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Purpose: Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking. Patients and Methods: We performed a single-arm, multicenter clinical trial using “flip dose” ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. Results: From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%–66%] and 37% (95% CI, 19%–55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%–95%) and 68% (95% CI, 46%–83%), respectively. Median RFS was 10.3 months (95% CI, 5.7–25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities. Conclusions: Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing.

Purpose:Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking.Patients and Methods:We performed a single-arm, multicenter clinical trial using “flip dose” ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network.Results:From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%–66%] and 37% (95% CI, 19%–55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%–95%) and 68% (95% CI, 46%–83%), respectively. Median RFS was 10.3 months (95% CI, 5.7–25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities.Conclusions:Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing.

Grade 3+ Adverse Events

Representativeness of Study Participants

Outcomes by Subgroups of Primary Site, Adjuvant Radiation, and R0/R1 Resection Margin Status

Related Treatment Adverse Events

Psychedelics have emerged as promising candidate treatments for various psychiatric conditions, and given their clinical potential, there is a need to identify biomarkers that underlie their effects. Here, we investigate the neural mechanisms of lysergic acid diethylamide (LSD) using regression dynamic causal modelling (rDCM), a novel technique that assesses whole-brain effective connectivity (EC) during resting-state functional magnetic resonance imaging (fMRI). We modelled data from two randomised, placebo-controlled, double-blind, cross-over trials, in which 45 participants were administered 100 μg LSD and placebo in two resting-state fMRI sessions. We compared EC against whole-brain functional connectivity (FC) using classical statistics and machine learning methods. Multivariate analyses of EC parameters revealed predominantly stronger interregional connectivity and reduced self-inhibition under LSD compared to placebo, with the notable exception of weakened interregional connectivity and increased self-inhibition in occipital brain regions as well as subcortical regions. Together, these findings suggests that LSD perturbs the Excitation/Inhibition balance of the brain. Notably, whole-brain EC did not only provide additional mechanistic insight into the effects of LSD on the Excitation/Inhibition balance of the brain, but EC also correlated with global subjective effects of LSD and discriminated experimental conditions in a machine learning-based analysis with high accuracy (91.11%), highlighting the potential of using whole-brain EC to decode or predict subjective effects of LSD in the future.

Adverse Events Per Patient

Study design (A) and patient disposition (B); data cutoff December 31, 2014.

Purpose: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC).Experimental Design: Two cohorts were studied: AAP-naïve and post-AAP patients who had received ≥6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day. Primary endpoint was ≥50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria. Secondary endpoints included time to PSA progression and time on treatment.Results: Forty-six patients enrolled in the AAP-naïve (n = 25) and post-AAP (n = 21) cohorts. The 12-week PSA response rate was 88% (22/25) and 22% (4/18), median time to PSA progression was 18.2 months [95% confidence interval (CI), 8.3 months–not reached) and 3.7 months (95% CI, 2.8–5.6 months), and median time on treatment 21 months (range, 2.6–37.5) and 4.9 months (range, 1.3–23.2), for the AAP-naïve and post-AAP cohorts, respectively. Eighty percent (95% CI, 59–93) and 64% (95% CI, 43–82) of AAP-naïve and 43% (95% CI, 22–66) and 10% (95% CI, 1–30) of post-AAP patients remained on treatment for 6+ and 12+ months, respectively. Common treatment-emergent adverse events in both cohorts were grade 1 or 2 fatigue, diarrhea, nausea, and abdominal pain.Conclusions: Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC, with 80% of AAP-naïve and 43% of post-AAP patients, remaining on treatment for 6 months or longer. Clin Cancer Res; 23(14); 3544–51. ©2017 AACR.

Background and HypothesisIn a complex world, gathering information and adjusting our beliefs about the world is of paramount importance. The literature suggests that patients with psychotic disorders display a tendency to draw early conclusions based on limited evidence, referred to as the jumping-to-conclusions bias, but few studies have examined the computational mechanisms underlying this and related belief-updating biases. Here, we employ a computational approach to understand the relationship between jumping-to-conclusions, psychotic disorders, and delusions.Study DesignWe modeled probabilistic reasoning of 261 patients with psychotic disorders and 56 healthy controls during an information sampling task—the fish task—with the Hierarchical Gaussian Filter. Subsequently, we examined the clinical utility of this computational approach by testing whether computational parameters, obtained from fitting the model to each individual’s behavior, could predict treatment response to Metacognitive Training using machine learning.Study ResultsWe observed differences in probabilistic reasoning between patients with psychotic disorders and healthy controls, participants with and without jumping-to-conclusions bias, but not between patients with low and high current delusions. The computational analysis suggested that belief instability was increased in patients with psychotic disorders. Jumping-to-conclusions was associated with both increased belief instability and greater prior uncertainty. Lastly, belief instability predicted treatment response to Metacognitive Training at the individual level.ConclusionsOur results point towards increased belief instability as a key computational mechanism underlying probabilistic reasoning in psychotic disorders. We provide a proof-of-concept that this computational approach may be useful to help identify suitable treatments for individual patients with psychotic disorders.

Major depressive disorder is a heterogeneous diagnostic category with multiple available treatments. With the goal of optimizing treatment selection, researchers are developing computational models that attempt to predict treatment response based on various pretreatment measures. In this paper, we review studies that use brain activity data to predict treatment response. Our aim is to highlight and clarify important methodological differences between various studies that relate to the incorporation of domain knowledge, specifically within two approaches delineated as data-driven and theory-driven. We argue that theory-driven generative modeling, which explicitly models information processing in the brain and thus can capture disease mechanisms, is a promising emerging approach that is only beginning to be utilized in treatment response prediction. The predictors extracted via such models could improve interpretability, which is critical for clinical decision-making. We also identify several methodological limitations across the reviewed studies and provide suggestions for addressing them. Namely, we consider problems with dichotomizing treatment outcomes, the importance of investigating more than one treatment in a given study for differential treatment response predictions, the need for a patient-centered approach for defining treatment outcomes, and finally, the use of internal and external validation methods for improving model generalizability.

Paranoid delusions or unfounded beliefs that others intend to deliberately cause harm are a frequent and burdensome symptom in early psychosis, but their emergence and consolidation still remains opaque. Recent theories suggest that aberrant prediction errors lead to a brittle model of the world providing a breeding ground for delusions. Here, we employ a Bayesian approach to test for a more unstable model of the world and investigate the computational mechanisms underlying emerging paranoia.We modelled behaviour of 18 first-episode psychosis patients (FEP), 19 individuals at clinical high-risk for psychosis (CHR-P), and 19 healthy controls (HC) during an advice-taking task, designed to probe learning about others’ changing intentions. We formulated competing hypotheses comparing the standard Hierarchical Gaussian Filter (HGF), a Bayesian belief updating scheme, with a mean-reverting HGF to model an altered perception of volatility.There was a significant group-by-volatility interaction on advice-taking suggesting that CHR-P and FEP displayed reduced adaptability to environmental volatility. Model comparison favored the standard HGF in HC, but the mean-reverting HGF in CHR-P and FEP in line with perceiving increased volatility, although model attributions in CHR-P were heterogeneous. We observed correlations between shifts in perceived volatility and positive symptoms generally as well as with frequency of paranoid delusions specifically.Our results suggest that FEP are characterised by a different computational mechanism – perceiving the environment as increasingly volatile – in line with Bayesian accounts of psychosis. This approach may prove useful to investigate heterogeneity in CHR-P and identify vulnerability for transition to psychosis.

BackgroundMismatch negativity (MMN) reductions are among the most reliable biomarkers for schizophrenia and have been associated with increased risk for conversion to psychosis in individuals at clinical high risk for psychosis (CHR-P). Here, we adopt a computational approach to develop a mechanistic model of MMN reductions in CHR-P individuals and patients early in the course of schizophrenia (ESZ).MethodsElectroencephalography (EEG) was recorded in 38 CHR-P individuals (15 converters), 19 ESZ patients (≤5 years), and 44 healthy controls (HC) during three different auditory oddball MMN paradigms including 10% duration-, frequency-, or double-deviants, respectively. We modelled sensory learning with the hierarchical Gaussian filter and extracted precision-weighted prediction error trajectories from the model to assess how the expression of hierarchical prediction errors modulated EEG amplitudes over sensor space and time.ResultsBoth low-level sensory and high-level volatility precision-weighted prediction errors were altered in CHR-P and ESZ groups compared to HC. Furthermore, low-level precision-weighted prediction errors were significantly different in CHR-P that later converted to psychosis compared to non-converters.ConclusionsOur results implicate altered processing of hierarchical prediction errors as a computational mechanism in early psychosis consistent with predictive coding accounts of psychosis. This computational model appears to capture pathophysiological mechanisms relevant to early psychosis and the risk for future psychosis in CHR-P individuals, and may serve as a predictive biomarker and mechanistic target for novel treatment development.

PURPOSE To provide recommendations for the management of patients with metastatic clear cell renal cell carcinoma (ccRCC). METHODS An Expert Panel conducted a systematic literature review to obtain evidence to guide treatment recommendations. RESULTS The panel considered peer-reviewed reports published in English. RECOMMENDATIONS The diagnosis of metastatic ccRCC should be made using tissue biopsy of the primary tumor or a metastatic site with the inclusion of markers and/or stains to support the diagnosis. The International Metastatic RCC Database Consortium risk criteria should be used to inform treatment. Cytoreductive nephrectomy may be offered to select patients with kidney-in-place and favorable- or intermediate-risk disease. For those who have already had a nephrectomy, an initial period of active surveillance may be offered if they are asymptomatic with a low burden of disease. Patients with favorable-risk disease who need systemic therapy may be offered an immune checkpoint inhibitor (ICI) in combination with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI); patients with intermediate or poor risk should be offered a doublet regimen (no recommendation was provided between ICIs or an ICI in combination with a VEGFR TKI). For select patients, monotherapy with either an ICI or a VEGFR TKI may be offered on the basis of comorbidities. Interleukin-2 remains an option, although selection criteria could not be identified. Recommendations are also provided for second- and subsequent-line therapy as well as the treatment of bone metastases, brain metastases, or the presence of sarcomatoid features. Participation in clinical trials is highly encouraged for patients with metastatic ccRCC. Additional information is available at www.asco.org/genitourinary-cancer-guidelines

Reductions in the auditory mismatch negativity (MMN) have been well-demonstrated in schizophrenia rendering it a promising biomarker for understanding the emergence of psychosis. According to the predictive coding theory of psychosis, MMN impairments may reflect disturbances in hierarchical information processing driven by maladaptive precision-weighted prediction errors (pwPEs) and enhanced belief updating. We applied a hierarchical Bayesian model of learning to single-trial EEG data from an auditory oddball paradigm in 31 help-seeking antipsychotic-naive high-risk individuals and 23 healthy controls to understand the computational mechanisms underlying the auditory MMN. We found that low-level sensory and high-level volatility pwPE expression correlated with EEG amplitudes, coinciding with the timing of the MMN. Furthermore, we found that prodromal positive symptom severity was associated with increased expression of sensory pwPEs and higher-level belief uncertainty. Our findings provide support for the role of pwPEs in auditory MMN generation, and suggest that increased sensory pwPEs driven by changes in belief uncertainty may render the environment seemingly unpredictable. This may predispose high-risk individuals to delusion-like ideation to explain this experience. These results highlight the value of computational models for understanding the pathophysiological mechanisms of psychosis.

9573 Background: Mucosal melanoma is a rare, highly aggressive form of melanoma with extremely high recurrence rates, despite definitive surgical resection. Median RFS has been reported to be 5.4m, with RFS rates at 1 and 2 years of 10%, and 0%, respectively (Lian B, Si L, Cui C, et al. Phase II Randomized Trial Comparing High-Dose IFN-α2b with Temozolomide Plus Cisplatin as Systemic Adjuvant Therapy for Resected Mucosal Melanoma. Clinical Cancer Research 2013, 19(16):4488-4498). Currently there is no consensus on recommendations for adjuvant therapy. Data on the use of immune checkpoint inhibitors (ICI) adjuvantly is lacking. Methods: We performed a single arm, multicenter clinical trial using “flip dose” ipilimumab (1mg/kg q3w x4 cycles),and nivolumab (3 mg.kg q3w x4 cycles), then Nivolumab 480 mg q4w x 11 cycles to complete a year of adjuvant therapy. The primary endpoint was recurrence-free survival (RFS), and the study had 85% power to detect an improvement in RFS between 5.5 and 9.5 months using a one-sided log rank test. Participants must have had R0/R1 resection

4504 Background: C, a multitargeted receptor tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment that may enhance response to immune checkpoint inhibitors (ICIs). COSMIC-021, a multicenter phase 1b study, is evaluating C + A (anti‒PD-L1 therapy) in various solid tumors (NCT03170960). C + A demonstrated encouraging clinical activity in cohort 2 of COSMIC-021 in patients (pts) with UC previously treated with platinum-containing chemotherapy (chemo) (Pal S et al. ASCO 2020. Abstract 5013). Outcomes of C + A from 3 other UC cohorts (C3, C4, C5) are presented. Methods: Pts with inoperable locally advanced/metastatic UC with transitional cell histology and ECOG PS 0‒1 were eligible. Pts enrolled in C3 and C4 had no prior therapy and were cisplatin-based chemo ineligible (C3) or eligible (C4). C5 enrolled pts with one prior ICI and no prior VEGFR-TKI therapy. Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for first year and Q12W thereafter. The primary endpoint is objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints: safety, duration of response (DOR), PFS, and OS. Results: Thirty pts each were enrolled in C3 and C4, and 31 in C5. Baseline characteristics for C3, C4, and C5, respectively: median age, 74 y, 66 y, 68 y; male, 67%, 73%, 55%; ECOG PS 1, 63%, 57%, 74%; lung/liver metastasis; 33%/17%, 40%/20%, 58%/23%; ≥3 tumor sites, 30%, 43%, 45%; bladder as primary site, 67%, 70%, 71%. As of Nov 30, 2021, the median follow-up for C3, C4, and C5 was 27.9, 19.1, and 32.9 mo, respectively, with 1, 6, and 1 pts on treatment. C + A demonstrated clinical benefit across all cohorts (Table). Most common treatment-related adverse events (TRAEs) of any grade across C3, C4, and C5, respectively, were diarrhea (43%, 33%, 35%), nausea (27%, 17%, 26%), fatigue (27%, 27%, 48%), and decreased appetite (33%, 27%, 39%); grade 3/4 TRAEs occurred in 63%, 43%, and 45%, and there was no grade 5 TRAE. Conclusions: C + A demonstrated encouraging clinical activity with manageable toxicity in inoperable locally advanced/metastatic UC as first-line systemic therapy in cisplatin-based chemo eligible/ineligible pts and as second- or later line in pts who received prior ICI. Clinical trial information: NCT03170960. [Table: see text]

High-dose interleukin-2 (HD IL-2) was approved in the 1990s after demonstrating durable complete responses (CRs) in some patients with metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC). Patients who achieve this level of disease control have also demonstrated improved survival compared with patients who progress, but limited data are available describing the long-term course. The aim of this study was to better characterize long-term survival following successful HD IL-2 treatment in patients with no subsequent systemic therapy. Eleven HD IL-2 treatment centers identified patients with survival ≥5 years after HD IL-2, with no subsequent systemic therapy. Survival was evaluated from the date of IL-2 treatment to June 2017. Treatment courses consisted of 2 1-week cycles of HD IL-2. Patients were treated with HD IL-2 alone, or HD IL-2 followed by local therapy to achieve maximal response. 100 patients are reported: 54 patients with mM and 46 patients with mRCC. Progression-free survival (PFS) after HD IL-2 ranges from 5+ years to 30+ years, with a median follow-up of 10+ years. 27 mRCC and 32 mM are alive ≥10 years after IL-2. Thus, a small subset of patients with mM and mRCC achieve long-term PFS (≥5 years) after treatment with HD IL-2 as their only systemic therapy. The ability of HD IL-2 therapy to induce prolonged PFS should be a major consideration in studies of new immunotherapy combinations for mM and mRCC.

Despite the popularity of theraphosids, detailed reports on bite symptoms are still limited to few geographic regions and subfamilies. We therefore examined 363 published bite reports and noticed muscles cramps caused by theraphosids from nearly all continents and subfamilies. Symptoms are mostly locally restricted and mild, but 12.7% of victims experience pronounced cramps with highest incidence rates by Poecilotheriinae, Harpactirinae and Stromatopelminae subfamilies. We discuss how variations in venom quantity correlate with muscle cramp prevalence.

Background CDX-1140 is an agonist anti-CD40 mAb selected to optimize systemic exposure and hence tumor microenvironment (TME) ingress. CDX-1140 activity may be enhanced by combining with CDX-301 (recombinant Flt3L), a dendritic cell growth factor, or with pembrolizumab, an anti-PD-1 mAb. Methods Patients with advanced solid or hematologic (Part 1 only) tumors are enrolled. Part 1 dose-escalation results have been presented (SITC 2019). In Part 2, CDX-1140 dose-escalation (0.09–1.5 mg/kg q4w) is in combination with CDX-301 (75 mcg/kg sc QD x 5 for 2 cycles). In Part 3, CDX-1140 dose-escalation (0.72–1.5 mg/kg q3w) is in combination with pembrolizumab 200 mg q3w. Part 1 and 2 expansion cohorts are dosed at the CDX-1140 MTD, 1.5 mg/kg q4w. Part 3 expansion cohorts are planned. Peripheral blood and tumor biomarkers analysis are ongoing. Results 92 patients have been treated (Part 1 n=57, Part 2 n=31, Part 3 n=4). Part 1 expansion cohorts in SCCHN (n=7) and RCC (n=5) are fully enrolled. Part 2 dose-escalation completed to the highest CDX-1140 dose and a SCCHN expansion cohort is ongoing. Part 3 dose-escalation recently initiated. Safety data is available for 23 and 10 patients at the MTD in Part 1 and 2, respectively. In general, the safety profiles were similar, with arthralgia (52% vs. 50%), pyrexia (44% vs 50%), fatigue (30% vs. 50%), chills (39% vs. 40%), vomiting (30% vs. 20%), nausea (26% vs 40%), myalgia (22% vs. 30%), increased ALT (22% vs. 20%), and increased AST (22% vs. 30%) being the most common drug related AEs at the MTD in Part 1 and 2, respectively. Most AEs were low grade. Across all cohorts, cytokine release syndrome (CRS) (G2 n=4, G3 n=2) occurred in 6 (Part 1 n=2; Part 2 n=4) and pneumonitis (G3) occurred in 5 (Part 1 n=4; Part 2 n=1) patients. Immune activation in the TME consistent with CD40 agonism and increases serum inflammatory cytokines were observed. Evidence of anti-tumor activity/clinical benefit include SD (n=13), tumor cavitation (n=2) and a uPR in solid tumors. A patient with follicular lymphoma has an ongoing durable complete metabolic response. Conclusions The CDX-1140 MTD dose of 1.5 mg/kg, a dose level expected to provide good systemic exposure and TME penetration, is generally well tolerated alone and with CDX-301. Transaminitis and CRS have generally been low grade and infrequent. A cohort combining CDX-1140 with chemotherapy will be initiated in patients with previously untreated metastatic pancreatic adenocarcinoma. Trial Registration NCT03329950 Ethics Approval The study was approved by the following: Providence St. Joseph Health IRB, approval number MOD2020001128; WIRB, approval number 1188814 (Hauke, Gabrail, Bordoni & Gordon); University of Pennsylvania IRB, approval number UPCC 18917; Mount Sinai School of Medicine IRB, approval number 18-00202; Memorial Sloan Kettering Cancer Center IRB, approval number 18-225A; Houston Methodist IRB, approval number MOD00000836

Background Avelumab, a human anti–PD-L1 monoclonal antibody, has shown a manageable safety profile and antitumor activity in multiple tumor types, including platinum-resistant metastatic or recurrent NSCLC,1 and is approved for patients with locally advanced or metastatic UC who have progressed after ≥1 previous line of platinum-based chemotherapy2 3 and as maintenance treatment for those who have not progressed with platinum-based chemotherapy.4 JAVELIN Medley VEGF (NCT03472560) evaluated the efficacy and safety of avelumab + axitinib, a potent inhibitor of VEGFR 1, 2, and 3, in patients with advanced or metastatic NSCLC or UC. Methods Eligible patients with NSCLC had received ≥1 prior platinum-containing therapy and ≤2 prior lines of systemic therapy for locally advanced or metastatic disease; patients with UC were treatment naive in the locally advanced or metastatic setting and ineligible for cisplatin-containing chemotherapy. Patients were immune checkpoint inhibitor naive and received avelumab 800 mg intravenously every 2 weeks + axitinib 5 mg orally twice daily. The primary endpoint was confirmed objective response (OR) per investigator assessment (RECIST 1.1). Secondary endpoints included progression-free survival (PFS) and safety. PD-L1 expression was assessed in baseline tumor samples (Ventana SP263 assay). Data have not undergone standard quality checks and are subject to change due to COVID-19–related healthcare burden. Results A total of 41 patients with NSCLC and 20 with UC received avelumab + axitinib. The confirmed OR rate was 31.7% (95% CI, 18.1–48.1) in the NSCLC cohort and 10% (95% CI, 1.2–31.7) in the UC cohort (all partial responses); 16 patients (39.0%) and 5 (25.0%) had stable disease, respectively. Responses were observed regardless of PD-L1 expression status. Median PFS was 5.5 months (95% CI, 2.5–7.0) in the NSCLC cohort and 2.3 months (95% CI, 1.8–5.6) in the UC cohort. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 24 patients (58.5%) in the NSCLC cohort; the most common was hypertension (n=7 [17.1%]). Grade ≥3 TRAEs occurred in 9 patients (45.0%) in the UC cohort; the most common were amylase increased, asthenia, decreased appetite, and palmar-plantar erythrodysesthesia syndrome (n=2 [10%] each). One patient in each cohort experienced a TRAE that led to death (gastric perforation and urinary bladder hemorrhage). Conclusions Avelumab + axitinib showed antitumor activity and a manageable safety profile in patients with advanced or metastatic NSCLC or UC consistent with findings from studies of each drug alone and in combination. Trial Registration NCT03472560 Ethics Approval The study was approved by each site’s independent ethics committee. Consent N/A References Gulley JL, Rajan A, Spigel DR, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol 2017;18:599–610. Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 2018;19:51–64. Bavencio(avelumab) injection. [package insert] Darmstadt, Germany: Merck KGaA; 2019. US Food and Drug Administration. FDA approves avelumab for urothelial carcinoma maintenance treatment. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-avelumab-urothelial-carcinoma-maintenance-treatment. Accessed August 19, 2020.

With a global estimate of tens of thousands of arachnid enthusiasts, spiders and scorpions are gaining increasing popularity as pets in industrialised countries in Europe, Northern America and Asia. As most spiders and all scorpions are venomous and due to their mostly negative image in the public media, several governments are already considering introducing legislation to regulate the domestic care of potentially dangerous captive animals. We aimed to investigate the circumstances and effects of exposure to arachnids kept in captivity. Thus, we collected and analysed data from 354 self-reported bites and stings attributed to pet arachnids. Our data revealed that on average there were less than 20 recorded envenomations per year with ~90% preventable by due care. We also categorized the severity of the resulting symptoms and found that the vast majority of symptoms were either local (60.7%) or minor (32.8%), 5.4% were asymptomatic, only 1.1% were severe and no fatalities were recorded. Based on our database of bite and sting reports, we performed a risk assessment for arachnid pet ownership and concluded that, with the proper care, arachnids can be safely kept as pets and pose a lower risk than many other recreational activities.

Background The open-label, phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab monotherapy 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma (RCC). Three cohorts included patients with predominantly clear cell histology, non-clear cell histologies, or brain metastases. We report safety and efficacy from the CheckMate 374 advanced clear cell RCC (ccRCC) cohort. Patients and Methods Eligible patients received prior treatment regimens (1-2 antiangiogenic; 0-3 systemic) with progression on/after last treatment and ≤ 6 months of enrollment. Patients received nivolumab 240 mg Q2W for ≤ 24 months or until confirmed progression/unacceptable toxicity. The primary endpoint was incidence of high-grade (grade 3-5) immune-mediated adverse events (IMAEs). Exploratory endpoints included objective response rate, progression-free survival, and overall survival. Results Ninety-seven patients had advanced predominantly ccRCC; 75.3% received only 1 prior systemic regimen in the advanced/metastatic setting. After a median follow-up of 17 months (range, 0.4-26.9 months), no grade 5 IMAEs occurred, and 9.3% of patients reported grade 3/4 IMAEs (hepatitis, 4.1%; diabetes mellitus, 2.1%; nephritis and renal dysfunction, 1.0%; rash, 1.0%; adrenal insufficiency, 1.0%). The objective response rate was 22.7% (95% confidence interval [CI], 14.8%-32.3%). Three patients had a complete response; 19 had partial responses. The median progression-free survival was 3.6 months (95% CI, 2.0-5.5 months). The median overall survival was 21.8 months (95% CI, 17.4 months to not estimable). Conclusions This study validates the safety and efficacy of nivolumab 240 mg Q2W flat-dose monotherapy for previously treated advanced ccRCC and adds to previous safety and efficacy data using the 3 mg/kg Q2W dose.

The open-label, phase IIIb/IV CheckMate 374 study (NCT02596035) was conducted to validate the safety and efficacy of flat-dose nivolumab monotherapy 240 mg every 2 weeks (Q2W) in previously treated advanced/metastatic renal cell carcinoma (RCC). Three cohorts included patients with predominantly clear cell histology, non-clear cell histologies, or brain metastases. We report safety and efficacy from the CheckMate 374 advanced clear cell RCC (ccRCC) cohort.Eligible patients received prior treatment regimens (1-2 antiangiogenic; 0-3 systemic) with progression on/after last treatment and ≤ 6 months of enrollment. Patients received nivolumab 240 mg Q2W for ≤ 24 months or until confirmed progression/unacceptable toxicity. The primary endpoint was incidence of high-grade (grade 3-5) immune-mediated adverse events (IMAEs). Exploratory endpoints included objective response rate, progression-free survival, and overall survival.Ninety-seven patients had advanced predominantly ccRCC; 75.3% received only 1 prior systemic regimen in the advanced/metastatic setting. After a median follow-up of 17 months (range, 0.4-26.9 months), no grade 5 IMAEs occurred, and 9.3% of patients reported grade 3/4 IMAEs (hepatitis, 4.1%; diabetes mellitus, 2.1%; nephritis and renal dysfunction, 1.0%; rash, 1.0%; adrenal insufficiency, 1.0%). The objective response rate was 22.7% (95% confidence interval [CI], 14.8%-32.3%). Three patients had a complete response; 19 had partial responses. The median progression-free survival was 3.6 months (95% CI, 2.0-5.5 months). The median overall survival was 21.8 months (95% CI, 17.4 months to not estimable).This study validates the safety and efficacy of nivolumab 240 mg Q2W flat-dose monotherapy for previously treated advanced ccRCC and adds to previous safety and efficacy data using the 3 mg/kg Q2W dose.

Purpose: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). Experimental Design: Two cohorts were studied: AAP-naïve and post-AAP patients who had received ≥6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day. Primary endpoint was ≥50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria. Secondary endpoints included time to PSA progression and time on treatment. Results: Forty-six patients enrolled in the AAP-naïve (n = 25) and post-AAP (n = 21) cohorts. The 12-week PSA response rate was 88% (22/25) and 22% (4/18), median time to PSA progression was 18.2 months [95% confidence interval (CI), 8.3 months–not reached) and 3.7 months (95% CI, 2.8–5.6 months), and median time on treatment 21 months (range, 2.6–37.5) and 4.9 months (range, 1.3–23.2), for the AAP-naïve and post-AAP cohorts, respectively. Eighty percent (95% CI, 59–93) and 64% (95% CI, 43–82) of AAP-naïve and 43% (95% CI, 22–66) and 10% (95% CI, 1–30) of post-AAP patients remained on treatment for 6+ and 12+ months, respectively. Common treatment-emergent adverse events in both cohorts were grade 1 or 2 fatigue, diarrhea, nausea, and abdominal pain. Conclusions: Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC, with 80% of AAP-naïve and 43% of post-AAP patients, remaining on treatment for 6 months or longer. Clin Cancer Res; 23(14); 3544–51. ©2017 AACR.

A screening of compound libraries based on nipecotic acid derivatives with lipophilic residues attached to the scarcely explored 5-position of the core structure was used for the search of new inhibitors of the γ-aminobutyric acid (GABA) transporter 1 (mGAT1). The generated compound libraries, which were based on hydrazone chemistry commonly used in dynamic combinatorial chemistry but rendered pseudostatic, were screened for their binding affinities toward mGAT1 by means of MS Binding Assays. With nipecotic acid derived hydrazone rac-16 h [rac-(3R,5S)-{5-[(E)-2-{[5-(2-phenylethynyl)thiophen-2-yl]methylidene}hydrazin-1-yl]piperidine-3-carboxylic acid}-sodium chloride (1/2)], one hit was found and evaluated displaying sub-micromolar potency (pKi =6.62±0.04) and a noncompetitive interaction mode at mGAT1. By bearing a 5-(2-phenylethynyl)thiophen-2-yl residue attached to the 5-position of nipecotic acid via a three-atom spacer, compound rac-16 h contains a structural moiety so far unprecedented for these kinds of bioactive molecules, and complements novel 5-substituted nipecotic acid derived ligands of mGAT1 revealed in a recently published screening campaign. This new class of ligands, with an inhibition mode distinct from that of benchmark mGAT1 inhibitors, could serve as research tools for investigations of mGAT1-mediated GABA transport.

Background: Recent network approaches suggest that transition to psychiatric disorders arise from divergent causal interactions among symptoms, whereby the emergence of one central symptom activates an interconnected set of other symptoms. Methods: Here, we used network analysis to test whether the transition to psychosis is preceded by aberrant symptom organisation. 63 at-risk mental state (ARMS) individuals without later transition to psychosis (ARMS-NT), 16 ARMS individuals with later transition to psychosis (ARMS-T), and 38 antipsychotic-free patients with first-episode psychosis (FEP group) were included. Symptoms were measured using Brief Psychiatric Rating Scale (BPRS) and graph theory was used to quantify global and local network properties. Group differences in symptom connectivity were assessed using functional data analysis and network-based statistics (NBS). Outcomes: While severity of BPRS items did not allow to differentiate ARMS-T and ARMS-NT patients, ARMS-T patients exhibited a widespread connectivity increase among symptoms relative to ARMS-NT individuals. AMRS-T and FEP patients also displayed highly segregated symptoms compared to ARMS-NT individuals. Furthermore, in both ARMS-T and FEP patients anxiety was the most binding (central) symptom. Interpretation: Our findings suggest that the risk of transition to psychosis relates to the consolidation of relationship among symptoms, but appears to be unrelated to the severity of symptoms per se. Phenomenological network approaches provide insight into novel prevention targets such as deconsolidation of symptom clustering. Funding Statement: This study was funded by CIHR Foundation Grant (375104/2017) to LP; AMOSO Opportunities fund to LP; Bucke Family Fund and Arcangelo Rea Family Foundation (London, Ontario). Declarations of Interests: LP reports personal fees from Otsuka Canada, SPMM Course Limited, UK, Canadian Psychiatric Association; book royalties from Oxford University Press; investigator-initiated educational grants from Janssen Canada, Sunovion and Otsuka Canada outside the submitted work. All other authors report no competing interests. Ethical Approval Statement: All participants provided written informed consent, and the study had research ethics committee permission.

e20594 Background: RRx-001 is a small molecule immunotherapeutic in Phase 3 for the treatment of SCLC that is associated with M2-M1 tumor associated macrophage (TAM) repolarization with CD47 downregulation, vascular normalization and reversal of chemoresistance. In a controlled, multicenter clinical trial called REPLATINUM that was prematurely halted due to COVID-19, data from 17 patients with third line or beyond SCLC was analyzed. Moving forward, REPLATINUM(restarted) has added SARS-CoV-2 exclusion criteria. Our aim was to explore the efficacy of RRx-001 in REPLATINUM and to assess the statistical assumptions of the REPLATINUM(restarted) trial in order to inform future clinical development in SCLC. Methods: Patients in REPLATINUM were randomized to receive 1 of 2 arms: 1) carboplatin AUC 5 IV on day 1 or cisplatin 60 mg/m2 IV on day 1 plus etoposide 100 mg/m2 IV on days 1 through 3 every 21 days for up to 4 cycles or 2) 4 mg of RRx-001 administered sequentially with 4 cycles of a platinum doublet (cisplatin or carboplatin plus etoposide as outlined above). Progression Free Survival (PFS) was the primary efficacy endpoint based on a blinded independent central review (BICR). Results: The trial was suspended prematurely after 17 patients had been enrolled due to widespread COVID-19 exposure with the plan to restart the trial. The decision to restart the trial has provided an opportunity to examine the data for preliminary evidence of treatment efficacy. At the time that the REPLATINUM trial was halted, there were 11 patients enrolled on the control arm and 6 on the investigational arm. The BICR assessed median PFS was approximately 7.1 months for RRx-001 + platinum doublet and 3.5 months for the platinum doublet alone based on the truncated database. The BICR assessed PFS hazard ratio was approximately 0.5. OS medians were approximately 8.2 and 6.3 months for RRx-001 + platinum doublet and platinum doublet alone, respectively. Additionally, patients on the RRx-001 + platinum doublet-treated experimental arm experienced less toxicity than patients on the platinum doublet-treated control arm. Conclusions: Despite the small sample size, preliminary results from REPLATINUM suggest a trend toward a favorable primary outcome and improved safety in RRx-001-treated patients and support the validity of the statistical assumptions that underlie the REPLATINUM(restarted) trial. Pivotal evidence will emerge from REPLATINUM(restarted), which is imminently recommencing. Clinical trial information: NCT03699956.

398 Background: Bladder cancer (BC) patients (pts) who are cisplatin ineligible/unfit for surgery, or locally advanced and unresectable have limited treatment options. DUART investigates if the combination of radiation therapy (RT) and checkpoint inhibitor, durvalumab (durva) is safe and effective in these pts. We recently reported that the combination was safe, tolerable and disease control rate (DCR) was 92% post durvaRT. Here we present interim efficacy data of our phase II study. Methods: Pts with pure or mixed urothelial bladder cancer (T2-4 N0-2 M0) were enrolled if their tumor was unresectable (35%), were unfit for surgery (50%) and/or cisplatin ineligible (89%). Primary endpoints: a) PFS at 1-yr b) DCR post adjuvant durva; Secondary endpoints: a) CR post durvaRT b) median PFS c) median OS. Pts were treated with durva (1500mg) Q4 wks x2 doses along with definitive RT (64.8Gy, 36 fractions over 7 wks) to the bladder and involved nodes followed by adjuvant durva Q4 wks x 1 yr. Response was evaluated with CT scan and cystoscopy+biopsy. Sample size was based on assumption that this regimen would increase 1 yr PFS by 25% compared to RT alone (50% to 75%); we assumed DCR of 75%. A total of 26 pts were needed to reach a statistical power of at least 80% at one-sided alpha of 5% and to allow for 10% drop out rate. Results: Twenty-six pts (19 males, 7 females) were enrolled, median age 74 yr (51-94). Sixty two percent of pts had >T2 disease, 31% had positive lymph nodes; 62% with unresectable tumor or were unfit for surgery due to comorbidities. At data cut off (9/30/2020) 20/26 pts were evaluable for DCR post adjuvant durva (3 pts with CR post durvaRT, did not get adjuvant therapy; 1 pt withdrew after 3 cycles for adjuvant durva and was on f/u with unconfirmed CR; 2 pts are still on adjuvant durva) and 25/26 for PFS and all 26 pts for OS. Post completion of adjuvant durva, DCR was seen in 70 % (14/20 with 10 CR; 3 PR; 1 SD; 6 PD). One-year probability of PFS was 73% (95% CI 56.4%, 94.4%), median PFS was 18.5 months. One-year OS probability was 83.8% (95% CI 70.4%, 99.7%) with two-year OS probability of 76.8 (95% CI 60.2%, 98%). Median OS has not been reached. We did not observe any correlation between clinical outcome and baseline tumor PD-L1 expression. Conclusions: DurvaRT followed by adjuvant durva demonstrated promising efficacy with 1-year PFS probability of 73%, 1- year OS probability of 83.8% and DCR of 70% in MIBC and locally advanced BC pts with comorbidities. Results will be updated prior to the final presentation. Efficacy was also seen in node (+) pts which led to the design of prospective randomized NCTN study. Induction chemo followed by chemo+durvaRT+ adjuvant durva vs. chemoRT combination is being evaluated in the ongoing EA8185 clinical trial (ECOG-ACRIN/NRG study) for node (+) BC pts. Clinical trial information: NCT02891161.

85 Background: Androgen receptor (AR) targeting therapies prolong survival of patients with metastatic castration-resistant prostate cancer (mCRPC); however, in many cases, resistance develops, resulting in disease progression. Activation of the PI3K/AKT/mTOR signaling pathway is common in mCRPC and contributes to resistance, mostly due to loss of PTEN, which occurs in 40–60% of patients. Preclinical studies have demonstrated reciprocal regulation between the AR and PI3K/AKT/mTOR pathways and significant anti-tumor activity when both pathways are inhibited, particularly in models with PTEN-loss. Thus, a rationale exists to inhibit both pathways in mCRPC patients. We report interim results of a phase 1 multicohort study (NCT04087174) to confirm the acceptable dose of capivasertib, a potent, selective pan-AKT inhibitor in combination with the androgen synthesis inhibitor abiraterone acetate (AA) in mCRPC patients. Methods: Patients who had received at least one prior systemic therapy (chemotherapy or novel hormonal agent) for mCRPC were given AA (1000 mg, once daily) with capivasertib (400 mg, twice daily, 4 days on/3 days off) until unacceptable toxicity or disease progression. Dose-limiting toxicity in the first 28 days of treatment and adverse events were recorded. Results: 15 patients, median age 67 (range 49–82) years, were recruited in the USA and Spain. Twelve patients had received prior chemotherapy; 7 had two or more prior lines. Seven patients had received prior AA and 10 had received prior enzalutamide. No dose-limiting toxicities were recorded. Eight patients reported at least one grade ≥ 3 adverse event (AE). Grade ≥ 3 AEs in 7 patients were related to capivasertib: allergic reaction to medication, asthenia, type 2 diabetes mellitus, diarrhea and fatigue were each reported in 1 patient, maculopapular rash − in 2 patients, both hypokalemia and acquired Fanconi syndrome − in 1 patient. Acute kidney injury was reported in 4 patients but was not considered related to capivasertib. The most common AEs of any grade related to capivasertib were: diarrhea, 6/15 patients (40%); maculopapular rash, 5/15 (33%); fatigue, 4/15 (27%); hyperglycemia/type 2 diabetes mellitus, 4/15 (27%); nausea, 3/15 (20%); hypokalemia, 2/15 (13%); hypophosphatemia, 2/15 (13%). Capivasertib was discontinued in 4/15 patients (27%) due to AEs. Between initial screening and day 29 of treatment, 5 patients had reduced (> 20%) PSA levels, with 3 patients showing sustained falls in PSA over 12 weeks. Conclusions: In this phase 1 study combined capivasertib and AA exhibits an acceptable safety and tolerability profile. Further data on the clinical efficacy and safety of the combination are being collected in the phase 3 CAPItello-281 trial. Acknowledgments: We thank Adam Errington, PhD, of Oxford PharmaGenesis, for medical writing assistance. Funding: This trial is funded by AstraZeneca. Clinical trial information: NCT04087174.

343 Background: With the emergence of multiple active treatment options in RCC, predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion151 and Javelin Renal 101 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. We aimed to describe the genomic and gene expression profiles in a multi-institutional database of patients with ccRCC, and its association with other biomarkers of interest. Methods: Whole transcriptome sequencing was performed for ccRCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) from February 2019 to September 2020. Tumor GEP and hierarchical clustering based on the validated 66-gene signature (D’Costa et al, 2020) were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included. Results: A total of 316 patients with ccRCC, median age 62 (range 32-90), 71.8% men, were included. Tissue samples were obtained from primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%) and other metastatic sites (27%). Gene expression analysis identified angiogenic, mixed and T-effector subgroups in 24.1%, 51.3% and 24.7%, respectively. Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009) and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), TMB (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup. PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (e.g. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup. Conclusions: Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.

Purpose To endorse the European Association of Urology guideline on muscle-invasive (MIBC) and metastatic bladder cancer. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. Methods The guideline on MIBC and metastatic bladder cancer was reviewed for developmental rigor by methodologists. The ASCO Endorsement Panel then reviewed the content and recommendations. Results The ASCO Endorsement Panel determined that the recommendations from the European Association of Urology guideline on MIBC and metastatic bladder cancer, published online in March 2015, are clear, thorough, and based on the most relevant scientific evidence. ASCO endorses the guideline on MIBC and metastatic bladder cancer and has added qualifying statements, including highlighting the use of chemoradiotherapy for select patients with MIBC and recommending a preference for clinical trials in the treatment of metastatic disease in the second-line setting. Recommendations Multidisciplinary care for patients with MIBC and metastatic bladder cancer is critical. The standard treatment of MIBC (cT2-T4a N0M0) is neoadjuvant cisplatin-based combination chemotherapy followed by radical cystectomy. In cisplatin-ineligible patients, radical cystectomy alone is recommended. Adjuvant cisplatin-based chemotherapy may be offered to high-risk patients who have not received neoadjuvant therapy. Chemoradiotherapy may be offered as an alternative to cystectomy in appropriately selected patients with MIBC and in some patients for whom cystectomy is not an option. Metastatic disease should be treated with cisplatin-containing combination chemotherapy or with carboplatin combination chemotherapy or single agents in patients ineligible for cisplatin. Additional information is available at http://www.asco.org/endorsements/MIBC and www.asco.org/guidelineswiki .

TPS9083 Background: Despite several recent checkpoint inhibitor approvals extensive stage small cell lung cancer (SCLC) is associated with a poor prognosis and remains an area of high unmet need. RRx-001 is a first-in-class, minimally toxic small molecule immunotherapeutic that inhibits c-Myc, downregulates the antiphagocytic checkpoint, CD47, repolarizes tumor associated macrophages (TAM) from protumor M2 to antitumor M1 and resensitizes to previously active first line therapies. On the basis of favorable results from a Phase 2 trial called QUADRUPLE THREAT (NCT02489903) in combination with a platinum doublet in later line SCLC, a Phase 3 trial called REPLATINUM was started in 3rd line or beyond SCLC in Q4 2019. Enrollment is ongoing. Methods: This US-based, open-label, randomized, phase 3 study (NCT03777657) compares RRx-001 4mg + a platinum doublet (carboplatin or cisplatin + etoposide) versus a platinum doublet for pts with 3rd line or beyond SCLC that have previously received a checkpoint inhibitor. Approximately 120 pts from 25 centers will be randomized 1:1 to receive RRx-001 4 mg in combination with a platinum doublet vs. a platinum doublet. The platinum doublet will be administered on both arms for up to 4 cycles; on the RRx-001 arm only patients with stable disease or better are eligible to continue on RRx-001 4 mg + carboplatin AUC 2-4 maintenance therapy. If radiologic progression occurs on the control arm prior to the 4th cycle, patients are eligible to crossover to the RRx-001 treatment arm. PFS is the primary endpoint. Secondary endpoints include OS and ORR. Exploratory endpoints include c-Myc, CD-47 and PD-L1 on circulating tumor cells and SIRP-alpha expression on circulating monocytes. Clinical trial information: NCT03777657.

TPS587 Background: Patients (pts) with cisplatin ineligible metastatic urothelial carcinoma (mUC) who progress after first-line PD1/PDL1 inhibition have limited treatment options. The concept of maintenance therapy with targeted agents and adding onto it at time of progression is a proven effective strategy. Preclinical data indicate that carboplatin+gemcitabine have immunomodulatory effect to potentially augment immune response. We hypothesize that in pts with cisplatin ineligible mUC, the use of atezolizumab+chemotherapy after progression on single-agent PD1/PDL1 inhibitor will result in clinical benefit. Methods: Multi-center, single arm, open label phase 2 trial of atezolizumab+carboplatin+gemcitabine in pts with cisplatin ineligible mUC. Eligible pts are adults with mUC (mixed histology allowed) who progressed after first line PD1/PDL1 inhibitor. Pts should be cisplatin ineligible based on consensus criteria. Neoadjuvant/adjuvant chemotherapy completed ≥12 months prior to enrollment is allowed. Treatment with atezolizumab will continue until disease progression or unacceptable toxicity while carboplatin+gemcitabine can be stopped after 4-6 cycles. Primary objective is progression-free survival per RECIST and secondary objectives are overall response rate, clinical benefit rate, and overall survival (OS). Exploratory endpoints include to compare OS of atezolizumab+carboplatin+gemcitabine in this trial compared to a virtual control arm of carboplatin+gemcitabine in mUC after progression on first-line PD1/PDL1 inhibitors. Other exploratory endpoints include to compare PD-L1 status at time of diagnosis and at time of enrollment (after progression on PD1/PDL1 inhibitor). Using an alternate hypothesis that atezolizumab+carboplatin+gemcitabine will have a median PFS of 9 months compared to historical control of 5 months with a platinum regimen in 2nd line setting, we plan to enroll 33 patients. This study is currently enrolling pts. A protocol amendment is under way that will allow pts with prior platinum-based chemotherapy to enroll on this trial. Clinical trial information: NCT03737123.

513 Background: Bladder cancer (BC) patients (pts) who are cisplatin ineligible/unfit for surgery, unresectable have limited treatment options. In this study, we investigate if the combination of radiation therapy (RT) and checkpoint inhibitor, durvalumab (durva) is safe and effective in these pts. Our results from phase (ph) Ib suggested that the combination was safe. Here we present the response rate post durvaRT and updated treatment related adverse events (TRAEs) amongst our evaluable pts in ph II. Methods: This is a single arm ph Ib-II study for T2-4 N0-2 M0 pts. The ph II primary endpoints a) PFS rate at 1 yr b) disease control rate (DCR); secondary endpoints were a) CR post durvaRT b) PFS c) OS. Pts were treated with durva (1500mg) Q4 wks x2 doses along with definitive RT (64.8Gy, 36 fractions over 7 wks) to the bladder and involved nodes followed by adjuvant durva Q4 wks x 1 yr. Response was evaluated with CT scan and cystoscopy+biopsy post durvaRT. We anticipated that durvaRT followed by durva would increase PFS at 1 yr from 50% to 75% when compared to RT; we assumed DCR of about 75%. A total of 26 pts were needed to reach a statistical power of at least 80% at one-sided alpha of 5% and to allow for 10% drop out rate. Results: Total N = 26 patients (male 19; female 7, median age 74yr). At the time of data cut off, 21/26 pts were evaluable for response post durvaRT. Post completion of durvaRT time point, clinical CR was seen in 15/21 pts (71.4%); PR 1/21 pts (4.7%); SD 4/21 (19%); PD 1/21 (4.7%). DCR was seen in 20/21 pts (95%) post durvaRT. Median follow up from D1 to last follow up was 6.1 mos. Grade ≥ 3 TRAE amongst 26 pts: anemia (1/26), lipase/amylase (1/26), immune nephritis (1/26), dyspnea (gr 4, copd/immune), fatigue (1/26), lymphopenia (6/26). Other TRAEs: Fatigue was the most common TRAE (16/26); UTI (5/26); cystitis (3/26). No fatal TRAEs were observed. Conclusions: DurvaRT demonstrated promising efficacy with clinical CR of 71.4% and DCR of 95% in unresectable, cisplatin ineligible locally advanced BC. It was generally well tolerated. Ph II study has completed accrual and longer-term results will further our understanding of this regimen’s efficacy in locally advanced BC. Clinical trial information: NCT02891161.

Mithramycin demonstrates preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with germline variants in genes involved in bile disposition: ABCB4 (multidrug resistance 3) rs2302387 and ABCB11 [bile salt export pump (BSEP)] rs4668115 reduce transporter expression (P < 0.05) and were associated with ≥grade 3 transaminitis developing 24 hours after the third infusion of mithramycin (25 mcg/kg, 6 hours/infusion, every day ×7, every 28 days; P < 0.0040). A similar relationship was observed in a pediatric cohort. We therefore undertook to characterize the mechanism of mithramycin-induced acute transaminitis. As mithramycin affects cellular response to bile acid treatment by altering the expression of multiple bile transporters (e.g., ABCB4, ABCB11, sodium/taurocholate cotransporting polypeptide, organic solute transporter α/β) in several cell lines [Huh7, HepaRG, HepaRG BSEP (-/-)] and primary human hepatocytes, we hypothesized that mithramycin inhibited bile-mediated activation of the farnesoid X receptor (FXR). FXR was downregulated in all hepatocyte cell lines and primary human hepatocytes (P < 0.0001), and mithramycin inhibited chenodeoxycholic acid- and GW4046-induced FXR-galactose-induced gene 4 luciferase reporter activity (P < 0.001). Mithramycin promoted glycochenodeoxycholic acid-induced cytotoxicity in ABCB11 (-/-) cells and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture (P < 0.01). Mithramycin is a FXR expression and FXR transactivation inhibitor that inhibits bile flow and potentiates bile-induced cellular toxicity, particularly in cells with low ABCB11 function. These results suggest that mithramycin causes hepatotoxicity through derangement of bile acid disposition; results also suggest that pharmacogenomic markers may be useful to identify patients who may tolerate higher mithramycin doses. SIGNIFICANCE STATEMENT: The present study characterizes a novel mechanism of drug-induced hepatotoxicity in which mithramycin not only alters farnesoid X receptor (FXR) and small heterodimer partner gene expression but also inhibits bile acid binding to FXR, resulting in deregulation of cellular bile homeostasis. Two novel single-nucleotide polymorphisms in bile flow transporters are associated with mithramycin-induced liver function test elevations, and the present results are the rationale for a genotype-directed clinical trial using mithramycin in patients with thoracic malignancies.

The γ-aminobutyric acid (GABA) transporter mGAT4 represents a promising drug target for the treatment of epilepsy and other neurological disorders; however, the lack of highly potent and selective inhibitors for mGAT4 still retards its pharmacological elucidation. Herein, the generation and screening of pseudostatic combinatorial hydrazone libraries at the murine GABA transporter mGAT4 for the search of novel GABA uptake inhibitors is described. The hydrazone libraries contained more than 1100 compounds derived from nipecotic acid derivatives substituted at the 5-position instead, as common, at the 1-position of the core structure. Two hits were found and evaluated, which display potencies in the lower micromolar range at mGAT4 and its human equivalent hGAT3. These compounds possess a lipophilic moiety derived from a biphenyl residue attached to the 5-position of the hydrophilic nipecotic acid moiety via a three-atom spacer. Thus, the novel structures with potencies close to that of the bench mark mGAT4 inhibitor (S)-SNAP-5114 add new insights into the structure-activity relationship of mGAT4 inhibitors and could provide a promising starting point for the development of new mGAT4 inhibitors with even higher potencies.

Purpose: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). Experimental Design: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. Results: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. Conclusions: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. Clin Cancer Res; 21(15); 3420–7. ©2015 AACR.

Purpose The guideline aims to optimize health and quality of life for the post-treatment prostate cancer survivor by comprehensively addressing components of follow-up care, including health promotion, prostate cancer surveillance, screening for new cancers, long-term and late functional effects of the disease and its treatment, psychosocial issues, and coordination of care between the survivor's primary care physician and prostate cancer specialist. Methods The American Cancer Society (ACS) Prostate Cancer Survivorship Care Guidelines were reviewed for developmental rigor by methodologists. The American Society of Clinical Oncology (ASCO) Endorsement Panel reviewed the content and recommendations, offering modifications and/or qualifying statements when deemed necessary. Results The ASCO Endorsement Panel determined that the recommendations from the 2014 ACS Prostate Cancer Survivorship Care Guidelines are clear, thorough, and relevant, despite the limited availability of high-quality evidence to support many of the recommendations. ASCO endorses the ACS Prostate Cancer Survivorship Care Guidelines, with a number of qualifying statements and modifications. Recommendations Assess information needs related to prostate cancer, prostate cancer treatment, adverse effects, and other health concerns and provide or refer survivors to appropriate resources. Measure prostate-specific antigen (PSA) level every 6 to 12 months for the first 5 years and then annually, considering more frequent evaluation in men at high risk for recurrence and in candidates for salvage therapy. Refer survivors with elevated or increasing PSA levels back to their primary treating physician for evaluation and management. Adhere to ACS guidelines for the early detection of cancer. Assess and manage physical and psychosocial effects of prostate cancer and its treatment. Annually assess for the presence of long-term or late effects of prostate cancer and its treatment.

Background Chemotherapy may exert immunomodulatory effects, thereby combining favorably with the immune checkpoint blockade. The pharmacodynamic effects of such combinations, and potential predictive biomarkers, remain unexplored. Objective To determine the safety, efficacy, and immunomodulatory effects of gemcitabine and cisplatin (GC) plus ipilimumab and explore the impact of somatic DNA damage response gene alterations on antitumor activity. Design, setting, and participants Multicenter single arm phase 2 study enrolling 36 chemotherapy-naive patients with metastatic urothelial cancer. Peripheral blood flow cytometry was performed serially on all patients and whole exome sequencing of archival tumor tissue was performed on 28/36 patients. Intervention Two cycles of GC followed by four cycles of GC plus ipilimumab. Outcome measurements and statistical analysis The primary endpoint was 1-yr overall survival (OS). Secondary endpoints included safety, objective response rate, and progression-free survival. Results and limitations Grade ≥3 adverse events occurred in 81% of patients, the majority of which were hematologic. The objective response rate was 69% and 1-yr OS was 61% (lower bound 90% confidence interval: 51%). On exploratory analysis, there were no significant changes in the composition and frequency of circulating immune cells after GC alone. However, there was a significant expansion of circulating CD4 cells with the addition of ipilimumab which correlated with improved survival. The response rate was significantly higher in patients with deleterious somatic DNA damage response mutations (sensitivity=47.6%, specificity=100%, positive predictive value=100%, and negative predictive value=38.9%). Limitations are related to the sample size and single-arm design. Conclusions GC+ipilimumab did not achieve the primary endpoint of a lower bound of the 90% confidence interval for 1-yr OS of >60%. However, within the context of a small single-arm trial, the results may inform current approaches combining chemotherapy plus immunotherapy from the standpoint of feasibility, appropriate cytotoxic backbones , and potential predictive biomarkers. Trial registration: ClinicalTrials.gov NCT01524991. Patient summary Combining chemotherapy and immune checkpoint blockade in patients with metastatic urothelial cancer is feasible. Further studies are needed to refine optimal combinations and evaluate tests that might identify patients most likely to benefit.

The public perception of spiders and scorpions is skewed towards the potential harm they can inflict in humans, despite recent scientific evidence that arachnid venom components might be useful as bioinsecticides or even human therapeutics. Nevertheless, arachnids are becoming more popular as pets in Europe, America and Asia, raising the question for regulatory agencies in these regions as to whether they need to take measurements to protect their citizens. In order to decide upon the necessary regulatory steps, they first need to determine which arachnids are actually dangerous to humans. This review therefore provides an overview of the current literature on verified bites and stings from spiders and scorpions with the aim of assessing their potential danger for human health. As a guideline, we also provide a list of those arachnid genera that we consider as potentially dangerous, which includes 10 spider and 11 scorpion genera. The arachnid genera classified as dangerous comprise less than a quarter of all extant scorpion species and only 0.5% of all spiders species, with the actual number most likely being much lower than that, as not all species in those genera might turn out to pose an actual threat for humans. In conclusion, we found that only a small percentage of scorpions and a minute percentage of all spiders can be considered as potentially dangerous to humans. While in some countries of origin the high incidence of envenomations by dangerous arachnids can result in a serious problem to the health system, we assessed the risk that the same species pose when kept as pets under controlled maintenance conditions as significantly lower.

The pathogenesis and transition of normal urothelium into bladder carcinoma are multifactorial processes. Chronic inflammation causes initiation and progression of the underlying pathophysiology of invasive and metastatic cancer. A dichotomy is observed in the role of immune cells in bladder cancer. While the immune response defends the host by suppressing neoplastic growth, several immune cells, including neutrophils, macrophages, and T-lymphocytes, promote tumor development and progression. The levels of human neutrophil peptide-1, -2, and -3, produced by neutrophils, increase in bladder cancer and might promote tumor angiogenesis and growth. The effect of macrophages is primarily mediated by pro-inflammatory cytokines, IL-6 and TNF-α. Additionally, the underlying immunological mechanisms of two treatments, BCG and cytokine gene-modified tumor vaccines, and future directions are critically discussed.

The specific role of C5a in cancer, especially in melanoma, has yet to be determined. Differential effects of C5a could be cancer specific. In the host defense system, C5a functions to protect the body from harmful entities via a plethora of mechanisms. Yet, C5a may also serve to potentiate cancerous process. C5a facilitates cellular proliferation and regeneration by attracting myeloid-derived suppressor cells and supporting tumor promotion. In this article, we critically reviewed the properties, mechanisms of action and functions of C5a, with particular emphasis on cancer inhibition and promotion, and clinical application of such knowledge in better management of patients with cancer. Outstanding questions and future directions in regard to the function of C5a in melanoma and other cancers are discussed.

Background Persecutory delusions (PD) constitute core symptoms in psychosis that may emerge from aberrant learning and inference about others’ intentions. Computational assays that use generative models of electrophysiological data to probe this learning process and its underlying neuronal mechanisms, in particular the effects of dopamine (DA) on synaptic plasticity, could provide mechanistic insights into the emergence of PD in psychosis. More importantly, they could enable prediction of individual treatment response to DA antagonists and thus help to address an important problem of clinical management of psychosis. Methods We tested 137 healthy volunteers (mean age: 22 ± 3) in a double-blind, placebo-controlled, between subject pharmacological study: placebo (n = 47), DA precursor L-Dopa (n = 45), and DA receptor antagonist amisulpride (n = 45). Electroencephalography was recorded using a 128-channel Brain-Vision system. Participants performed a social learning task that required learning about an adviser’s intentions and how they changed over time. Subsequently, we modeled participants’ behavior with the hierarchical Gaussian filter (HGF), a model in which learning is driven by hierarchical prediction error (PE) updates: At the first level, positive PEs indicate that advice was better than expected (advice PE: aPE). At the second level, a positive PE signals that the adviser’s intentions were less stable than predicted (volatility PE: vPE). Using the trial-wise estimates from the HGF, we performed single-trial EEG analyses of PE activity at sensor and source levels. We also examined DA effects on effective connectivity with dynamical causal modelling (DCM). To this end, we divided event-related potentials (ERPs) according to PE magnitudes into 2 bins corresponding to positive and negative PEs. Results At the sensor-level, we identified distinct temporal profiles of hierarchical PEs (peak effects: aPE at 112ms, vPE at 276ms). In source space, three sources showed significant effects for both PEs: anterior temporo-parietal junction (TPJ), dorsal middle cingulate cortex (MCC) and supplementary motor cortex (SMA). To identify the connections that convey PEs, we compared two DCM families that allowed input to different nodes of the network, and different modulatory effects of PE magnitude. The family with input entering the SMA and propagating via MCC to TPJ explained aPE-evoked activity best, whereas the family with input into the TPJ and propagating in the opposite direction best described the effects of vPE-evoked activity. Bayesian model selection identified the winning model for aPE effects; this model proposed PE magnitude modulations of input gain and effective connectivity from TPJ to MCC, and MCC to SMA. Conversely, a model with connectivity modulation from MCC to TPJ best described the effects of vPE. Second, we investigated the impact of dopaminergic perturbations of the network by comparing DCM parameters of the winning models across pharmacological groups. Post hoc t-tests revealed that DA impacted on aPE-induced perturbations only, which is in line with previous findings that aPEs are represented in dopaminergic regions while vPEs are likely encoded by activity in cholinergic regions. Specifically, DA modulated TPJ-MCC and SMA-MCC connectivity. Discussion Model-based analysis of EEG data in a social learning task detects DA effects on connectivity, even when behavior (accuracy, reaction time) was not affected by the drugs. Currently, we are extending our computational approach to first-episode schizophrenia patients, where we hope to use parameters from neuronal and behavioral models to predict individual treatment response.

562 Background: Initial safety results from the phase 3b/4 CheckMate 374 study showed that flat-dose nivolumab (NIVO) at 240 mg every 2 wk (Q2W) had a consistent safety profile across patients (pts) with clear cell and non-clear cell advanced RCC. We report updated safety and first disclosure of efficacy for pts with non-clear cell RCC (nccRCC) in CheckMate 374. Methods: Eligible pts in this cohort were adults with advanced or metastatic nccRCC who received 0–3 prior systemic therapies. Pts received NIVO 240 mg IV Q2W for ≤24 mo or until confirmed progression, unacceptable toxicity, or withdrawal of consent. Pts who benefited after 24 mo continued treatment according to the standard of care. The primary endpoint was incidence of high-grade immune-mediated adverse events (IMAEs). Exploratory endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR). Results: In CheckMate 374, 44 pts had nccRCC. Histological subtypes included papillary (n = 24), chromophobe (n = 7), unclassified (n = 8), and other (n = 5). Most pts with nccRCC (66%) were treatment-naïve. After a median follow-up of 11.1 mo, median OS was 16.3 mo (95% confidence interval [CI] 9.2–not estimable [NE]). OS was similar regardless of baseline PD-L1 expression. ORR was 13.6% (95% CI 5.2–27.4). One pt had complete response (chromophobe histology) and 5 pts had partial response (2 pts with papillary and 1 pt each with chromophobe, collecting duct, and unclassified histology). Median DOR was 10.2 mo (95% CI 5.6–NE). Median PFS was 2.2 mo (95% CI 1.8–5.4). The 1-year PFS rate was 14% (95% CI 5–27). No new safety concerns were identified. No treatment-related grade 5 AEs or grade 3–4 IMAEs were reported. Conclusions: Clinically meaningful antitumor activity was observed in the first prospective study of NIVO monotherapy in nccRCC. Responses were observed in several histological subtypes. The safety profile of flat-dose NIVO at 240 IV Q2W is consistent with the initial outcomes reported from this study and across the NIVO program. Clinical trial information: NCT02596035.

TPS681 Background: Abexinostat is a pan-histone deacetylase (HDAC) inhibitor that has shown promising activity in prior pre-clinical studies and early phase clinical trials. A phase 1b study of pazopanib plus abexinostat (Aggarwal et al. J Clin Oncol 2017) demonstrated strikingly durable responses in patients (pts) with clear cell renal cell carcinoma (RCC), including one patient with previously refractory disease with ongoing response for > 5 years’ duration. Induction of histone acetylation in peripheral blood mononuclear cells (PBMCs) was associated with durable treatment response. We hypothesize that the addition of abexinostat to pazopanib will significantly improve outcomes in patients with clear cell RCC. Methods: RENAVIV is a global, randomized, double-blind, placebo-controlled, two arm phase 3 study of pazopanib plus abexinostat versus pazopanib plus placebo, in pts with locally advanced or metastatic RCC with clear cell component. Up to one prior line of immunotherapy is allowed. Prior VEGF-targeting tyrosine kinase inhibitor treatment is prohibited. Stratification factors include: 1) Prior immunotherapy (yes/no) and 2) prognostic group (good, intermediate, poor). Pts randomized to pazopanib + placebo have the option of crossing over to receive pazopanib plus abexinostat at the time of disease progression. The primary endpoint is PFS by independent review committee. Secondary endpoints include PFS by investigator assessment, overall survival, safety, objective response rate (ORR), duration of response, patient-reported quality of life, and outcomes in cross-over population. Planned correlative studies include association between histone acetylation and HDAC expression in PBMCs with clinical outcomes. The total planned accrual is 413 pts, estimated to provide 90% power to detect a hazard ratio of 0.67 in the comparison of PFS between experimental versus control arms, with an overall two-sided type I error rate of 0.025. A pre-specified minimum of 50% of patients are required to have received prior immunotherapy. The first patient was enrolled in October 2018. Clinical trial information: NCT03592472.