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Background: Recent reports indicated declines in HCV testing during the first half of 2020 in the United States due to COVID-19, but it is unclear whether a longer-term impact on HCV testing and treatment initiations was observed. The objective of this study was to investigate the nationwide impact of the pandemic on HCV testing and treatment in the United States through the end of 2020. Methods: We obtained monthly state-level volumes of HCV Ab testing and HCV treatment initiation, stratified by age, spanning two years from January 2019 until December 2020 from two large national labs (Quest and LabCorp). We performed segmented regression analysis by obtaining the estimated numbers of tests and treatments for each state from a mixed effects negative binomial model with Month as the main fixed predictor, and State as a random intercept. The predicted values from the model were aggregated by calculating the sum of the predicted number of tests or treatment initiations for each month and then aggregated values were regressed on month. Maximum likelihood estimation was used. Months from 1/2019 to 2/2020 (Months 1-14 in Figure) were designated the 'pre-COVID period' and 3/2020 to 12/2020 (Months 15-24) were designated the 'COVID period'. Results: During the pre-COVID period, the monthly number of HCV antibody tests in the US remained relatively stable with slight declines (p=0.712). Between February 2020 and March 2020, the predicted number of tests dropped significantly by 33% (p=0.004;similar trend in males and females and by state). During the COVID period through the end of 2020 (compared to the month-to-month trend before the COVID period) there was a significant increase in month-to-month testing (p=0.008;Figure 1). During the pre-COVID period, HCV treatment initiations were stable, but dropped significantly from March 2020 to April 2020 by 31% (p

Background Arginine starvation depletes the micronutrients required for DNA synthesis and interferes with both thymidylate synthetase activity and DNA repair pathways in preclinical models of hepatocellular carcinoma (HCC). Pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, potentiates the cytotoxic activity of platinum and pyrimidine antimetabolites in HCC cellular and murine models. Methods This was a global, multicenter, open-label, single-arm, phase 2 trial of ADI-PEG 20 and modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients who had HCC with Child-Pugh A cirrhosis and disease progression on ≥2 prior lines of treatment. The primary objective was the objective response rate assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary objectives were to estimate progression-free survival, overall survival, safety, and tolerability. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 36 mg/m2 . Results In total, 140 patients with advanced HCC were enrolled. The median patient age was 62 years (range, 30-85 years), 83% of patients were male, 76% were of Asian race, 56% had hepatitis B viremia, 10% had hepatitis C viremia, 100% had received ≥2 prior lines of systemic therapy, and 39% had received ≥3 prior lines of systemic therapy. The objective response rate was 9.3% (95% confidence interval [CI], 5.0%-15.4%), with a median response duration of 10.2 months (95% CI, 5.8 months to not reached). The median progression-free survival was 3.8 months (95% CI, 1.8-6.3 months), and the median overall survival was 14.5 months (95% CI, 13.6-20.9 months). The most common grade ≥3 treatment-related events were neutropenia (32.9%), white blood cell count decrease (20%), platelet count decrease (19.3%), and anemia (9.3%). Conclusions Concurrent mFOLFOX6 plus ADI-PEG 20 exhibited limited antitumor activity in patients with treatment-refractory HCC. The study was terminated early, and no further evaluation of the combination will be pursued. Lay summary Arginine is an important nutrient for hepatocellular carcinoma (HCC). The depletion of arginine with pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, appeared to make chemotherapy (FOLFOX) work better in animal models of HCC and in patients with HCC on an early phase clinical trial. To formally test this hypothesis in the clinical setting, a large, global, phase 2 clinical trial was conducted of ADI-PEG 20 and FOLFOX in the treatment of patients with refractory HCC. The study showed limited activity of ADI-PEG 20 and FOLFOX in advanced HCC and was stopped early.

Purpose: In patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR)-targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory PTEN activates PI3K/AKT signaling and contributes to resistance to androgen deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance. Patients and Methods: In this phase I study (NCT02215096), patients with PTEN-deficient mCRPC who progressed on prior enzalutamide received once-daily enzalutamide 160 mg plus PI3Kβ inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100-mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended phase II dose, and assess the 12-week non-progressive disease (PD) rate. Results: Overall, 37 patients were enrolled; 36 received ≥1 dose of GSK2636771 (200 mg: n = 22; 300 mg: n = 12; 400 mg: n = 2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n = 1; 300 mg: n = 2, 400 mg: n = 2). No new or unexpected adverse events or evidence of drug–drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% confidence interval: 28.2–71.8, n = 22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. Four of 34 (12%) patients had prostate-specific antigen reduction of ≥50%. Conclusions: Although there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed.

The purpose of this paper is to explore the state of existing research on microfinance lending discrimination against people with disabilities. It argues that existing literature suggests people with disabilities face notable discrimination in accessing microfinance (Labie et al., 2015). The attitudes of employees within microfinance institutions (MFIs) are one of the principal sources of such discrimination, which has important implications for the lives of people with disabilities (Cramm & Finkenflugel, 2008; Mersland et al., 2009; Labie et al., 2015). Moreover, studies conducted by Beisland & Mersland (2012) and Nuwagaba et al. (2012) found that people with disabilities tend not to apply for microfinance due to the anticipation of such rejection. People with disabilities face both ‘taste-based discrimination’ (prejudice) and ‘statistical discrimination’ (when a decision-maker uses individuals’ observable characteristics as a substitute for unobservable ones). It is reasonable to assume that reducing discrimination in the microfinance market would greatly benefit existing and prospective entrepreneurs with disabilities. However, this requires targeted interventions aimed at inducing systematic institutional reforms, changing the mindsets of employees and people with disabilities, and integrating appropriate accommodations within microfinance operations. In order to implement these changes, I conclude that microfinance regulators must work to identify areas of discrimination that are not correctly covered by existing lending practices.

Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/dose-expansion study in advanced HCC using FGF19 expression measured by IHC as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum tolerated dose (600 mg once daily) was expanded in 81 patients. Fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients [median duration of response: 5.3 months (95% CI, 3.7–not reached)] and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC. Significance: Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection. See related commentary by Subbiah and Pal, p. 1646. This article is highlighted in the In This Issue feature, p. 1631

Purpose: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. Experimental Design: We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). Results: MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC–targeted immunotherapy. Conclusions: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).

BackgroundMTL-CEBPA is a novel immunotherapy targeting the myeloid cell lineage which has shown promising clinical activity as monotherapy and combination therapy with tyrosine kinase inhibitors in hepatocellular carcinoma (HCC). Immunosuppressive myeloid cells are associated with worse outcomes to checkpoint inhibitors. Pre-clinical data have shown that MTL-CEBPA potentiates the oncological effect of PD-1 inhibitors.MethodsThis phase 1A/B, first-in-human, open-label, multicenter study evaluates the safety, tolerability, PK, and efficacy of MTL-CEBPA in combination with a pembrolizumab in adult patients with advanced solid tumours across 3 dose cohorts (70mg/98mg/130mg/m2 MTL-CEBPA once weekly for 3 consecutive weeks with final week break per cycle, with 200mg pembrolizumab every 3 weeks). The primary endpoint is safety and ORR; key secondary endpoints include PK, CR rate & DCR. Key inclusion criteria: Patients with advanced solid tumours who have progressed on standard of care therapy or for whom no standard therapy is available, measurable disease, ECOG PS 3 months. A dose exploration will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D).Results10 pts (3 men, 7 women; median age 50.5yrs), all with different tumor types (1 each of triple negative breast, methothelioma, squamous thymic, cholangiocarcinoma, eccrine, fibrolamellar hepatocellular, colorectal, pancreatic and 2 platinum resistant high-grade serous ovarian). 4 pts had ≥4 prior lines of treatment. All pts reported treatment-related AEs, 7 pts reported AEs considered related to MTL-CEBPA only and all were grade 1 or 2. The most common was nausea (n=3) followed by anaemia, headache, insomnia, neutropenia, pyrexia, transaminase increase and ventricular extrasystole (all n=1). Five pts reported AEs considered related to pembrolizumab only, 2AEs in 1 pt only were grade 3 (ALT and AST increases) There were no DLTs, SAEs or AEs leading to discontinuation or to death in the study. Tumor response was evaluated in 9 pts. 2 pts had a PR (epithelioid mesothelioma at 2 months with 83% tumour reduction, pt ongoing at 9 months & serous ovarian cancer at 2 months with 69% reduction in tumour, pt progressed at 6 months). Three pts had SD, 4 pts had PD as BOR, and 4 pts are continuing to receive treatment.ConclusionsMTL-CEBPA in combination with pembrolizumab demonstrated manageable toxicity at the dose levels tested and has shown antitumor activity. MTD was not reached and RP2D was determined at 130mg/m2 on day 1, 8 and 15 of a 28 day cycle. Enrolment into the dose expansion is ongoing.Trial RegistrationThis study was registered with ClinicalTrials.gov, number NCT04105335.Ethics ApprovalThe study was approved by the North East - Newcastle & North Tyneside 2 Research Ethics Committee, approval number 19/NE/0312.

Pancreatic cancer (PCa) is associated with a poor prognosis and high mortality rate. The causes of PCa are not fully elucidated yet, although certain exposome factors have been identified. The exposome is defined as the sum of all environmental factors influencing the occurrence of a disease during a life span. The development of an exposome approach for PCa has the potential to discover new disease-associated factors to better understand the carcinogenesis of PCa and help with early detection strategies. Our systematic review of the literature identified several exposome factors that have been associated with PCa alone and in combination with other exposures. A potential inflammatory signature has been observed among the interaction of several exposures (i.e., smoking, alcohol consumption, diabetes mellitus, obesity, and inflammatory markers) that further increases the incidence and progression of PCa. A large number of exposures have been identified such as genetic, hormonal, microorganism infections and immune responses that warrant further investigation. Future early detection strategies should utilize this information to assess individuals’ risk for PCa.

Introduction Margin accentuation (MA) using Irreversible electroporation (IRE) offers an unique opportunity to reduce the R1 resections in resectable pancreatic cancer (RPC). This study aims to assess the rate of margin positivity using IRE for MA during pancreaticoduodenectomy (PD) for resectable pancreatic head tumours. Materials and methods Following ethical approval, MA using IRE was carried out in 20 consecutive patients to posterior and superior mesenteric vein (SMV) margin, and the pancreatic neck, prior to the PD resection. The control group (non-IRE; n = 91) underwent PD without MA over the study period, March 2018 to March 2020. Results There was no difference between the two groups in terms of patients’ age, gender, pre-op biliary drainage, site of malignancy or pre-operative TNM stage. The overall margin positive rate for IRE group was lesser (35.0%) when compared to non-IRE group (51.6%; p = 0.177), with significantly less posterior pancreatic margin positivity (5.0% vs. 25.3%; p = 0.046). When only treated margins (SMA margin excluded) were compared, the IRE group had significantly lower margin positive rates (20.0% vs. 51.6%; p = 0.013). There was no difference between the two groups in terms of intra- or post-operative complications. With a median follow-up of 15.6 months, the median DFS and OS for IRE and non-IRE groups were 17 and 18 months (p = 0.306) and 19 and 22 months (p = 0.227) respectively. Conclusion Our pilot study confirms the safety of MA using IRE for RPC, with reduction in margin positivity. These results as a proof of concept are promising and need further validation with a randomised controlled trial.

Summary Background Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers. Methods ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0–2 (later limited to 0–1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov , NCT03037385 , and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis. Findings Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion–positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48–89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46–73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52–100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event. Interpretation Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer. Funding Blueprint Medicines.

Introduction Cabozantinib and ramucirumab are approved for the treatment of adults with hepatocellular carcinoma (HCC) following prior sorafenib treatment; ramucirumab is restricted to use in patients with serum alpha-fetoprotein (AFP) ≥ 400 ng/mL. This matching-adjusted indirect comparison evaluated the efficacy and safety of both drugs after sorafenib in patients with HCC and AFP ≥ 400 ng/mL. Methods Individual patient data (IPD) from the CELESTIAL trial (cabozantinib) and population-level data from the REACH-2 trial (ramucirumab) were used. To align with REACH-2, the CELESTIAL population was limited to patients who received first-line sorafenib only and had baseline serum AFP ≥ 400 ng/mL. The IPD from CELESTIAL were weighted to balance the distribution of 11 effect-modifying baseline characteristics with those of REACH-2. Overall survival (OS; primary endpoint) and progression-free survival (PFS) were compared for the CELESTIAL (matching-adjusted) and REACH-2 populations using weighted Kaplan-Meier (KM) curves and parametric (OS, Weibull; PFS, log-logistic) modeling. Rates of treatment-related adverse events (TRAEs) and TRAE-related discontinuations were also compared. Results After matching and weighting, baseline characteristics were balanced between populations (REACH-2, N = 292; CELESTIAL, effective sample size = 105). Weighted KM estimates for OS (median [95% CI]) were not significantly different between cabozantinib and ramucirumab (10.6 [9.5–17.3] months versus 8.7 [7.3–10.8] months; p = 0.104), but PFS was significantly longer for cabozantinib than for ramucirumab (5.5 [4.6–7.4] months versus 2.8 [2.7–4.1] months; p = 0.016). Parametric modeling results were consistent with the weighted KM analysis. Rates of some grade 3 or 4 TRAEs were lower with ramucirumab than with cabozantinib; however, TRAE-related discontinuation rates were similar (p = 0.271). Conclusion In this MAIC, cabozantinib significantly prolonged median PFS compared with ramucirumab after prior sorafenib treatment in patients with HCC and AFP ≥ 400 ng/mL; rates of some grade 3 or 4 TRAEs were lower with ramucirumab than cabozantinib but related discontinuation rates were not significantly different between treatments. Trial Registration Clinical trials.gov identifiers: CELESTIAL trial (NCT01908426) and REACH-2 trial (NCT02435433). Graphic abstract These slides can be retrieved under Electronic Supplementary Material. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01700-2.

Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1–15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6–15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC., All-trans retinoic acid - ATRA- is known to remodulate the stroma of pancreatic cancer in mice. Here, the authors carried out a Phase Ib trial in pancreatic patients and show that ATRA in combination with chemotherapy is a safe potential treatment for patients with advanced pancreatic cancer, and demonstrate a stromal modulatory effect.

ObjectiveTo compare the whole genomes sequencing (WGS) results in the 100K Genomes project with the results of routine molecular diagnostics in precision medicine.Materials and methodsWe analysed 374 cancers including a high tumour mutational burden (TMB-high) subgroup, defined as >10 non-synonymous single nucleotide variations per megabase. Colon cancers were evaluated for microsatellite instability (MSI), mismatch repair (MMR) genes and NRAS, KRAS and BRAF mutations using routine molecular diagnostics. Fluorescence in-situ hybridisation/immunohistochemistry was used to evaluate the Her2Neu status in breast cancers.ResultsThere was high correlation between WGS and routine diagnostic testing results irrespective of TMB status in colon cancers. Her2Neu status was discordant in 3 out of the 5 TMB-high breast cancers (p=0.049). The presence of ductal carcinoma in-situ correlated significantly with discordance (p=0.04). There were 3 (5%) discordant colorectal cases, all in the KRAS gene, 2 of which were from the non-invasive adenomatous component (p=0.0058). Of the 374 cases we identified 24 tumours with a TMB >10; comprising (colorectal carcinomas (CRCs) n=16, breast carcinomas n=5, bladder urothelial cell cancers n=3). Of the 16 TMB-high colorectal adenocarcinomas, 13 had MSI-high status. The same 13 had defective MMR protein expression. TMB-high colorectal cancers had 100% concordant results between WGS and NGS testing for KRAS, BRAF and NRAS (16/16).ConclusionThe microsatellite and mutational status of colorectal cancers evaluated by WGS seem to correlate well with the routine diagnostic testing if it is ensured that the invasive component is sequenced. Evaluation of WGS results need to be carefully correlated with histomorphology, as tumour heterogeneity/contamination with pre-malignant components needs to be taken into account.

Highlights • Treatment of T-47D breast cancer cells with silvestrol sensitised them to radiation. • 1 nM silvestrol caused a 34% reduction in cells exposed to 2 Gy. • Clonogenic assays revealed silvestrol had a dose modifying factor of 1.4. • Radiation was delivered to the tissue culture plate using a clinical LINAC machine., Purpose eIF4A is an RNA helicase that forms part of the machinery of translation initiation. Proteomic analysis demonstrated eIF4A expression to be at least two-fold greater in a radioresistant derivative of T-47D breast cancer cells compared to parental cells. Inhibition of eIF4A has previously been shown to re-sensitize lymphomas to chemotherapeutic agents that cause DNA damage. The objective of this work is to investigate whether inhibition of eIF4A using silvestrol sensitizes breast cancer cells to radiotherapy in tissue culture, using T-47D as a model system. Methods and materials T-47D cells were incubated in medium containing 0 nM to 1 nM silvestrol either for 24 h prior to irradiation at 0 Gy to 10 Gy, delivered by linear accelerator (LINAC) or continually for six days post irradiation. MTT viability and clonogenic assays were used to quantify response. Results Pre-treatment of T-47D cells with 1 nM silvestrol caused a 34% reduction (p = 0.014) in viability on irradiation at 2 Gy compared to treatment with a DMSO control, as assessed by MTT assay. Maintenance of cells in 1 nM silvestrol for six days following irradiation at 2 Gy caused a 58% reduction (p =

IntroductionPoorly differentiated (PD), extrapulmonary (EP), neuroendocrine carcinomas (NECs) are rare but aggressive neuroendocrine neoplasms. First-line treatment for advanced disease is an etoposide and platinum-based chemotherapy combination. There is no established second-line treatment for patients with PD-EP-NEC, and this is an area of unmet need.Methods and analysisNET-02 is a UK, multicentre, randomised (1:1), parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive PD-EP-NEC. One hundred and two eligible participants will be randomised to receive either nal-IRI/5-FU/folinic acid or docetaxel. The primary objective is to determine the 6-month progression-free survival (PFS) rate. The secondary objectives of this study are to determine PFS, overall survival, objective response rate, toxicity, quality of life and whether neuron-specific enolase is predictive of treatment response. If either treatment is found to have a 6-month PFS rate of at least 25%, that treatment will be considered for a phase III trial. If both treatments meet this target, prespecified selection criteria will be applied to establish which treatment to take forward.Ethics and disseminationThis study has ethical approval from the Greater Manchester Central Research Ethics Committee (reference no. 18/NW/0031) and clinical trial authorisation from the Medicine and Healthcare Products Regulatory Agency. Results will be published in peer-reviewed journals and uploaded to the European Union Clinical Trials Register.Trial registration numbersISRCTN10996604,NCT03837977, EudraCT Number: 2017-002453-11

Background: Emerging evidence points to potential roles of the humoral immune responses in the development of pancreatic cancer. Epidemiological studies have suggested involvement of viral and bacterial infections in pancreatic carcinogenesis. Experimental studies have reported high expression levels of antigens in pancreatic cancer cells. Therefore, we aimed to investigate the role of different components of humoral immunity in the context of pancreatic cancer. We evaluated associations between pre-diagnostic serum markers of the overall humoral immune system [immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM)], and the risk of pancreatic cancer in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) study. Methods: We selected all participants (≥20 years old) with baseline measurements of IgA, IgG or IgM (n = 41,900, 136,221, and 29,919, respectively). Participants were excluded if they had a history of chronic pancreatitis and individuals were free from pancreatic cancer at baseline. Multivariate Cox proportional hazards regression was used to estimate risk of pancreatic cancer for medical cut-offs of IgA, IgG, and IgM. Results: Compared to the reference level of 6.10–14.99 g/L, risk of pancreatic cancer was elevated among those with IgG levels

Purpose: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. Patients and Methods: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). Results: Thirty-eight participants have been treated across six dose levels (28–160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment–related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. Conclusions: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.

Many economically activepeople with disabilities do not haveaccess to affordable financialproducts and services. The consequence is that not only do people with disabilities experience social exclusion, but they also struggle to secure their financial lives. Althoughmicrofinance has been widely used in Bangladesh formore than three decades as a tool for reducing poverty and empowering poor people, few Microfinance Institutions (MFIs) recently started providing microfinance to some selected economically active people with disabilities. However, very little evidence exists to show how people with disabilitiesaccess microfinance. Therefore, the aim of this research is to identify the barriers or challenges that people with disabilities face to access microfinance. This study uses a qualitative case study approachbased on interviews with thirty-five economically active people with disabilities and ten stakeholdersalong with document analysis and observation as a tool for research data collection. Data analysis was conducted usingthematic analysis, with findings showingthat people with disabilities face substantial barriers to access microfinance. These barriers includeharder credit conditions, lack of social capital, negative staff attitudes,no or insufficient training,andabsence of an integrated approach. Theresearch suggests that the government should formulate an integrated policy framework aiming to help people with disabilities for financial inclusion. Moreover, Non-GovernmentalOrganizations (NGOs), Disabled People Organizations (DPOs), MFIsandpeople with disabilities couldcome together todevelop an effective partnership for designing social and economic development programs that canempower people with disabilities. Finally, this research suggestssome of the key strategies such as to develop MFI’s anti-discrimination policiesand theirimplementation, convenient credit designfor people with disabilities, improve skills, enhance capacitiesand, build self-confidence of people with disabilities. Furthermore, this research recommendsthat MFIs couldprovide financial literacy to people with disabilities, trainingto MFIs staffon disability issues, raise awareness among credit group membersabout disability, and more importantly identify people with disabilitiesespecially in the rural areas to enhance financial inclusionof people with disabilities.

Background Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. γ-Secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer. Methods This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5–100 mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478. Results A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared with 75 mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an ∼80% inhibition of plasma Aβ, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45–100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma. Conclusion Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing. Clinicaltrials.gov ID NCT01695005.

PurposeAfatinib, an irreversible ErbB family blocker, has demonstrated preclinical antitumor activity with chemotherapy.MethodsAs part of a phase I trial in patients with advanced solid tumors (NCT00809133; 3 + 3 dose-escalation design), we determined the maximum tolerated dose (MTD) of afatinib with carboplatin (A/C) or with carboplatin plus paclitaxel (A/C/P). Starting doses: afatinib 20 mg/day, carboplatin AUC6 (A/C) with paclitaxel 175 mg/m2 (A/C/P) (chemotherapy: Day 1 of 21-day cycles). The primary objective was to determine the MTDs; safety, pharmacokinetics and antitumor activity were also evaluated.ResultsThirty-eight patients received A/C (n = 12) or A/C/P (n = 26). No dose-limiting toxicities (DLTs) were reported with A(20 mg)/C(AUC6). One patient experienced DLT in the A(40 mg)/C(AUC6) cohort (grade 3 acneiform rash); A(40 mg)/C(AUC6) was determined as the recommended phase II dose (RP2D) for A/C. Two patients each had DLTs with A(20 mg/day)/C(AUC6)/P(175 mg/m2): fatigue, infection, diarrhea, small intestine hemorrhage, dehydration, renal impairment, neutropenic sepsis (n = 1), mucositis (n = 1); A(40 mg)/C(AUC5)/P(175 mg/m2): febrile neutropenia (n = 1), mucositis, fatigue (n = 1); and A(30 mg)/C(AUC5)/P(175 mg/m2): stomatitis (n = 1), mucositis (n = 1). No DLT was observed with A(20 mg)/C(AUC5)/P(175 mg/m2), determined as the RP2D for A/C/P. The most frequent drug-related adverse events were (A/C; A/C/P): rash (75%; 73%), fatigue (67%; 69%), and diarrhea (58%; 88%). Drug plasma concentrations were similar between cycles, suggesting no drug–drug interactions. Objective response rates in these heavily pretreated patients were A/C, 3/12 (25%); A/C/P, 5/26 (19%).ConclusionsAfatinib 40 mg/day (approved monotherapy dose) with carboplatin AUC6, and afatinib 20 mg/day with carboplatin AUC5 and paclitaxel 175 mg/m2 demonstrated manageable safety and antitumor activity. Afatinib > 20 mg/day in the triple combination was not well tolerated.

Summary Background Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Interpretation Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding Merck & Co, Inc.

Background Pancreatic cancer diagnosis and staging can be difficult in 10–20% of patients. Positron emission tomography (PET)/computed tomography (CT) adds precise anatomical localisation to functional data. The use of PET/CT may add further value to the diagnosis and staging of pancreatic cancer. Objective To determine the incremental diagnostic accuracy and impact of PET/CT in addition to standard diagnostic work-up in patients with suspected pancreatic cancer. Design A multicentre prospective diagnostic accuracy and clinical value study of PET/CT in suspected pancreatic malignancy. Participants Patients with suspected pancreatic malignancy. Interventions All patients to undergo PET/CT following standard diagnostic work-up. Main outcome measures The primary outcome was the incremental diagnostic value of PET/CT in addition to standard diagnostic work-up with multidetector computed tomography (MDCT). Secondary outcomes were (1) changes in patients’ diagnosis, staging and management as a result of PET/CT; (2) changes in the costs and effectiveness of patient management as a result of PET/CT; (3) the incremental diagnostic value of PET/CT in chronic pancreatitis; (4) the identification of groups of patients who would benefit most from PET/CT; and (5) the incremental diagnostic value of PET/CT in other pancreatic tumours. Results Between 2011 and 2013, 589 patients with suspected pancreatic cancer underwent MDCT and PET/CT, with 550 patients having complete data and in-range PET/CT. Sensitivity and specificity for the diagnosis of pancreatic cancer were 88.5% and 70.6%, respectively, for MDCT and 92.7% and 75.8%, respectively, for PET/CT. The maximum standardised uptake value (SUVmax.) for a pancreatic cancer diagnosis was 7.5. PET/CT demonstrated a significant improvement in relative sensitivity (p = 0.01) and specificity (p = 0.023) compared with MDCT. Incremental likelihood ratios demonstrated that PET/CT significantly improved diagnostic accuracy in all scenarios (p p = 0.001). PET/CT influenced management in 250 (45%) patients. PET/CT stopped resection in 58 (20%) patients who were due to have surgery. The benefit of PET/CT was limited in patients with chronic pancreatitis or other pancreatic tumours. PET/CT was associated with a gain in quality-adjusted life-years of 0.0157 (95% confidence interval –0.0101 to 0.0430). In the base-case model PET/CT was seen to dominate MDCT alone and is thus highly likely to be cost-effective for the UK NHS. PET/CT was seen to be most cost-effective for the subgroup of patients with suspected pancreatic cancer who were thought to be resectable. Conclusion PET/CT provided a significant incremental diagnostic benefit in the diagnosis of pancreatic cancer and significantly influenced the staging and management of patients. PET/CT had limited utility in chronic pancreatitis and other pancreatic tumours. PET/CT is likely to be cost-effective at current reimbursement rates for PET/CT to the UK NHS. This was not a randomised controlled trial and therefore we do not have any information from patients who would have undergone MDCT only for comparison. In addition, there were issues in estimating costs for PET/CT. Future work should evaluate the role of PET/CT in intraductal papillary mucinous neoplasm and prognosis and response to therapy in patients with pancreatic cancer. Study registration Current Controlled Trials ISRCTN73852054 and UKCRN 8166. Funding The National Institute for Health Research Health Technology Assessment programme.

Tumor associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are widely implicated in the suppression of immune responses in cancer and are associated with negative clinical outcomes. We report that in mouse tumor models, therapeutic up-regulation of the transcriptional factor C/EBPα with small activating RNA (MTL-CEBPA) blocks the suppressive activity of monocytic (M) MDSC and TAM without affecting polymorphonuclear (PMN) MDSC. MTL-CEBPA treatment demonstrated antitumor activity that was dependent on T cells. Combination of MTL-CEBPA and anti-PD1 antibody or with PMN-MDSC targeted therapy resulted in marked antitumor effect. A phase I trial was conducted in 36 patients with advanced hepatocellular carcinoma (HCC). Marked decrease in M-MDSC and the expression of genes and proteins involved in immune suppressive activity of these cells were observed. Combined treatment with MTL-CEBPA and sorafenib resulted in a 27% objective radiological response and three complete responses in patients with virally associated HCC. Tissue biopsies from these patients demonstrated decrease in M2 polarized macrophages within the tumors. Thus, therapeutic up-regulation of C/EBPα inhibited suppressive myeloid cells that resulted in potent antitumor effect in mice and with encouraging clinical response in cancer patients. We are currently recruiting to a multi-centre study of MTL-CEBPA in combination with a PD-1 inhibitor (pembrolizumab) in adult patients with advanced solid tumors (TIMEPOINT - ClinicalTrials.gov Identifier: NCT04105335). Citation Format: Ayumi Hashimoto, Debashis Sarker, Vikash Reebye, Sheba Jarvis, Mikael H. Sodergren, Andrew Kossenkov, Nina Raulf, Jenni Vasara, Pinelopi Andrikakou, Tim Meyer, Kai-Wen Huang, Ruth Plummer, Cheng Ean Chee, Duncan Spalding, Madhava Pai, David J. Pinato, Rohini Sharma, Bristi Basu, Daniel Palmer, Yuk-Ting Ma, Robert Habib, Anna Martirosyan, Naouel Elasri, Adeline Reynaud, John Rossi, Mark Cobbold, Nagy Habib, Dmitry Gabrilovich. Up-regulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1730.

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. This is attributed to the disease already being advanced at presentation and having a particularly aggressive tumor biology. The PDAC tumor microenvironment (TME) is characterized by a dense desmoplastic stroma, dominated by cancer-associated fibroblasts (CAF), extracellular matrix (ECM) and immune cells displaying immunosuppressive phenotypes. Due to the advanced stage at diagnosis, the depletion of immune effector cells and lack of actionable genomic targets, the standard treatment is still apoptosis-inducing regimens such as chemotherapy. Paradoxically, it has emerged that the direct induction of apoptosis of cancer cells may fuel oncogenic processes in the TME, including education of CAF and immune cells towards pro-tumorigenic phenotypes. The direct effect of cytotoxic therapies on CAF may also enhance tumorigenesis. With the awareness that CAF are the predominant cell type in PDAC driving tumorigenesis with various tumor supportive functions, efforts have been made to try to target them. However, efforts to target CAF have, to date, shown disappointing results in clinical trials. With the help of sophisticated single cell analyses it is now appreciated that CAF in PDAC are a heterogenous population with both tumor supportive and tumor suppressive functions. Hence, there remains a debate whether targeting CAF in PDAC is a valid therapeutic strategy. In this review we discuss how cytotoxic therapies and the induction of apoptosis in PDAC fuels oncogenesis by the education of surrounding stromal cells, with a particular focus on the potential pro-tumorigenic outcomes arising from targeting CAF. In addition, we explore therapeutic avenues to potentially avoid the oncogenic effects of apoptosis in PDAC CAF.

OBJECTIVE Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma (HCC), but data on its use in the elderly are inconclusive. METHODS All consecutive HCC patients who were treated in our institution with sorafenib since its licensing were included in the analysis. Patients were divided into two groups: (A) up to 75 and (B) older than 75 years old. Our endpoints were overall survival (OS) and time to treatment failure (TTF) because of disease progression or toxicity. Safety parameters and the prognostic effect of HCC characteristics were also investigated. RESULTS Data from 190 patients (157 men), median age 66 (26-87) years, were studied (A=151 and B=39). No significant difference in OS and TTF was detected between the two groups [7.1 (5.5-8.7) vs. 10.4 (6.5-14.3) months, P=0.360 and 4.2 (2.3-6.2) vs. 5.6 (3.1-8.1) months, P=0.369, respectively]. Incidence of toxicities at all grades and dose reductions were comparable between groups A and B. In a multivariate setting, patients with Child-Pugh B score at baseline were associated with a higher risk of death (adjusted hazard ratio=2.17, 95% confidence interval:1.24-3.79, P=0.007) and treatment failure (adjusted hazard ratio=4.64, 95% confidence interval: 2.55-8.42, P=0.001) and had shorter OS and TTF compared with patients with a Child-Pugh A (P=0.004 and P

BackgroundThis phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor.MethodsE7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50–800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines.ResultsForty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue,n = 4, 800 mg; anaphylaxis,n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50–800-mg oral dosing.ConclusionThe results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP.Clinical trial registrationwww.ClinicalTrials.gov code: NCT01618136.

BACKGROUND: Nested case-control studies examining the association between serum markers of chronic inflammation, focused on three specific biomarkers (CRP, IL-8 and TNF-α), and risk of pancreatic cancer have reported no associations. In this study, we evaluated associations between standard pre-diagnostic serum markers of chronic inflammation (CRP, albumin, haptoglobin and leukocytes) and pancreatic cancer risk in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) prospective cohort study.METHODS: We selected all participants (≥20 years old) with baseline measurements of CRP, albumin, haptoglobin and leukocytes between 1985 and 1996 (n = 61,597). Participants were excluded if they had a history of chronic pancreatitis and all individuals were free from pancreatic cancer at baseline. Cox proportional multivariable hazards regression analysis was carried out for medical cut-offs of CRP, albumin, haptoglobin and leukocytes.RESULTS: We observed an increased risk of pancreatic cancer for those individuals with higher levels of serum haptoglobin (≥1.4 g/L), CRP (≥10 mg/L) and leukocytes (≥10 × 109 cells/L) compared to those with haptoglobin levels CONCLUSIONS: We found an increased risk of pancreatic cancer associated with pre-diagnostic serum levels of haptoglobin, CRP and leukocytes. Our finding suggests a possible role of chronic inflammation in the aetiology of pancreatic cancer and highlight the need to further investigate this association.

3612 Background: The COVID-19 pandemic has hugely affected the spectrum of cancer care. Worldwide healthcare systems have rapidly reorganized cancer services to ensure patients continue to receive essential care whilst optimizing the use of systemic anti-cancer treatments (SACT) and minimizing exposure to SARS-CoV-2 infection. Our study aimed to identify the outcome of patients with gastrointestinal (GI) cancers in our Cancer Centre during the pandemic compared to the same period in 2019. Methods: Retrospective analysis of all GI patients receiving any SACT at Guy’s Cancer Centre from the 1 March-31 May 2020 and 2019. Demographic data (age, ethnicity, socio-economic status (SES), Performance status, cancer and SACT characteristics (type, intent and treatment-line) were collected during both periods. Also we collated the number of COVID-19 infections confirmed by PCR and severity defined by the WHO classification. Patients with clinical or radiological diagnosis were excluded. Results: 567 patients received SACT in 2019 and 417 patients in 2020 (26.4% less). No differences were observed in the demographic or tumour type characteristics. Commonest cancers in both periods were similar: colorectal (47.1, 47%), oesophago-gastric (29, 27.6%), pancreatic-biliary and NET tumours (23.8, 25.4%). However, there were a higher proportion of patients with advanced disease treated in 2020 (70.3% versus 55.2%). Treatment intent was similar in both years: radical (3.5 vs 3.8%), adjuvant (18.2% vs 17.3%), neoadjuvant (15.3% vs 12.7%) and palliative (63% vs 66.2%). There was an increase in the proportion of patients treated in the palliative first line setting (63.8% in 2020 vs 47.6% in 2019) and a reduction in the proportion of third or more treatment (8.7% versus 16.2%) mainly in the colorectal patients. Of 417 GI patients receiving SACT, 14 (3.35%) were diagnosed with COVID-19 infection. Of these, 64.3% were male, 92.9% were low SES and 35.7% were of Caucasian ethnicity. Colorectal cancer was the commonest (57.1%) tumour-type in the COVID-positive group and 57.1% had advanced disease. All the patients that died from COVID-19 were male. 13 patients were on chemotherapy and 1 was on targeted/biological treatment . None was in immunotherapy (n=4). Only one patient was neutropenic (grade 1). 8 patients (57.1%) had severe infection and there were 3 (21.4%) COVID-related deaths. Conclusions: Our study shows the delivery of SACT through the COVID-19 pandemic is relatively safe with low COVID-related mortality rate. It also reflects how we tailored the delivery of anti-cancer treatments to reduce the possible detrimental myelo-suppressive toxicities that could potentially put GI patients at higher risk of severe SARS-CoV-2 infection. This is crucial data that can inform anti-cancer treatment decision making during the protracted COVID-19 pandemic.

455 Background: The COVID-19 pandemic has prompted difficult decisions around the use of SACT. These were based on limited early data suggesting cancer patients receiving SACT were at an increased risk of COVID-19 severe infection and death. Our study aim was to identify the COVID-19 infection and mortality rates of GI cancer patients receiving SACT. Methods: All GI patients receiving SACT at Guy’s Cancer Centre between March, and May 31, 2020 were included. Demographic data (age, ethnicity, socio-economic status (SES)) and cancer characteristics (stage, SACT type, intent and treatment-line) were collected. COVID-19 infection was confirmed by PCR and severity defined by the World Health Organisation (WHO) classification. Patients with clinical or radiological diagnosis alone were excluded. Results: Of 417 GI patients receiving SACT during the study period, 345 (82.7%) received chemotherapy (alone or combined with targeted/biological treatment), 68 (16.3%) targeted/biological treatment alone and 4 (1%) immunotherapy. 14 (3.4%) patients were diagnosed with COVID-19, 13 were on chemotherapy and 1 on targeted/biological treatment. Commonest cancers in the COVID-19 positive group were colorectal (57.1%) and hepatobiliary (21.4%), followed by oesophago-gastric (14.3%) and neuroendocrine tumours (7.1%); 57.1% had stage IV disease. 64.3% of the positive patients were male (compared to 57.3% in the COVID-19 negative population), mean age was 57.7 years (63.1 years) and 85.7% had low SES (79.7%). 8 (57.1%) patients had severe infection and there were 3 (21.4%) COVID-19 related deaths. All the patients who died from COVID-19 were male and were receiving palliative chemotherapy. Only one patient was neutropenic (grade 1) when diagnosed with COVID-19. Conclusions: The rate of COVID-19 infection in our population was relatively low (3.4 %). Of the 14 COVID-19 positive patients, 57.1% had severe infection, 21.4% died (compared to 3.7% mortality in the non-infected group) and all but one were on chemotherapy. This prospective data, from a large UK comprehensive Cancer Centre, provides some evidence that continuing SACT through the pandemic is relatively safe. The risk of COVID-19 related infection and death must be off-set against the cancer-related morbidity and mortality associated with treatment delays.

309 Background: MIV-818 is an orally administered troxacitabine (TRX)-based nucleotide prodrug. It is highly metabolized by human hepatocytes, directing high levels of the chain-terminating nucleotide tri-phosphate to the liver, while minimizing exposure to other organs. The tri-phosphate is incorporated into DNA during replication, which leads to DNA double strand breaks, DNA damage responses, and cytotoxicity. Methods: Patients (pts), ≥18 years, ECOG performance status < 1, adequate organ function, with treatment-refractory hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA) or liver metastases (LM) from solid tumors were enrolled. In phase Ia, MIV-818 monotherapy was administered in an intra-patient dose-escalation design with doses of 3-70mg for 3-5 days in cycles of 21 days. Phase Ib is an inter-patient dose escalation in a 3+3 cohort design and is currently ongoing. Treatment is given until disease progression or unacceptable toxicity. The primary objective is to assess safety and tolerability and, for phase Ia, also to establish the starting dose for phase Ib. Key secondary objective was to evaluate the overall response rate based on RECIST v1.1. The pharmacokinetics of MIV-818 and its metabolites were evaluated, and on-treatment liver biopsies were collected to assess the pharmacokinetics and the pharmacodynamic effects of MIV-818. Results: Nine patients (7M; 2F), ECOG performance status 0 (n=3) or 1 (n=6), median age = 57 years (range: 50-84) with HCC (2 pts), iCCA (1) or LM (6) from solid tumors (mainly GI tract), previously treated with median 2 (1-5) lines of therapy, were included in phase Ia. Patients were dosed up to 60 mg 5 days/week. The most common treatment related AEs were those in the hematological system: neutropenia grade (gr) 1-4, neutropenic sepsis gr 4; thrombocytopenia gr 1-2, anemia gr 1-2. Elevated bilirubin gr 1-3 and liver enzymes gr 3 were also reported. Most of the AEs were reversible. Five pts discontinued due to AE and 4 pts discontinued due to progressive disease outside the liver after 2-4 cycles. Starting dose of phase Ib was determined to be 40mg 5 days/week. Tumor biopsies showed evidence of selective DNA damage in tumor tissue, including in hypoxic regions, with minimal or no impact of MIV-818 observed in healthy liver tissue. Conclusions: MIV-818 had an acceptable safety and tolerability profile. Biomarker data of liver biopsies demonstrated a selective effect of MIV-818 on cancer cells. Updated safety and efficacy data from phase Ib will be presented at the meeting. (NCT03781934). Clinical trial information: 2018-000995-14.

297 Background: Results from cohort 1 of KEYNOTE-224, an open-label, single-arm, multi-country phase II trial, demonstrated that pembro monotherapy was efficacious and tolerable in patients (pts) with advanced HCC previously treated with sorafenib. Here, we report results from KEYNOTE-224 cohort 2, which enrolled pts with advanced HCC and no prior systemic therapy. Methods: Eligible pts in cohort 2 had radiologically, histologically, or cytologically confirmed, incurable HCC not amenable or refractory to locoregional therapy, Child Pugh A liver disease, measurable disease based on RECIST 1.1 by blinded independent central review (BICR), ECOG PS 0-1, and BCLC stage C or B. Pts received pembro 200 mg IV Q3W for ~2 years or until disease progression, unacceptable toxicity, consent withdrawal, or investigator decision. Primary endpoint was ORR (RECIST 1.1 by BICR). Secondary endpoints included DOR, DCR, TTP, PFS, OS, and safety/tolerability. Response was assessed every 9 weeks. Efficacy and safety were assessed in pts who received ≥1 dose of study treatment. DOR was assessed in responders. The estimate and 95% CI of the ORR and DCR were based on the Clopper-Pearson method. Kaplan-Meier method was used to estimate OS, PFS, and DOR. A sample size of ~50 pts was chosen to provide acceptable precision for the assessment of ORR. Results: Cohort 2 enrolled 51 pts. The median time from the first dose to data cutoff (July 31, 2020) was 21 (range, 17-23) mo. The median age of pts was 68 (range, 41-91) years, one pt was HBV+, 80% had alcohol use, 8% were HCV+, 18% had vascular invasion, 35% had extrahepatic disease, 33% had BCLC Stage B disease, and 67% had BCLC Stage C HCC. ORR was 16% (95% CI, 7-29) and was similar across most subgroups. Median DOR was not reached (range, 3-20+ mo); 70% were estimated to have response duration ≥12 mo. Best overall responses were 0 CR, 8 (16%) PRs, 21 (41%) SDs, and 17 (33%) PDs; response was not evaluable or not assessed for 5 (10%) pts. DCR was 57%. The median TTP was 4 (95% CI, 3-8) mo. The median PFS was 4 (95% CI, 2-6) mo, and median OS was 17 (95% CI, 8-NA) mo. PFS rate at 18 mo was 16%, and OS rate at 18 mo was 46%. Treatment-related AEs (TRAEs) occurred in 27 (53%) pts; the most common TRAEs were diarrhea, fatigue, hypothyroidism, and myalgia. Grade ≥3 TRAEs occurred in 7 (14%) pts. TRAEs led to treatment discontinuation in 6% of pts. Immune-mediated AEs and infusion reactions occurred in 11 (22%) pts. One treatment-related death occurred due to myocarditis, with associated immune-related hepatitis. Conclusions: In pts with advanced HCC and no prior systemic therapy, pembro monotherapy provided durable anti-tumor activity, promising overall survival, and demonstrated a safety profile consistent with that previously observed for pembro in advanced HCC. These findings support further evaluation of pembro-based regimens for the treatment of HCC in the frontline setting. Clinical trial information: NCT02702414.

BACKGROUND S-222611 is an oral, reversible ErbB tyrosine kinase inhibitor of EGFR and HER2 with potent pre-clinical activity. MTD was not reached during the dose-escalation phase, (maximum dose 1600 mg QD). PK and efficacy data supported a daily dose of 800 mg. An expansion cohort of patients has been treated to further explore safety and efficacy. METHODS Subjects with advanced solid tumors expressing EGFR and/or overexpressing HER2 were enrolled. S-222611 800 mg daily was administered until disease progression or unacceptable toxicity. RESULTS 76 patients were included in this phase 1 expansion cohort with a variety of tumor types. Dose reduction was required because of adverse events in 15 patients; the most frequent of which being diarrhea and elevated bilirubin. Two patients discontinued treatment due to drug- related adverse events. Of the 25 patients with HER2-positive metastatic breast cancer (MBC), 4 partial responses were observed, and prolonged stable disease (≥ 6 months) was observed in 3 additional patients. These 25 patients had received prior HER2-directed therapy as shown in Table 1. Table 1. Prior therapies received by patients with HER2-positive MBCPrior therapyn (%)Trastuzumab22 (88)T-DM13 (12)Lapatinib16 (64)Chemotherapy23 (92) Six of these patients had brain metastases, in whom 1 intracranial response and 2 prolonged stable disease (≥ 6 months) were observed (Table 2). Table 2. HER2-positive MBC patients with brain metastases - best overall response to S-222611Pts #HER2 IHCBrain metastasesBest overall response (RECIST 1.1)Patient 13+Target lesionPRPatient 23+Target lesionSD (≥12 M)Patient 33+Target lesionSD (6.0 M)Patient 43+Non-target lesionSD (4.7 M)Patient 53+Non-target lesionSD (3.3 M)Patient 63+Non-target lesionNE The patient showing intracranial response was previously treated with lapatinib and capecitabine after diagnosis of BM. CONCLUSIONS S-222611 was well tolerated at a dose of 800 mg once daily. Anti-tumour activity, including shrinkage of brain metastases, was evident in a heavily pre-treated population of patients with HER2-positive breast cancer. Citation Format: Baird RD, Arkenau H-T, Deva S, Cresti N, Garcia-Corbacho J, Hogarth L, Frenkel E, Kawaguchi K, Arimura A, Donaldson K, Posner J, Sarker D, Jodrell D, Plummer R, Spicer J, Italiano A. Phase I expansion of S-222611, a reversible inhibitor of EGFR and HER2, in advanced solid tumors, including HER2-positive breast cancer patients with brain metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-26.

4601 Background: MTL-CEBPA is the first small activating RNA to enter clinical trials and upregulates C/EBPα, a master regulator of myeloid cell differentiation. We previously reported a favourable safety profile of MTL-CEBPA as a single agent in HCC (Sarker D et al, ASCO 2018). After discontinuation of MTL-CEBPA, 3 out of 5 patients (pts) treated with sorafenib off study had a complete response (CR) of 7-18 months duration; 2 pts of which demonstrated resolution of lung metastases for > 1 year. Here we provide new data on pts prospectively treated with MTL-CEBPA + sorafenib. Methods: Primary objective was to assess safety and tolerability of MTL-CEBPA 90-130mg/m2 QW or BIW in combination with sorafenib 400mg BD administered to HCC patients either concomitantly or sequentially, in cohorts either tyrosine kinase inhibitor (TKI) naive or resistant. Secondary objectives included preliminary assessment of activity by response rate (RECIST v1.1) and immune landscape analysis. Results: As at the cut off date of 1 Feb 2020, 12 pts have been treated with MTL-CEBPA co-administered with sorafenib and 14 pts with MTL-CEBPA followed by sorafenib (23M/3F, median age 65.5years, range 44-83, ECOG PS 0/1: 18/8). The most common treatment-related AEs (all grades/grade 3-4) in these groups include facial flushing (4/0), raised AST (4/2) raised ALT (2/1), fatigue (5/0), raised ALP (2/0), and anaemia (2/2), diarrhoea (3/0), rash (2/0) and anorexia (1/0). Of 14 evaluable pts in the TKI naive cohorts, 2 pts had CR, 3 pts had partial response and 7 had stable disease. 9/10 pts in the TKI resistant cohorts evaluable for efficacy had stable disease. Flow cytometry demonstrated statistically significant decreases in frequency of immature CD66+CD10− neutrophils and myeloid derived suppressor cells. IHC demonstrated significant reduction in M2 macrophages in tumour biopsies. Conclusions: MTL-CEBPA + sorafenib is well tolerated with an acceptable safety profile. This study has confirmed signals of objective response to the combination treatment in TKI naïve HCC patients with viral aetiology, warranting expanded development in these patients. Updated efficacy and safety data will be presented. Clinical trial information: NCT02716012. [Table: see text]

554 Background: MTL-CEBPA is the first saRNA to enter clinical trials and targets the transcription factor C/EBPα, a master regulator of myeloid cell differentiation. We have previously reported a favourable safety profile of MTL-CEBPA given as a single agent QWx3 every 28 days, in patients with HCC (Sarker D et al, ASCO 2018). After discontinuation of MTL-CEBPA, three out of five patients treated with sorafenib off study have had maintained complete radiological response (CR) of 7-18 months duration; 2 patients demonstrated resolution of lung metastases > 1 year. Here we provide updated data on phase 1 patients treated with sorafenib off study as well as subsequent combination cohorts. Methods: MTL-CEBPA 130mg/m2 QWx3 or BIW and sorafenib 400mg bd were administered to patients with HCC using combination or sequential dosing regimens, in cohorts either tyrosine kinase inhibitor naive or resistant. On treatment liver biopsies evaluated changes in M2 macrophages (CD163). Flow cytometry of peripheral blood determined changes in myeloid cell populations. Results: 12 patients have been treated with MTL-CEBPA co-administered with sorafenib and 14 patients treated with MTL-CEBPA followed by sorafenib (23M/3F, median age 65.5years, range 44-83, ECOG PS 0/1: 18/8). The most common treatment-related AEs (all grades/grade 3) in this group include facial flushing (4/0), raised AST (3/1) raised ALT (2/1), fatigue (5/0), raised ALP (2/0), and anaemia (2/2), diarrhoea (3/0), rash (2/0) and anorexia (1/0). 1 TKI naïve patient in the co-administration cohort has maintained CR at 7 months and two patients have SD (ongoing at 3 & 4 months both in sequential cohort). IHC in the patient with CR has demonstrated 95% reduction in M2 macrophages with significant decrease in frequency of immature CD10- neutrophils (-85.7%; p = 0.0078), PMN-MDSCs (-49.3%; p = 0.00145) and M-MDSCs (-18.4%; P = 0.0072). All responding patients have underlying HBV or HCV. Conclusions: MTL-CEBPA is a novel saRNA targeting myeloid cells which may result in a significantly enhanced oncological response in HCC of viral aetiology. Updated safety and efficacy data will be presented. Clinical trial information: NCT02716012.

// Emma J. Jordan 1 , James Spicer 1, 2 and Debashis Sarker 1, 2 1 School of Cancer and Pharmaceutical Sciences, King’s College London, London, UK 2 Guy’s and St Thomas’ NHS Foundation Trust, Guy’s Hospital, London, UK Correspondence to: Debashis Sarker, email: debashis.sarker@kcl.ac.uk Keywords: adverse events; phase I trials; molecularly targeted agents; cytotoxic agents Received: June 02, 2018 Accepted: August 27, 2018 Published: September 21, 2018 ABSTRACT Background: Grade 3 and 4 adverse events (AEs) during cycle 1 are traditionally used for dose escalation decisions in Phase I oncology trials. With molecularly targeted agents (MTAs), assessment of lower grade AEs and those in later cycles is considered increasingly relevant. Methods: We conducted a retrospective analysis of AEs in patients enrolled onto relevant phase I trials of MTAs and cytotoxic combinations (CCs) at our UK centre between 2006 and 2016. All AEs in the first six cycles deemed at least ‘possibly related’ were recorded. Results: A total of 912 AEs were identified in 127 patients across 15 trials. Mean AE totals for CCs or MTAs respectively was 4.7 versus 3.0 in cycle 1, 3.8 versus 2.8 in cycles 2-6. Patients on CCs had higher mean AEs in six cycles compared to those on MTAs (8.5 vs. 5.7, p = 0.0005). For patients experiencing grade 3 AEs, 58% (CCs) and 60% (MTAs) occurred for the first time after cycle 1. Conclusion: Overall AE incidence was lower in MTAs than CCs across six cycles. For MTAs, more frequent incidence of first grade 3/4 AEs after cycle 1 supports incorporation of delayed AEs into recommendations for Phase 2 dosing.

Introduction: Multi-modal therapy for adrenocortical carcinoma (ACC) includes surgery, therapy with the adrenolytic agent mitotane and systemic chemotherapy. Achievement of therapeutic mitotane concentrations (≥14 mg/l) has been related to improved outcomes. Aim: To evaluate the effectiveness of a defined* high dose protocol mitotane therapy in patients with advanced ACC (stages III and IV). Methods: Review of patients presenting to KCH with stage III or IV ACC and the mitotane concentration achieved through the Lysosafe monitoring service. Results: N=57 patients were referred and first diagnosed with ACC (2008-17) of whom 44 patients had stage III or IV disease at diagnosis and were managed actively with surgery and/or mitotane therapy. 40/44 patients underwent surgical resection of the primary tumour;11/22 patients with stage IV disease subsequently received systemic chemotherapy [10 patients received a combination of etoposide, doxorubicin and cisplatin (EDP) and 1 patient received a combination of carboplatin and etoposide]. 38/44 patients were initiated on mitotane therapy. The median overall survival of patients with stage IV disease was 25.3 months. The median survival for stage III has not been reached. An additional 9 patients had prior management, including surgery, elsewhere and were referred for mitotane initiation. A total of 47 patients were therefore included in the mitotane pharmacokinetic analysis. Six patients were excluded: 3 patients died shortly after mitotane initiation, 1 patient withdrew due to a severe reaction and 2 patients had not completed 12 weeks therapy at the time of submission. Of the remaining 41 patients, 33 commenced the ‘high dose’ protocol and the remainder the ‘low dose’ protocol. For patients on the high dose protocol, 25/33 (76%) reached a mitotane concentration ≥14 mg/l within 12 weeks of initiation of therapy, compared to 3 patients from the low dose protocol group (P=0.084). In the high dose protocol group, 21 patients (84%) maintained therapeutic drug concentrations in ≥50% of the subsequent follow-up samples and 12 patients (48%) maintained therapeutic drug concentrations in ≥75% of subsequent samples. Conclusion: The use of high dose protocol mitotane therapy is a successful strategy to achieve and maintain therapeutic drug concentrations when treating patients with advanced ACC (stages III and IV). In combination with an assertive surgical approach and optimal chemotherapy, this has resulted in outcomes that compare favourably (median OS 25.5 months in stage IV disease) with previously published series which describe a median OS

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme - arginine deiminase - conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and Patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2:1 to ADI-PEG 20 18 mg/m2 vs. placebo intramuscular (IM) injection weekly. The primary endpoint was overall survival (OS), with 93% power to detect a 4 to 5.6 months increase in median OS (1-sided α = 0.025). Secondary endpoints included progression-free survival (PFS), safety, and arginine correlatives. Results: 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 vs 7.4 for placebo (p = 0.88, HR = 1.02) and median PFS 2.6 months vs. 2.6 (p = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in less than 5% of patients. Two patients on ADI-PEG 20 had ≥ grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 vs. 10.4% on placebo, none related to therapy. Post-hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number: www.clinicaltrials (NCT 01287585).

Background MTL-CEBPA is a first-in-class small activating RNA (saRNA) oligonucleotide which specifically up-regulates the myeloid cell master regulator, C/EBP-α (CCAAT/enhancer-binding protein alpha). Methods We conducted a phase I, 3 + 3 dose escalation and dose expansion trial of MTL-CEBPA in adults with HCC or secondary liver cancer. Patients received intravenous MTL-CEBPA at 28-160 mg/m2 for 3 weeks either QW, BIW at d1 and d2, BIW at d1 and d3, or TIW at d1, d2, and d3 followed by a rest period of 1 week. Adverse events (AEs), serum PK, WBC biomarkers and anti-tumour activity were assessed. Results 38 participants (31 HCC, 4 colorectal, 2 fibrolamellar, 1 ampullary) have been treated across 6 dose levels (28-160 mg/m2) and 3 dosing schedules: 29M/9F, median age 66 years (range 27 - 80), ECOG PS 0/1: 16/22. In 28 HCC patients evaluable for efficacy, PR was achieved in 1 pt, SD > 1 year in 1 patient and SD Conclusions MTL-CEBPA is a first-in-class therapy targeting the myeloid cell master regulator C/EBP-α. In HCC patients MTL-CEBPA demonstrated a good safety profile, induced altered gene expression in WBC and as well as anti-tumour activity. These encouraging phase I data validate targeting of CEBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC. Clinical trial identification NCT02716012. Legal entity responsible for the study MiNA Therapeutics. Funding MiNA Therapeutics. Disclosure D. Sarker: Travel / Accommodation / Expenses: MiNA Therapeutics; Honoraria (self): MSD; Honoraria (self): EISAI; Honoraria (self): BAYER; Honoraria (self), Travel / Accommodation / Expenses: IPSEN. K. HUANG: Research grant / Funding (self): MiNA Therapeutics. N. Habib: Shareholder / Stockholder / Stock options: MiNA Therapeutics. All other authors have declared no conflicts of interest.

Neuroendocrine tumors are heterogeneous cancers that can present with advanced disease. Treatment stratification is often based on limited characterization of tumor behavior from histological grade and imaging assessments. Personalized medicine strategies focus on tailoring therapy through characterization of cancer pathways and the development of biomarkers. This review article explores the current personalized medicine landscape in gastroenteropancreatic neuroendocrine tumors, from tissue and circulating biomarkers development through to tumor heterogeneity and reimbursement issues.

In the last decade treatment for colorectal cancer (CRC) has evolved with the addition of contemporary chemotherapy drugs and targeted therapies. Despite this progress, our drug armamentarium is by no means complete and modern molecular biology techniques have led to the identification of a number of 'druggable' targets. One of the most important current drug targets is the phosphatidyl-inositol 3-kinase (PI3K) pathway, which is frequently deregulated in patients with CRC. In vitro and in vivo data strongly support the clinical development of compounds affecting signal transduction via the PI3K pathway. In this review we outline the role of PI3K in the development and progression of CRC and discuss data from current and ongoing clinical trials targeting this pathway. In addition we make suggestions toward the optimization of future research in order to derive the maximum benefit for patients with CRC.

Background S-222611 is a reversible inhibitor of EGFR, HER2 and HER4 with preclinical activity in models expressing these proteins. We have performed a Phase 1 study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and efficacy in patients with solid tumours expressing EGFR or HER2. Patients and methods Subjects had advanced tumours not suitable for standard treatment, expressing EGFR or HER2, and/or with amplified HER2 . Daily oral doses of S-222611 were escalated from 100 mg to 1600 mg. Full plasma concentration profiles for drug and metabolites were obtained. Results 33 patients received S-222611. It was well tolerated, and the most common toxicities, almost all mild (grade 1 or 2), were diarrhoea, fatigue, rash and nausea. Only two dose-limiting toxicities occurred (diarrhoea and rash), which resolved on interruption. MTD was not reached. Plasma exposure increased with dose up to 800 mg, exceeding levels eliciting pre-clinical responses. The plasma terminal half-life was more than 24 h, supporting once daily dosing. Responses were seen over a wide range of doses in oesophageal, breast and renal tumours, including a complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Four patients have remained on treatment for more than 12 months. Downregulation of pHER3 was seen in paired tumour biopsies from a responding patient. Conclusions Continuous daily oral S-222611 is well tolerated, modulates oncogenic signalling, and has significant antitumour activity. The recommended Phase 2 dose, based on PK and efficacy, is 800 mg/day.