patients were treated with 35 Gy in 5 fractions, 5 with 30 Gy in 5 fractions, and 1 patient with 36 Gy in 3 fractions. Seven (35%) patients had common terminology criteria for adverse events (CTCAE) V4.0 toxicity grade of 1-2, and 3 patients had a CTCAE V4.0 toxicity grade of 3-4, 2 with dehydration, and 1 had episodes of gastrointestinal bleeding. Three patients recurred locally, 10 had distant metastases, 4 of whom were found on the first posttreatment scan. Median overall survival was 6.4 months (95% confidence interval, 3.5-10.8 mo). Median recurrence-free survival was 6.8 months (95% confidence interval, 1.3-23.5 mo). Two patients survived >23 months. SBRT for pancreatic cancer appears to be a safe and effective method for treatment of elderly patients, even in the setting of severe comorbidities.

Quantitative tool to evaluate the somatic burden due to chemotherapy-induced adverse events: the somatic burden score.

Although there are several established methods like the Common Terminology Criteria for Adverse Events (CTCAE), heretofore, no objective, quantitative measurement exists for the somatic burden due to chemotherapy-induced adverse events (SB-CHINAE). We developed the Somatic Burden Score (SBS-AE) that combines the severity grade and duration of an AE. This paper describes the development and validation of the SBS-AE. SBS-AE's calculation was based on the number of days of CTCAE grades of a particular AE. The target value was the weighted, relative duration of an AE grade using CTCAE v3.0. We applied the SBS-AE in 64 patients with hematological malignancies and high-dose chemotherapy (HDC). The ratio measurement scale of the SBS-AE allows all statistical measures using SBS-AE, as all necessary mathematical operations are defined for it. We calculated an overall-SBS-HDC, defined as the total SB-CHINAE of HDC. To determine SBS-AE's criterion and construct validity, three self-rating scales and one clinician rating scale were used (German Clinical Trials Register, Main ID: DRKS00003453). The SBS-AE's criterion validity could be verified both with statistical significance and at least medium-to-large effects (p < 0.05, Cohen's d > 0.79, f (2) > 0.18). The quantitative measured SB-CHINAE was equally associated with subjectively assessed physical health-related quality of life (0.15 ≤ R (2) ≤ 0.49), objectively evaluated toxicities (0.48 ≤ R (2) ≤ 0.67), transfusion-dependent thrombocytopenia, and anemia (Cohen's d > 0.89). Patients' somatic burden of HDC was 5.8-fold greater compared with standard chemotherapy regimens. The SBS-AE indicates psychometric and clinical properties and may prove useful in the future design of cancer clinical trials and supportive care interventions inside of the inpatient setting.

Attention must be paid: adverse event reporting needs improvement

The insightful review by Russell and Colevas discusses various tools used in the reporting of adverse events, highlighting the need for consistent adverse event reporting guidelines [1]. With clinical trial data being larger and more complex than ever, accurate toxicity reporting is necessary to assess a drug’s efficacy and safety profile – the two factors that serve as an integral base for regulatory decision making. Both in and out of clinical trial settings, reporting rates are low and adverse event reports are often incomplete. To date there is no standard approach for adverse event reporting. The Common Terminology Criteria for Adverse Events (CTCAE) serves as a lexicon used to define an adverse event and its severity. In clinical trials, reports are graded in terms of the CTCAE v4.0 terminology – this system uses definitions from the Medical Dictionary for Regulatory Activities (MedDRA). To improve medication safety initiatives, established reporting guidelines are needed. In oncology trials, adverse events may arise from iatrogenic causes or from an underlying disease. The CTCAE v4.0 defines an adverse event as “any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medical treatment or procedure.” Adverse events can be symptoms, exam finding, abnormal laboratory values, or irregular radiology reports. A serious adverse event is life threatening, requires hospitalization, results in disability, or results in an abnormality or birth defect. In the CTCAE v4.0, adverse events are organized into System Organ Classes. These groups are based on anatomical, physiological or etiological criteria and are easily mapable to the MedDRA. The terminology was agreed upon by the National Cancer Institute and the European Medicines Agency. The severity of the adverse event is ranked on a 1–5 scale; one being the least severe and five resulting in death. This scale is not included in the MedDRA definitions – as it is unique to the CTCAE. Adverse event categories cover a wide array of laboratory values and clinical findings. Russell et al. examine adverse event reporting in clinical trials and provided eight recommendations for clinical investigators [1]: ■ Collect all serious adverse events without regard to causality;

Effect of CTCAE v4 grading of hypertension on reported toxicity in advanced cancer patients receiving vascular endothelial growth factor (VEGF)-targeting agents.

e15600 Background: The NCI Common Terminology Criteria for Adverse Events (CTCAE) system changed to version 4 in 2009, and several AE categories underwent changes in grading (Gr), including HTN. As many anti-neoplastic agents, particularly those targeting VEGF are associated with HTN, changing in the grading system may result in changes to maximum tolerated or recommended phase II doses in early dose-escalation studies or overall HTN AE reporting across all studies. Methods: We initially reviewed individual patient data of a multicenter phase I/II trial of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma (RCC), which graded AE’s using CTCAE v3. Individual patient (pt) data was reviewed and HTN AE’s were re-graded using CTCAE v4 criteria for up to 12 cycles of therapy on study. A separate (confirmatory) data set in pts with metastatic colorectal cancer (CRC) treated on a phase IIIb study of regorafenib was subsequently analyzed. Results: In the RCC study, only 1 of 23 pts with complete source documents available had stable highest HTN Gr across both CTCAE versions. In the CRC study, 0 of 8 pts had stable Gr. Table 1 compares each individual’s highest CTCAE v3 versus v4 grading of HTN in each study. Across both studies, all pts had HTN AE’s using CTCAE v4. Only 1 pt maintained grading using both versions (Gr 3), with 30 (96.8%) changing grades. Four (12.9%) moved from Gr 0 to Gr 1, fifteen (48.4%) from Gr 0 to Gr 2, five (16.1%) from Gr 1 to Gr 2, one from Gr 1 to Gr 3, and six (19.4%) from Gr 2 to Gr 3. Conclusions: Re-classification of grading in this study demonstrates that only 3.2% maintained stable grading of HTN across systems, with 51.6% increasing by 2 grades. The change in AE reporting criteria has the potential to significantly impact results of clinical trials. This may be particularly important with VEGF-targeted agents, with emerging data pointing towards HTN as a pharmacodynamic marker in pts with RCC, and may affect dosing and AE reporting of other drugs with blood pressure effects. Clinical trial information: NCT00121251, NCT01538680. [Table: see text]

Association of CTCAE v4 grading of hypertension with toxicity in patients with renal cancer receiving vascular endothelial growth factor (VEGF)-targeting agents.

447 Background: The NCI Common Terminology Criteria for Adverse Events (CTCAE) system underwent a change to version 4 in May 2009. In addition to system re-organization, several AE categories underwent changes in grading, including hypertension (HTN). As many anti-neoplastic agents, particularly those targeting VEGF are associated with HTN, changing in the grading system may result in changes to maximum tolerated or recommended phase II doses (MTD or RP2D) in dose-escalation studies using classic trial schemas (such as 3+3 design). Methods: We reviewed individual patient data of a phase I/II trial of sorafenib plus gemcitabine and capecitabine for advanced renal cell carcinoma (RCC). The phase I portion of the study was conducted to define the dose-limiting toxicity and RP2D of the combination (Am J Clin Oncol, 2011). The phase II portion further assessed efficacy as defined by objective response rate. Initial grading of AE’s during this study used CTCAE v3. Individual patient data was reviewed and HTN AE’s were re-graded using CTCAE v4 criteria for up to 12 cycles of therapy on study. Results: Of 28 pts enrolled, 23 (82.1%) had complete source documents available for the complete evaluation of HTN. The table compares each individual’s highest CTCAE v3 versus v4 grading of HTN on study. All pts had HTN AE’s using CTCAE v4. Only 1 pt maintained grading using both versions (Gr 3), with 22 (95.7%) changing grades. Two (8.7%) moved from Gr 0 to Gr 1, fourteen 60.9(%) from Gr 0 to Gr 2, four (17.4%) from Gr 1 to Gr 2, one from Gr 1 to Gr 3, and two (8.7%) from Gr 2 to Gr 3. Conclusions: Re-classification of grading in this study demonstrates that only 4.3% maintained stable grading of HTN across systems, with 65.2% increasing by 2 grades. The change in AE reporting criteria has the potential significantly impact results of clinical trials. This may be particularly important with VEGF-targeted agents, with emerging data pointing towards HTN as a pharmacodynamic marker in pts with RCC, and may affect dosing of other drugs with blood pressure effects, including CYP17 inhibitors for prostate cancer. Clinical trial information: NCT00121251. [Table: see text]

Common Terminology Criteria for Adverse Events (CTCAE) v4.0 Based Hybrid Patient and Physician Questionnaire for Head and Neck (HN) Radiotherapy Symptom Reporting

HN patients often experience multiple worsening symptoms during radiotherapy (RT), and some are unable to speak or have hoarseness. Physician driven systematic patient symptom questioning and obtaining comprehensible answers from the HN cancer patient can be challenging. To more efficiently monitor patient symptoms, a CTCAE v4.0 based hybrid patient and physician weekly questionnaire was created.