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To assess efficacy and toxicity of combination immunotherapy with ipilimumab plus nivolumab in routine practice in a retrospective multicentre cohort of patients with advanced melanoma.This retrospective analysis included patients with advanced melanoma treated with ipilimumab and nivolumab between October 2015 and January 2020 at six centres in Australia, Europe and the United States of America. We describe efficacy outcomes (overall survival [OS], progression-free survival [PFS] and objective response rate [ORR]) in treatment-naïve and pre-treated patients, with and without brain metastases, plus treatment-related adverse events (trAEs) in all patients treated.A total of 697 patients were identified; 472 were treatment-naïve of which 138 (29.2%) had brain metastases, and 225 were previously treated of which 102 (45.3%) had brain metastases. At baseline, 32.3% had stage M1c and 34.4% stage M1d disease. Lactate dehydrogenase was high in 280 patients (40.2%). With a median follow-up of 25.9 months, median OS in the 334 treatment-naïve patients without brain metastases was 53.7 months (95% confidence interval [CI] 40.8-NR) and 38.7 months (95% CI 18.6-NR) for the 138 treatment-naïve patients with brain metastases. For the entire cohort the ORR was 48%, for treatment-naïve patients without brain metastases ORR was 56.6% with a median PFS of was 13.7 months (95% CI 9.6-26.5). Median PFS was 7.9 months (95% CI 5.8-10.4) and OS 38 months (95% CI 31-NR) for the entire cohort. Grade 3-4 trAE were reported in 44% of patients, and 4 (0.7%) treatment-related deaths (1 pneumonitis, 2 myocarditis and 1 colitis) were recorded.The outcome and toxicity of combination immunotherapy with ipilimumab and nivolumab in a real-world patient population are similar to those reported in pivotal trials.

Purpose: CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus is selectively taken up by α-FR–overexpressing tumors. Patients and Methods: A 3+3 dose escalation design was used. During dose escalation, CT900 doses of 1–6 mg/m2 weekly and 2–12 mg/m2 every 2 weeks (q2Wk) intravenously were evaluated. Patients with high-grade serous ovarian cancer were enrolled in the expansion cohorts. Results: 109 patients were enrolled: 42 patients in the dose escalation and 67 patients in the expansion cohorts. At the dose/schedule of 12 mg/m2/q2Wk (with and without dexamethasone, n = 40), the most common treatment-related adverse events were fatigue, nausea, diarrhea, cough, anemia, and pneumonitis, which were predominantly grade 1 and grade 2. Levels of CT900 more than 600 nmol/L needed for growth inhibition in preclinical models were achieved for >65 hours at a dose of 12 mg/m2. In the expansion cohorts, the overall response rate (ORR), was 14/64 (21.9%). Thirty-eight response-evaluable patients in the expansion cohorts receiving 12 mg/m2/q2Wk had tumor evaluable for quantification of α-FR. Patients with high or medium expression had an objective response rate of 9/25 (36%) compared with 1/13 (7.7%) in patients with negative/very low or low expression of α-FR. Conclusions: The dose of 12 mg/m2/q2Wk was declared the recommended phase II dose/schedule. At this dose/schedule, CT900 exhibited an acceptable side effect profile with clinical benefit in patients with high/medium α-FR expression and warrants further investigation.

Over the past decade, various liquid biopsy techniques have emerged as viablealternatives to the analysis of traditional tissue biopsy samples. Such surrogate ‘biopsies’ offer numerous advantages, including the relative ease of obtaining serial samples and overcoming the issues of interpreting one or more small tissue samples that might not reflect the entire tumour burden. To date, the majority of research in the area of liquid biopsies has focused on bloodbasedbiomarkers, predominantly using plasma- derived circulating tumour DNA (ctDNA). However, ctDNA can also be obtained from various non- blood sources and these might offer unique advantages over plasma ctDNA. In this Review, we discuss advances in the analysis of ctDNA from non- blood sources, focusing on urine, cerebrospinal fluid, and pleural or peritoneal fluid, but also consider other sources of ctDNA. We discuss how these alternative sources can have a distinct yet complementary role to that of blood ctDNA analysis and consider varioustechnical aspects of non- blood ctDNA assay development. We also reflect on the settings in which non- blood ctDNA can offer distinct advantages over plasma ctDNA and explore some of the challenges associated with translating these alternative assays from academia into clinical use.

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mp3 file (10 MB). In the March edition of the Cancer Discovery podcast, Executive Editor Mark Landis talks with David A. Tuveson about his paper, which provides mechanistic insight into the clinical cooperation observed between gemcitabine and nab-paclitaxel in the treatment of pancreatic cancer.

Nanoparticle albumin-bound (nab)-paclitaxel, an albumin-stabilized paclitaxel formulation, demonstrates clinical activity when administered in combination with gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDA). The limited availability of patient tissue and exquisite sensitivity of xenografts to chemotherapeutics have limited our ability to address the mechanistic basis of this treatment regimen. Here, we used a mouse model of PDA to show that the coadministration of nab-paclitaxel and gemcitabine uniquely demonstrates evidence of tumor regression. Combination treatment increases intratumoral gemcitabine levels attributable to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase. Correspondingly, paclitaxel reduced the levels of cytidine deaminase protein in cultured cells through reactive oxygen species–mediated degradation, resulting in the increased stabilization of gemcitabine. Our findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PDA and highlight the advantages of genetically engineered mouse models in preclinical therapeutic trials.Significance: This study provides mechanistic insight into the clinical cooperation observed between gemcitabine and nab-paclitaxel in the treatment of pancreatic cancer. Cancer Discovery; 2(3); 260–9. ©2012 AACR.Read the Commentary on this article by Clark, p. 208This article is highlighted in the In This Issue feature, p. 193

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Supplementary Figure from A Phase I Trial of CT900, a Novel α-Folate Receptor–Mediated Thymidylate Synthase Inhibitor, in Patients with Solid Tumors with Expansion Cohorts in Patients with High-Grade Serous Ovarian Cancer

Supplementary Table from A Phase I Trial of CT900, a Novel α-Folate Receptor–Mediated Thymidylate Synthase Inhibitor, in Patients with Solid Tumors with Expansion Cohorts in Patients with High-Grade Serous Ovarian Cancer

Purpose:CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus is selectively taken up by α-FR–overexpressing tumors.Patients and Methods:A 3+3 dose escalation design was used. During dose escalation, CT900 doses of 1–6 mg/m2 weekly and 2–12 mg/m2 every 2 weeks (q2Wk) intravenously were evaluated. Patients with high-grade serous ovarian cancer were enrolled in the expansion cohorts.Results:109 patients were enrolled: 42 patients in the dose escalation and 67 patients in the expansion cohorts. At the dose/schedule of 12 mg/m2/q2Wk (with and without dexamethasone, n = 40), the most common treatment-related adverse events were fatigue, nausea, diarrhea, cough, anemia, and pneumonitis, which were predominantly grade 1 and grade 2. Levels of CT900 more than 600 nmol/L needed for growth inhibition in preclinical models were achieved for >65 hours at a dose of 12 mg/m2. In the expansion cohorts, the overall response rate (ORR), was 14/64 (21.9%). Thirty-eight response-evaluable patients in the expansion cohorts receiving 12 mg/m2/q2Wk had tumor evaluable for quantification of α-FR. Patients with high or medium expression had an objective response rate of 9/25 (36%) compared with 1/13 (7.7%) in patients with negative/very low or low expression of α-FR.Conclusions:The dose of 12 mg/m2/q2Wk was declared the recommended phase II dose/schedule. At this dose/schedule, CT900 exhibited an acceptable side effect profile with clinical benefit in patients with high/medium α-FR expression and warrants further investigation.

Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors

Purpose:To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib.Patients and Methods:This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non–small cell lung cancer. The study comprised four arms: (i) AZD8186 monotherapy dose finding; (ii) monotherapy dose expansion; (iii) AZD8186/abiraterone acetate (with prednisone); and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses.Results:In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60-mg twice daily [BID; 5 days on, 2 days off (5:2)] and 120-mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The PKs of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited antitumor activity by imaging and, in prostate cancer, PSA reduction.Conclusions:AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate/prednisone or vistusertib was also tolerated. There was preliminary evidence of antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway–dependent cancers.

Supplementary Data from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors

Effective treatment for gastrointestinal (GI) cancers is a significant unmet need. Gremlin-1, secreted by cancer-associated fibroblasts, downregulates bone morphogenetic proteins (BMP), members of the transforming growth factor β superfamily, resulting in tumor stemness, hyperproliferation, and invasiveness. Ginisortamab, a fully human IgG4P mAb, neutralizes gremlin-1, thus restoring BMP signaling. Preclinical studies showed that ginisortamab binds to gremlin-1 and has antitumor activity in several mouse models, including GI cancers. Here we report the initial findings from Part A (monotherapy dose escalation) of the first-in-human study. ONC001 (NCT04393298) is an ongoing multi-part, multicenter, nonrandomized, open-label, Phase I/II study assessing the safety, PK/PD, and antitumor activity of intravenous (IV) ginisortamab as monotherapy or in combination with selected standard of care regimens in patients (pts) with advanced solid tumors. ONC001 includes 3 dose escalation modules (Parts A-C) and a dose adaptation module (Part A1). To be eligible for Part A, pts had to be aged ≥18 years (y) with advanced disease, resistant or refractory to standard therapy, with ECOG PS ≤1. We present the primary (safety, tolerability), secondary (PK/PD), and exploratory (antitumor activity) endpoints, as well as the monotherapy RP2D from Part A. At data cutoff (June 20, 2022), 25 pts received ≥1 dose of ginisortamab (median [range] age: 64 [37-74] y; 68% male; 88% White; 36% had >3 lines of prior therapy). The most common tumor type enrolled was colorectal adenocarcinoma (44%). Ginisortamab was escalated using a modified rolling 6 design through 5 levels (100, 250, 500, 1000, and 2000 mg IV Q2W) in 28-day cycles. No DLTs, Grade ≥3 AEs related to ginisortamab, or serious related AEs were observed; the 2000 mg dose was deemed safe for further development. Temporary treatment interruption and study discontinuation due to AEs unrelated to ginisortamab occurred in 7 (28%) and 2 pts (8%), respectively. Ginisortamab PK aligned with expectations from preclinical models for an IgG4 mAb, allowing favorable dosing intervals. Confirmation of target occupancy was demonstrated by increases in total circulating gremlin-1. Antidrug antibody formation was not observed. The best overall response of stable disease was observed in 7/24 pts (29%); 4 pts had a reduction of the sum of the dimensions of their target lesions relative to baseline. Favorable safety and PK/PD data at the maximum dose of 2000 mg and preliminary antitumor activity were observed with the first-in-class anti-gremlin antibody ginisortamab. These data support further evaluation of the efficacy and safety of ginisortamab monotherapy at 2000 mg Q2W, or in combination with standard of care regimens (FOLFOX, trifluridine/tipiracil) in advanced solid tumors. Citation Format: Debashis Sarker, Sarah Blagden, Natalie Cook, Thomas R. Evans, Ruth Plummer, Angelos Angelakas, Saira Bashir, Salma El Badri, Leonidas Mavroeidis, Cienne Morton, Abdul (Moe) Muhith, Mark White, Rupert Dixon, Elodie Garric, Joanne Mann, Ivan Matthews, Udai Banerji. Phase I dose-escalation study evaluating the safety and tolerability of ginisortamab (UCB6114), a first-in-class anti-gremlin-1 monoclonal antibody (mAb), as monotherapy in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT094.

Despite significant advances in outcomes with immunotherapy, most cancer patients do not benefit from currently approved immune checkpoint inhibitors (ICI). The reasons for ICI resistance are multi-faceted and suggest that additional immunomodulation is required to improve outcomes. MTL-CEBPA is a novel immunotherapy based on RNA activation that upregulates expression of a master myeloid transcription factor, CEBPA. The small activating RNA for CEBPA is encapsulated within a NOV340 liposome that targets the myeloid cell lineage. MTL-CEBPA has shown favorable safety and promising clinical activity in combination with tyrosine kinase inhibitors (Sorafenib) in hepatocellular carcinoma (NCT-02716012) [Hashimoto et al, CCR 2021; Sarker et al, CCR 2020]. We recently reported preliminary clinical data from the ongoing multi-center phase 1 TIMEPOINT study (NCT-04105335) evaluating the safety, pharmacokinetics, immunomodulation, and clinical activity of MTL-CEBPA in combination with pembrolizumab in patients with solid tumors who have exhausted standard therapy. This demonstrated a favorable safety profile and initial clinical activity [Plummer et al, JITC 2021]. Here we report the findings from a biomarker pharmacodynamic analysis of paired baseline and cycle 2 tumor sample biopsies in 23 patients from the TIMEPOINT trial. Brightplex® IHC and digital pathology analyses of the samples for myeloid and T cell panels were undertaken, alongside gene expression (Nanostring I/O 360). Prior to study treatment, nine patients out of 23 had an immune cold tumor microenvironment (TME) at baseline as measured by the Immunosign®21 score. Following the combination of MTL-CEBPA with pembrolizumab, seven of these patients converted to an inflamed TME by Immunosign®21 (P=0.008). This change in the TME was associated with infiltration of CD8 and cytotoxic T cells (CD8+, GrzB+, Ki-67+) (P=0.1). GSEA analysis indicated that a Tstem-like signature was enriched post-treatment. A Brightplex® IHC analysis of myeloid cells in these patients indicated that, post treatment, there was a significant influx of HLA-DR+ myeloid cells into the TME (P=0.04). We also observed a significant increase in the expression of CXCL9, 10, and 11. The remaining 14 patients had an inflamed TME at baseline. Here, we also observed an increase in HLA-DR+ cells, T cells, and chemokines, though to a lesser extent. Further, however, in these inflamed tumors—which have significantly greater infiltration of myeloid-derived suppressor cells (MDSCs) than desert tumors—we observed a reduction in 8/10 patients with detectable PMN-MDSCs (P=0.1) post treatment, consistent with the mechanism of action of CEBPA. An expression signature based on 18 genes significantly enriched for clinical response across all patients. Collectively, these data suggest a positive immunomodulatory TME effect of the combination of MTL-CEBPA with pembrolizumab. In both hot and cold TME tumors, the combination drives directed differentiation of progenitor monocytes into HLA-DR+ myeloid cells secreting chemokines that stimulate the ingress of T cells into the TME. We observe a significant positive correlation between the change in cytotoxic T cells and HLA-DR+ myeloid cells post treatment (P=0.004). These effects are most pronounced in cold tumors. Citation Format: Ruth Plummer, Mikael Sodergren, Brid Ryan, Ilian Tchakov, Nina Raulf, Rose Hodgson, CP Tan, Joanna P. Nicholls, Alison Adderkin, N Vasileiadou, Vikash Reebye, Tim Meyer, David J. Pinato, Debashis Sarker, Bristi Basu, Sarah Blagden, Natalie Cook, Jeff Evans, Jeffrey Yachnin, Cheng Ean Chee, Dan Li, Anthony El-Khoueiry, Maria Diab, Kai-Wen Huang, Marcus S. Noel, Bridget Keenan, Devalingam Mahalingam, Melanie Grosso, Denis Arnaud, Aurelie Auguste, Jan Storkholm, Iain McNeish, Robert Habib, John J. Rossi, Nagy Habib. MTL-CEBPA in combination with pembrolizumab converts an immune desert to an inflamed TME in solid tumors resistant to checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB192.

Circulating tumor DNA (ctDNA) is tumor-derived fragmented DNA in the bloodstream that has come from primary or metastatic cancer sites. Neoplasm-specific genetic and epigenetic abnormalities are increasingly being identified through liquid biopsy: a novel, minimally invasive technique used to isolate and analyze ctDNA in the peripheral circulation. Liquid biopsy and other emerging ctDNA technologies represent a paradigm shift in cancer diagnostics because they allow for the detection of minimal residual disease in patients with early-stage disease, improve risk stratification, capture tumor heterogeneity and genomic evolution, and enhance ctDNA-guided adjuvant and palliative cancer therapy. Moreover, ctDNA can be used to monitor the tumor response to neoadjuvant and postoperative therapy in patients with metastatic disease. Using clearance of ctDNA as an endpoint for escalation/de-escalation of adjuvant chemotherapy for patients considered to have high-risk disease has become an important area of research. The possibility of using ctDNA as a surrogate for treatment response–including for overall survival, progression-free survival, and disease-free survival–is an attractive concept; this surrogate will arguably reduce study duration and expedite the development of new therapies. In this review, we summarize the current evidence on the applications of ctDNA for the diagnosis and management of gastrointestinal tumors. Gastrointestinal cancers–including tumors of the esophagus, stomach, colon, liver, and pancreas–account for one-quarter of global cancer diagnoses and contribute to more than one-third of cancer-related deaths. Given the prevalence of gastrointestinal malignancies, ctDNA technology represents a powerful tool to reduce the global burden of disease.

BackgroundThis is a first-in-human study with TAS-119, an Aurora A kinase (AurA) inhibitor.MethodsPatients with advanced, refractory, solid tumours were enrolled into 5 dose escalation cohorts (70–300 mg BID, 4 days on/3 days off, 3 out of 4 weeks or 4 out of 4 weeks). The expansion part consisted of patients with small-cell lung cancer, HER2-negative breast cancer,MYC-amplified/β-catenin-mutated (MT) tumours or other (basket cohort).ResultsIn the escalation part (n = 34 patients), dose-limiting toxicities were one grade 3 nausea, two grade 2 and one grade 3 ocular toxicity and a combination of fatigue, ocular toxicity and nausea in one patient (all grade 2) at dose levels of 150, 200, 250 and 300 mg, respectively. Most frequent treatment-related adverse events were fatigue (32%), diarrhoea (24%) and ocular toxicity (24%). Toxicity grade ≥3 in ≥10% of patients were diarrhoea (15%) and increased lipase (12%). The maximum tolerated dose was 250 mg BID. Due to one additional grade 1 ocular toxicity, the RP2D was set at 200 mg BID (4 days on/3 days off, 3 out of 4 weeks), which was further explored in the expansion part (n = 40 patients). Target inhibition in paired skin biopsies was shown.ConclusionsTAS-119 has a favourable and remarkably distinct safety profile from other AurA inhibitors.Clinical trial registrationNCT02448589.

Clinical Scenario: Concussions are severely underreported, with only 47.3% of high school athletes reporting their concussion. The belief was that athletes who were better educated on the signs and symptoms and potential dangers of concussion would be more likely to report. However, literature has shown inconsistent evidence on the efficacy of concussion education, improving reporting behaviors. Factors such as an athlete’s attitude, subjective norms, and perceived behavioral control have shown promise in predicting intention to report concussions in athletes. Focused Clinical Question: Do attitudes, subjective norms, and perceived behavioral control influence adolescent athletes’ intention to report? Summary of Key Findings: Three studies (1 randomized control and 2 cross-sectional surveys) were included. Across the 3 studies, attitudes, subjective norms, and perceived behavioral control positively influenced athletes’ reporting intention. The studies found that attitude toward concussion reporting and perceived behavioral control were the most influential predictors of reporting intention. Clinical Bottom Line: There is moderate evidence to suggest that positive attitudes, supportive subjective norms, and increased perceived behavioral control influence reporting intention in secondary school athletes. Strength of Recommendation: Grade B evidence exists that positive attitudes, supportive subjective norms, and increased perceived behavioral control positively influence concussion reporting intention in secondary school athletes.

Although small cell lung cancer (SCLC) is treated as a homogeneous disease, biopsies and preclinical models reveal heterogeneity in transcriptomes and morphology. SCLC subtypes were recently defined by neuroendocrine transcription factor (NETF) expression. Circulating-tumor-cell-derived explant models (CDX) recapitulate donor patients’ tumor morphology, diagnostic NE marker expression and chemotherapy responses. We describe a biobank of 38 CDX models, including six CDX pairs generated pretreatment and at disease progression revealing complex intra- and intertumoral heterogeneity. Transcriptomic analysis confirmed three of four previously described subtypes based on ASCL1, NEUROD1 and POU2F3 expression and identified a previously unreported subtype based on another NETF, ATOH1. We document evolution during disease progression exemplified by altered MYC and NOTCH gene expression, increased ‘variant’ cell morphology, and metastasis without strong evidence of epithelial to mesenchymal transition. This CDX biobank provides a research resource to facilitate SCLC personalized medicine. Simpson et al. present a living biobank of 38 small cell lung cancer circulating-tumor-cell-derived explants and use them to study tumor heterogeneity. These models can be used further to study SCLC biology, progression and therapy responses.

Background Many patients referred with a provisional diagnosis of cancer of unknown primary (pCUP) present with presumed metastatic disease to the liver. Due to the lack of definitive histological markers, intrahepatic cholangiocarcinoma (iCCA) may be overlooked. This study assessed the frequency of iCCA within a pCUP cohort. Methods A single UK cancer-center study of sequential patients referred with pCUP from January 2017 to April 2020. Baseline diagnostic imaging was reviewed independently by a radiologist and oncologist; those with radiological features of iCCA (dominant liver lesion, capsular retraction) were identified. Results Of 228 patients referred with pCUP, 72 (32%) had malignancy involving the liver. 24/72 patients had radiological features consistent with iCCA; they were predominantly female (75%) with an average age of 63 years and 63% had an ECOG PS ≤ 2. The median overall survival (OS) of the iCCA group and the remaining liver-involved CUP group were similar (OS 4.1 vs 4.4 months, p-value = 0.805). Patients, where a primary diagnosis was subsequently determined, had better OS (10.2 months, p-values: iCCA = 0.0279: cCUP = 0.0230). Conclusions In this study, 34% of patients with liver-involved pCUP, fulfilled the radiological criteria for an iCCA diagnosis. Consideration of an iCCA diagnosis in patients with CUP could improve timely diagnosis, molecular characterisation and treatment.

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. The aim is to assess, using network meta-analysis (NMA), the effectiveness and safety of interventions for preventing relapse-recurrence of depression in adults in a primary care setting. NMA is a technique for comparing three or more interventions simultaneously in a single analysis by combining both direct and indirect evidence across a network of studies. The objectives are to:. estimate the relative effectiveness of pharmacological, psychological and other interventions to prevent relapse-recurrence, compared with each other and controls (e.g. pill placebo, treatment as usual) on relapse-recurrence outcomes and adverse events; assess the effect of interventions on quality of life outcomes and social and occupational functioning; estimate the relative ranking of included interventions on relapse-recurrence, quality of life, and adverse events; summarise availability and principal findings of eligible economic evaluations.

ObjectivesThe study aimed to explore patients’ experiences of experimental cancer medicine (ECM) clinical trials.DesignThe study’s design was qualitative. Two focus groups with patients were undertaken followed by semistructured interviews, to explore patients’ experiences of ECM clinical trials. Interviews and focus groups were audiorecorded and transcribed verbatim. Data were analysed using thematic analysis.SettingA regional cancer centre (tertiary care) in North-West England.ParticipantsTwelve patients (aged 52–79) participated in one of the two focus groups and 22 patients (aged 42–83) participated in interviews.Primary outcome measurePatients’ experiences of an ECM trial.ResultsFour main themes were identified from the analysis: decision making, information needs, the experience of trial participation and impact of trial participation. Subthemes are presented in the manuscript.ConclusionTo make fully informed decisions about trial participation, patients required the simplification of trial information and wanted more information about side effects, their response to trial treatment and the overall trial progress throughout the trial. Patients highlighted the need for improvement for the support provided to their family and friends.

BACKGROUND: Cancer immunotherapy is being developed as a promising alternative for advanced non-small cell lung cancer (NSCLC). However, novel biomarkers are required to select patients that will benefit from treatment with immune checkpoint inhibitors (ICIs) for a long period of time. The gut microbiome is expected to be a promising biomarker of ICI response owing to the regulation of the immune status within the host. METHODS: In this retrospective study, we included 17 Japanese patients with advanced NSCLC who were treated with ICIs for >3 months in our hospital. Fecal samples obtained from the patients during ICI treatment were analyzed by 16S ribosomal RNA gene sequencing. We examined the correlation between the diversity of the gut microbiome and treatment with ICIs. RESULTS: Several bacterial species were more abundant in ICI responders than in non-responders. Patients with abundant Lactobacillus and Clostridium tended to have a longer time to treatment failure (TTF) after receiving ICI than those with a lower abundance. CONCLUSIONS: In conclusion, the composition of the gut microbiome is associated with better clinical benefits from ICI treatment in Japanese patients with NSCLC. A further large-scale study is warranted to validate the composition of the gut microbiome as a novel clinical factor influencing the response to ICIs for an extended time in NSCLC.

Background We conducted a first-in-human dose-escalation study with the oral FASN inhibitor TVB-2640 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), as monotherapy and with a taxane. Methods This completed open-label outpatient study was conducted at 11 sites in the United States and United Kingdom. Patients with previously-treated advanced metastatic solid tumors and adequate performance status and organ function were eligible. TVB-2640 was administered orally daily until PD. Dose escalation initially followed an accelerated titration design that switched to a standard 3 + 3 design after Grade 2 toxicity occurred. Disease-specific cohorts were enrolled at the MTD. Statistical analyses were primarily descriptive. Safety analyses were performed on patients who received at least 1 dose of study drug. (Clinicaltrials.gov identifier NCT02223247) Findings The study was conducted from 21 November 2013 to 07 February 2017. Overall, 136 patients received TVB-2640, 76 as monotherapy (weight-based doses of 60 mg/m2 to 240 mg/m2 and flat doses of 200 and 250 mg) and 60 in combination, (weight-based doses of 60 mg/m2 to 100 mg/m2 and flat dose of 200 mg) (55 paclitaxel, 5 docetaxel). DLTs with TVB-2640 were reversible skin and ocular effects. The MTD/RP2D was 100 mg/m2. The most common TEAEs (n,%) with TVB-2640 monotherapy were alopecia (46; 61%), PPE syndrome (35; 46%), fatigue (28; 37%), decreased appetite (20; 26%), and dry skin (17; 22%), and with TVB-2640+paclitaxel were fatigue (29 ; 53%), alopecia (25; 46%), PPE syndrome (25; 46%), nausea (22; 40%), and peripheral neuropathy (20; 36%). One fatal case of drug-related pneumonitis occurred with TVB-2640+paclitaxel; no other treatment-related deaths occurred. Target engagement (FASN inhibition) and inhibition of lipogenesis were demonstrated with TVB-2640. The disease control rate (DCR) with TVB-2640 monotherapy was 42%; no patient treated with monotherapy had a complete or partial response (CR or PR). In combination with paclitaxel, the PR rate was 11% and the DCR was 70%. Responses were seen across multiple tumor types, including in patients with KRASMUT NSCLC, ovarian, and breast cancer. Interpretation TVB-2640 demonstrated potent FASN inhibition and a predictable and manageable safety profile, primarily characterized by non-serious, reversible adverse events affecting skin and eyes. Further investigation of TVB-2640 in patients with solid tumors, particularly in KRASMUT lung, ovarian, and breast cancer, is warranted. Funding This trial was funded by 3-V Biosciences, Inc. (now known as Sagimet Biosciences Inc.).

Specialist Palliative Care aims to effectively support the quality of life of patients and those close to them through progressive, life-limiting disease. Quality of life, an individual concept, requires a personalized approach to support and maintain it. Primarily achieved through the management of symptoms, both physical and psychological, alongside social and spiritual support, this approach is of the utmost importance to patients with advanced malignancy. Several randomized, controlled trials suggest earlier provision of specialist palliative care may increase quality of life, improve symptoms and facilitate considered end of life care planning. This appears beneficial; however, evidence is mixed about the effectiveness of early specialist palliative care and its potential benefits. Results, therefore, should be interpreted with caution. In reviewing the literature, it is clear that implementing early specialist palliative care is fraught with obstacles and requires increased resources and funding. Until the benefits and cost implications for such provision are better understood, it will not be accessible to all that may have potential to benefit.

Purpose Quizartinib, a potent, selective FMS-like tyrosine kinase 3 (FLT3) inhibitor, is currently in phase 3 development for patients with FLT3–internal tandem duplication-mutated acute myeloid leukemia (AML). Acid-reducing agents (ARAs; e.g., proton pump inhibitors) are frequently used during AML treatment. Since quizartinib demonstrates pH-dependent solubility, the effect of lansoprazole coadministration on pharmacokinetics (PK) of quizartinib tablet formulation was assessed. Methods An open-label, parallel-group study randomized 64 healthy adults to single-dose quizartinib 30 mg alone (reference) or lansoprazole (60 mg once daily, days 1–5) + single-dose quizartinib 30 mg (day 5) (test). Plasma concentrations of quizartinib and its active metabolite, AC886, were measured to 504 h postdose; the effect of lansoprazole on quizartinib PK was assessed by analysis of variance. Results Quizartinib geometric mean ratios (test/reference) and 90% confidence intervals for maximum observed plasma concentration (Cmax), area under the concentration–time curve to last measurable drug concentration (AUClast), and AUC to infinity were 86.11% (78.4%, 94.6%), 93.96% (79.6%, 110.9%), and 95.30% (80.2%, 113.3%), respectively. Comparisons showed a modest decrease in quizartinib absorption when co-administered with lansoprazole, with lower limits for Cmax and AUClast just below 80–125% limits. Treatment-emergent adverse events were mild or moderate; the most frequent in either treatment group were headache [quizartinib alone: (n = 3) 10%], upper respiratory tract infection [quizartinib alone: (n = 2) 6.7%; lansoprazole + quizartinib: (n = 3) 9.1%], and muscle tightness [quizartinib alone: (n = 2) 6.7%]. Conclusions Concomitant lansoprazole had minimal effect on quizartinib PK as a formulated tablet, indicating that quizartinib can be administered with ARAs. Electronic supplementary material The online version of this article (10.1007/s00280-019-03915-1) contains supplementary material, which is available to authorized users.

Background With the advent of immunotherapy, substantial progress has been made in improving outcomes for patients with advanced cancer. However, not all patients benefit equally from treatment, and confounding immune-related issues may have an impact. Several studies suggest that antibiotic use (which alters the gut microbiome) may result in poorer outcomes for patients treated with immune checkpoint inhibitors (ICI). Materials and Methods This is a large, single-site retrospective review of n = 291 patients with advanced cancer treated with ICI (n = 179 melanoma, n = 64 non-small cell lung cancer, and n = 48 renal cell carcinoma). Antibiotic use (both single and multiple courses/prolonged use) during the periods 2 weeks before and 6 weeks after ICI treatment was investigated. Results Within this cohort, 92 patients (32%) received antibiotics. Patients who did not require antibiotics had the longest median progression-free survival (PFS), of 6.3 months, and longest median overall survival (OS), of 21.7 months. With other clinically relevant factors controlled, patients who received a single course of antibiotics had a shorter median OS (median OS, 17.7 months; p = .294), and patients who received multiple courses or prolonged antibiotic treatment had the worst outcomes overall (median OS, 6.3 months; p = .009). Progression-free survival times were similarly affected. Conclusion This large, multivariate analysis demonstrated that antibiotic use is an independent negative predictor of PFS and OS in patients with advanced cancer treated with ICIs. This study highlighted worse treatment outcomes from patients with cumulative (multiple or prolonged courses) antibiotic use, which warrants further investigation and may subsequently inform clinical practice guidelines advocating careful use of antibiotics.

Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) supports blood-based genomic profiling but is not yet routinely implemented in the setting of a phase I trials clinic. TARGET is a molecular profiling program with the primary aim to match patients with a broad range of advanced cancers to early phase clinical trials on the basis of analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated-gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumor and results were turned round within a clinically acceptable timeframe for Molecular Tumor Board (MTB) review. When a 2.5% variant allele frequency (VAF) threshold was applied, actionable mutations were identified in 41 of 100 patients, and 11 of these patients received a matched therapy. These data support the application of ctDNA in this early phase trial setting where broad genomic profiling of contemporaneous tumor material enhances patient stratification to novel therapies and provides a practical template for bringing routinely applied blood-based analyses to the clinic.

Cancers of Unknown Primary (CUP) comprise a heterogeneous group of metastatic cancers where the primary site is undetectable. It accounts for 2% of all new UK cancer diagnoses and is the 6th leading cause of cancer death. Favourable subsets of CUP exist, based on clinico-pathological features, and although these patients have improved clinical outcomes, they make up only 20% of patients with CUP. The evolution of molecular profiling and tissue-of-origin (TOO) classifiers has the potential to transform diagnosis and management of patients with CUP. Reliable molecular profiling requires good quality and quantity tumour tissue material, often scarce in patients with CUP. Liquid biopsies offer an alternative, minimally invasive approach. We developed a novel cell-free DNA (cfDNA)-based multi-omics assay combining methylation profiling with mutation and copy number alterations (CNA) detection, to enable TOO prediction and biomarker discovery to aid treatment stratification. Methods: Two novel library preparation methods were applied to 41 CUP cfDNA samples, 80 non-cancer controls and 80 cfDNA samples from known tumour types (breast, lung, colorectal cancer): 1) Targeted (641 gene panel) next generation sequencing (NGS); 2) A multiplex genome-wide methylation capture assay (T7-MBDSeq). Both sequencing outputs can estimate CNA. Cancer Genome Interpreter (CGI) was used to evaluate the potential actionability of molecular alterations detected. A novel TOO classifier, generated utilising in silico dilution mixture sets derived from The Cancer Genome Atlas (TCGA) methylation data, demonstrated an AUROC of 0.96 across 15 different cancer groups. This was applied to cfDNA methylation data from known tumour types to test performance accuracy and subsequently applied to CUP cfDNA samples. Results: Multi-omics profiling from cfDNA was completed for 34/41 patients with CUP. cfDNA mutation profiling and estimated CNA analysis so far revealed >350 alterations across 225 genes. 17/34 (50%) of patients harboured potentially actionable alterations by CGI and, where performed, 68% of tumour mutations were concordant in the cfDNA. cfDNA methylation profiling revealed tumour-specific methylation changes in breast, lung and colorectal cancers. Our preliminary TOO classifier performance in these tumour types had an overall sensitivity and specificity of 85% and 98%, respectively. In patients with CUP, a predicted TOO was made in 26/41 (63%) patients and for 6 patients, where a subsequent primary tumour diagnosis was made, the TOO prediction was correct. Conclusions: cfDNA multi-omics profiling revealed potential therapeutic benefit in 77% of this retrospective CUP cohort and illustrates the potential to re-classify patients to primary tumour types where alternative therapies may improve clinical outcomes. Further multi-omics cfDNA profiling of the CUP cohort and validation in known primary cancer types are ongoing. Citation Format: Alicia-Marie Conway, Alexandra Clipson, Francesca Chemi, Simon Pearce, Katarzyna Kamieniecka, Saba Ferdous, Sophie Richardson, Elaine Kilgour, Matthew G. Krebs, Alastair Kerr, Dominic Rothwell, Natalie Cook, Caroline Dive. cfDNA multi-omics profiling and tissue of origin predictions in cancers of unknown primary [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2808.

TPS3637 Background: The Wnt pathway is a critical driver of cancer. RXC004 is a potent, selective, orally active inhibitor of the key Wnt pathway regulator, Porcupine. Inhibition of Porcupine blocks the release of all Wnt ligands from cells, preventing both tumour growth and tumour immune evasion. Wnt pathway alterations, including loss-of-function (LoF) RNF43 mutations and RSPO gene fusions, increase expression of the Wnt receptor Frizzled (Fzd) on the tumour cell surface, driving Wnt-ligand signalling. These alterations are present in ̃8% (Gao, 2013; Cerami, 2012; Shesagiri, 2012; Shinmura, 2014; Kleeman, 2019) of colorectal cancers (CRC). LoF RNF43 mutations are associated with poor prognosis in MSS CRC (Yaeger, 2018 ). Preclinical genetically selected CRC models showed disease stabilisation, differentiation towards a normal colonic phenotype with increased mucin secretion, and reduced metabolic activity on FDG-PET. In a Phase 1 study in patients with advanced solid tumours (NCT03447470), RXC004 was safe and tolerated at doses up to 2mg QD, the recommended phase 2 dose (RP2D), and showed a differentiated efficacy signal in Wnt-ligand dependent tumours (Cook, 2021 ). Methods: The PORCUPINE (NCT04907539) trial is a 2-arm Phase 2 trial of RXC004 monotherapy (Arm A) and RXC004 in combination with nivolumab (Arm B). 20 evaluable patients will be enrolled into each Arm. The study initially opened with Arm A; Arm B will be opened once the RP2D for RXC004 in combination with nivolumab is established in a separate phase 1 study. Once Arm B is opened, patients in Arm A may be treated with RXC004 + nivolumab if they have progressive disease on the first RECIST assessment scan. To be eligible for this study, patients must have metastatic microsatellite stable (MSS) CRC that has progressed following standard therapies. Tumours must have a LoF RNF43 mutation, or an RSPO2/3 fusion. As Wnt inhibition can affect bone metabolism, patients undergo a screening DEXA scan and receive prophylactic denosumab throughout the treatment period. The primary endpoint for Arm A is the disease control rate (DCR= CR+PR+SD at 16 wks), and for Arm B is objective response rate (ORR). Secondary endpoints are Safety and PK. Exploratory endpoints include FDG-PET changes and on-treatment changes in protein and gene expression in tumour biopsies. For Arm A, a target value (TV) of 60% DCR is considered a clinically significant improvement over standard of care against a lower reference value (LRV) of 40% DCR (Grothey, 2013; Mayer, 2015 ). For Arm B, a TV of 30% ORR is considered clinically significant against a LRV of 10% ORR (Eng, 201 9). RXC004 is also being investigated in a second Phase 2 trial, PORCUPINE 2 (NCT04907851), in Biliary Tract Cancers and RNF-43 mutated Pancreatic Cancers. Clinical trial information: NCT04907539.

5057 Background: Activating AR mutations ensure a continued AR activation by non-androgen steroid ligands, e.g. progesterone and glucocorticoids. CYP11A1 is the only enzyme that catalyzes the conversion of cholesterol to pregnenolone, from which all steroid hormones (glucocorticoids, mineralocorticoids, and sex steroids) are subsequently derived. ODM-208, an oral, selective inhibitor of CYP11A1, is being evaluated for safety and efficacy as a treatment of mCRPC in the ongoing CYPIDES phase I/II trial in men previously treated with both novel hormonal therapies and taxanes (ClinicalTrials.gov identifier: NCT03436485). Preliminary phase 1 results were previously reported (Fizazi K et al., ASCO GU 2022). Here we confirm that the in-vitro sensitivity of common AR mutations to ODM-208 treatment is mirrored in patient response in CYPIDES phase 1. Methods: ODM-208 was administered at daily doses between 6-150 mg (phase 2 dose: 10 mg) with dexamethasone and fludrocortisone, resulting in maximal suppression in all measured steroids at all doses. AR ligand-binding domain (LBD) mutations (L702H, V716M, W742L, W742C, H875Y, F877L, T878A, T878S, M896T, M896V) were assessed using a BEAMing assay (Sysmex Inostics) from plasma circulating cell-free DNA (cfDNA) collected before the first dose of ODM-208. The activation of wild-type (wt) and LBD mutated AR with various ligands was also studied in vitro using a luciferase reporter assay in AR negative PC3 cells. Results: 17 of 44 patients had at least one AR activating mutation, the most frequent being L702H (n = 11), T878A (n = 10), and H875Y (n = 6). Eleven out of the 16 evaluable patients (68%) with an AR LBD mutation achieved ≥50% reduction in serum PSA compared with 2 out of the 24 evaluable patients (8%) without an AR LBD mutation (P

This paper reports on patient participant experiences of a larger randomised controlled trial evaluating a shared-care pathway intervention designed to support outpatients at home during their first three cycles of systemic anti-cancer therapies delivered in two large tertiary hospitals in Sydney, Australia. This qualitative study explores the perspectives of patient participants who received the intervention, which involved targeted home visits by community nurses post treatment administration.A qualitative inductive thematic analysis was used to examine data from semi-structured interviews with patients who received the intervention.Twenty-five patient participants were interviewed. We identified four themes: Stepping into the unknown; Impact of availability of health and social care support; Building confidence to manage self-care; Uncertainty, frailty and co-morbidities. Targeted support at home is seen to be effective and welcomed by patients as early stages of each treatment cycle can be extremely challenging, particularly for those who are elderly, frail or with co-morbidities, and for those with limited health and social support.Regular contact with community nursing services can, at least for some patients, support the development of patient self-efficacy in managing aspects of their own care. Some patients are sufficiently confident to self-manage some treatment side effects by treatment cycle four.

Introduction older patients represent the majority of cancer patients but are under-represented in trials, particularly early phase clinical trials (EPCTs). Material and Methods observational retrospective study of patients referred for EPCTs (January–December 2018) at a specialist cancer centre in the UK. The primary aim was to analyse the successful enrolment into EPCTs according to age ( Results 555 patients were referred for EPCTs with a median age of 60 years, of whom 471 were assessed in new patient clinics (38% were 65+). From those assessed, a randomly tumour-matched sample of 318 patients (159 per age cohort) was selected. Older patients had a significantly higher comorbidity score measured by ACE-27 (P Discussion older age did not affect the enrolment into EPCTs. However, the selected minority referred for EPCTs suggests a pre-selection upstream by primary oncologists.

18 Background: ODM-208 is a novel, oral, non-steroidal and selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. ODM-208 suppresses the production of all steroid hormones and their precursors that may activate the androgen receptor (AR) signalling pathway. This is particularly relevant in patients with AR ligand binding domain (LBD) activating somatic point mutations, a mechanism of resistance to hormone-based therapies in metastatic castration-resistant prostate cancer (mCRPC). We report the first results of the first-in-man phase I CYPIDES trial. Methods: ODM-208 was examined in a dose finding phase 1 trial with a 3+3 design in patients with progressive mCRPC who had previously received ≥1 line of AR signalling inhibitor and ≥1 line of taxane-based chemotherapy. ODM-208 was administered up to 150 mg/day with glucocorticoid (GC) and mineralocorticoid replacement therapy and androgen deprivation therapy (ADT). The phase 1 endpoints included dose-limiting toxicities (DLTs), adverse events, pharmacokinetics, pharmacodynamics, PSA and RECIST response, and exploratory genetic profiling. Results: By Jan 22 2021, 41 patients (median age 70 yrs.) had received ODM-208. The dose finding was completed and included doses ranging from 10 to 150 mg/day. 22 (54%) patients had previously received both abiraterone and enzalutamide, and 23 (56%) patients both docetaxel and cabazitaxel. Although tolerated by most patients, the main safety finding was adrenal insufficiency (AI). Overall, 15/41 (37%) patients experienced Grade 3 AI requiring short-term high-dose GC treatment. ODM-208 plasma exposure was dose proportional. Serum testosterone was undetectable after 4 weeks of start of ODM-208 in almost all patients, as were serum DHEA sulphate, androstenedione, 11β-hydroxyandrostenedione, 11-ketotestosterone and pregnenolone. Overall 12/36 (33%) evaluable patients achieved a PSA decline of ≥50%. In evaluable patients with AR LBD mutation 10/15 (67%) achieved a PSA decline of ≥50%. Clinical improvement in symptoms such as pain was also observed in some men. Conclusions: Administration of ODM-208 to mCRPC men pretreated with abiraterone/enzalutamide and taxanes was highly effective in blocking the production of steroid hormones and showed promising antitumor activity, especially in men with AR mutation-positive cancers. The phase 2 dose expansion part of CYPIDES is ongoing. Clinical trial information: NCT03436485.