BackgroundThe immune checkpoint inhibitors (ICIs) revolutionized cancer therapeutic landscape and substantially improved the survival of patients (pts) with advanced malignancies. Several predictive biomarkers are under evaluation, in order to identify patients who can benefit from ICI. Recently, elevated NLR, calculated from absolute neutrophil count and white cell count, were found to be independent predictors of reduced survival and increased risk of progression in melanoma patients receiving ICI. The purpose of this study is to retrospectively investigate relationship of NLR with inflammation-immune mediators.MethodsGene profiling analysis was performed from 78 basal PBMCs of metastatic melanoma pts treated in first line with anti-PD1 using NanoString IO360 panel. Patient’s characteristics are listed in table 1. To identify the best genes signature the Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) was applied.ResultsOverall, 78 patients were included in the analysis. Pts with high NLR at baseline (ratio >5.57) had a poorer PFS (HR=7.27, 95% CI = 3.57–14.8; p < 0.0001) and OS (HR=3.98; 95% CI = 2.0–7.9) than the pts with low NLR. Brain metastases were present in a higher proportion of pts with high NLR compared to those with low NLR (p=0.01). In the trascriptomic analysis, NLR was associated with SH2D1A, CD3, ZAP70, CD45RA genes, while a high NLR with CCNA1, LDHA, IL18R1, CD39, PTEN, MYD88 and MMP9 genes (ROC curve, AUC=0.97, p<0001). The signatures are also associated to response. In addition, CD39 expression is higher in NLR high and is associate with increase of N2 neutrophils. NLR increase on treatment is also associated to worse outcome and a specific genetic signature.ConclusionsNLR high is related with immunosuppressive, inflammatory and tumor related genes; in particular with N2 neutrophils associate to adenosine pathway activation. This could explain the prognostic role of NLR. Further investigations are needed to get additional information.AcknowledgementsThis work was supported by the Italian Ministry of Health Ricerca Corrente fundsEthics ApprovalThis study was approved by the Ethics Committee of Istituto Nazionale Tumori—IRCCS—Fondazione ‘G. Pascale’, Naples, Italy, protocol number 17/17 oss. All patients released informed consent to participate.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal. 41 Table 1

179 Background: EPI-7386 is a next generation aniten designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain (NTD) of the AR while effectively blocking transcription despite AR resistance mechanisms driven by the ligand-binding domain (LBD), including point mutations and splice variants. Preclinical models demonstrate the combination of EPI-7386 with enzalutamide (enz) results in a deeper blockade of the AR pathway (per RNAseq and ChIPseq data) and greater antitumor activity, prompting initiation of this trial. Methods: This Phase 1/2 multicenter, open-label clinical trial (NCT05075577) is enrolling mCRPC pts on androgen deprivation therapy and naïve to second-generation antiandrogens (one line of prior chemotherapy allowed). Phase 1 (P1) of the trial examines escalating doses of EPI-7386 in combination with a fixed dose of enz. The primary and secondary endpoints of P1 are to evaluate the safety and pharmacokinetics (PK) aspects of EPI-7386 and enz when administered in combination to establish the recommended Phase 2 combination doses (RP2CDs) and address any possible drug-drug interactions. Once the RP2CDs are established, Phase 2 of the trial will commence as a two -arm, 2:1 randomized trial evaluating the antitumor activity of EPI-7386 in combination with enz versus enz alone. Results: Seven pts have been enrolled in the first 2 cohorts: 3 in cohort 1 (600 mg QD EPI-7386 + 120 mg QD enz) and 4 in cohort 2 (800 mg QD EPI-7386 + 120 mg QD enz). No DLTs were observed, and the safety profile was consistent with second-generation antiandrogens (e.g., Grade 1 or 2 AEs of fatigue and hot flashes). PK results demonstrated enz exposure was minimally impacted by EPI-7386, while, as expected, EPI-7386 exposure was reduced 60-80% by enz (well-established CYP3A4 inducer). The observed EPI-7386 exposures remained in the clinically relevant range suggested by preclinical xenograft studies. 4/6 evaluable patients showed a PSA decrease &gt;90% at/before week 12 regardless of the pt’s previous chemotherapy status and 5/6 evaluable patients achieved a PSA decrease of at least 85%; all 6 patients showed stable disease by imaging. Conclusions: With no safety concerns from cohorts 1 and 2, cohort 3 is enrolling at 600 mg BID EPI-7386 + 120 mg QD enz to assess if the exposure of EPI-7386 can be further increased in light of the augmented metabolism of the drug induced by enz. Clinical trial information: NCT05075577 .

177 Background: EPI-7386 is a next generation aniten, a novel class of compounds designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain. Preclinical data supports disruption of AR regulated gene transcription even in the presence of resistance mechanisms including ligand-binding domain point mutations and truncated splice variants. Here we report results of the Part 1a first-in-human trial of EPI-7386 in mCRPC (NCT04421222). Methods: This Phase 1, open-label, multicenter, dose escalation (Part 1a) and expansion (Part 1b) trial was designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of EPI-7386 in mCRPC patients (pts) progressing on standard of care treatment, including next generation antiandrogen(s) and chemotherapy. Originally designed to assess up to 5 doses of EPI-7386 (200, 400, 600, 800, and 1000 mg QD), two additional cohorts were added examining 400 and 600 mg BID due to 600 mg QD showing exposure saturation while demonstrating a favorable safety profile. Results: 31 pts were enrolled in the QD cohorts and 8 in the BID cohorts. Pts had a median of 4 lines of prior therapy for mCRPC: 83% received abiraterone and at least one next generation AR inhibitor, and 58% had at least one line of prior chemotherapy. No DLTs were observed; EPI-7386 was safe and well tolerated at all doses/schedules evaluated. All related adverse events (AEs) were Grade 1 and 2 and consistent with AEs associated with second-generation antiandrogens. For doses above 400 mg QD, exposures were at or above those associated with antitumor activity in animal models. Evidence of antitumor activity (including significant and durable PSA responses and/or decreases in ctDNA, and/or radiographically documented tumor shrinkage) were observed in pts with fewer than 3 lines of treatment for mCRPC, no visceral metastases and no prior chemotherapy (9/31 pts). Conclusions: Part 1a treatment with EPI-7386 monotherapy was safe, well tolerated up to a daily dose of 1200 mg (600 mg BID), achieved target clinical exposures and showed preliminary signals of antitumor activity in heavily-pretreated mCRPC. Part 1b is open with enrollment focused on pre-chemotherapy, post-second generation antiandrogen treated mCRPC pts in one cohort, and treatment-naïve non-mCRPC pts in a window of opportunity proof-of-concept second cohort. Two doses will be evaluated (600 mg BID and QD) based on FDA Project Optimus recommendations. Clinical trial information: NCT04421222 .

Background: Androgen receptor (AR) signaling is a main driver of prostate cancer progression and remains a crucial target for therapeutic intervention even in late stages of the disease. While current antiandrogen therapies that directly or indirectly target the AR ligand binding domain (LBD) are initially effective, resistance ultimately develops and new methods of inhibiting the AR pathway are needed. Recent advances in targeted protein degradation using the PROteolysis TArgeting Chimera (PROTAC) technology demonstrate that AR-LBD targeted PROTACs can selectively degrade AR but not splice variant forms of AR that are found in advanced castration-resistant prostate cancer (CRPC) patients.

Human herpes virus-8 (HHV8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder sustained by pro-inflammatory cytokines, including interleukin-6 (IL-6). According to the international evidence-based criteria developed by the Castleman Disease Collaborative Network (CDCN), siltuximab, which works by inhibiting IL-6, is the recommended choice for iMCD treatment. We report a case of a 63-year-old white male with iMCD who has been on maintenance therapy with siltuximab for 15 years – representing one of the longest treatment periods of any patient with iMCD treated with siltuximab. The patient initially presented with fatigue and night sweats, with progressive worsening of the symptoms. Whole-body positron emission tomography/computed tomography revealed hypermetabolic lymphadenopathy. The patient had histopathologically confirmed Castleman disease, plasma cell type, and was negative for HHV8 and human immunodeficiency virus. The patient had abnormally high C-reactive protein (CRP) levels, a surrogate measure for IL-6. The patient was treated with high-dose steroids but had recurring lymphadenopathy early on. He was enrolled in the phase I dose-finding clinical trial of siltuximab, during which he achieved marked clinical improvement and sustained inhibition of CRP. The patient was enrolled in the long-term safety study and continues to receive siltuximab at 11 mg/kg every 3 weeks. He is presently receiving commercial siltuximab and has remained asymptomatic, with no evidence of lymphadenopathy. The case study presented is consistent with the evidence that siltuximab is a safe and effective therapy for the long-term management of iMCD. In addition, this case highlights the importance of prompt diagnosis for patients with iMCD, as effective therapy is available for patients as described in the CDCN and National Comprehensive Cancer Network iMCD treatment guidelines.Plain Language SummaryThe case of a 63-year-old white male with idiopathic multicentric Castleman disease who was successfully treated with siltuximab for 15 yearsIdiopathic multicentric Castleman disease (iMCD) is a group of rare lymphoproliferative disorders with shared histopathological features that affect lymph nodes in multiple regions of the body. The signs and symptoms of iMCD can be varied, with the disease being mild in some patients while life-threatening in others. A timely diagnosis of iMCD can be challenging but is required for effective management. We report a case of a patient who was diagnosed with iMCD. The patient was given high-dose steroids but continued to show progressive disease. He was then started on siltuximab, a targeted antibody therapy against a specific cytokine (interleukin-6) involved in inflammation. The patient responded well to the treatment, has shown evidence of long-term disease control, and has not reported any serious adverse events related to long-term siltuximab use. He has received 11 mg/kg of siltuximab every 3 weeks for the past 15 years. This case emphasizes the value of using siltuximab therapy for long-term management of this rare disorder. In addition, it highlights the importance of prompt diagnosis for patients with iMCD, as effective therapy is available, as described in iMCD treatment guidelines.

EPI-506 is the first of a new class of drugs targeting the N-terminal domain (NTD) of the androgen receptor (AR), potentially overcoming known resistance mechanisms to androgen receptor pathway inhibitors (ARPIs) among men with metastatic castration resistant prostate cancer (mCRPC). Patients with mCRPC who had progressed on prior ARPI were enrolled in this phase 1 open-label, adaptive 3 + 3 dose escalation study. The primary outcome was safety and tolerability of oral EPI-506. Secondary objectives included determination of the maximal tolerated dose (MTD), pharmacokinetic profile, and antitumor efficacy. 28 mCRPC patients were enrolled into 7 dose cohorts of EPI-506 ranging from 80-3600mg given once daily and 1800mg given twice daily. Six DLTs occurred in 4 patients; Grade 4 elevated amylase; Grade 3 abdominal pain; Grade 3 elevated ALT and Grade 3 elevated AST; Grade 2 nausea and Grade 1 vomiting which resulted in study drug intake of < 75% of the expected dose during the DLT assessment period. The most common drug-related adverse events included diarrhea, nausea and fatigue. Six patients had a PSA decline not meeting PSA response criteria. The study was terminated prior to reaching the MTD due to poor oral bioavailability. This phase 1 trial established the safety of EPI-506 and provides proof of concept for targeting the AR NTD. Next generation compounds with improved bioavailability and potency are in clinical development.

Background and ObjectiveA topical formulation of diclofenac (FLECTOR diclofenac epolamine topical system (FDETS)) is approved in adults for the treatment of acute pain due to minor strains, sprains, and contusions; however, its safety and efficacy have not been investigated in a pediatric population. This study assessed the safety and efficacy of the FLECTOR (diclofenac epolamine) topical system in children.MethodsThis was an open-label, single-arm, phase IV study at ten USA-based family medicine or pediatric practices in children aged 6–16 years with a clinically significant minor soft tissue injury sustained within the preceding 96 h and at least moderate spontaneous pain on the Wong-Baker FACES® Pain Rating Scale. The FLECTOR topical system was applied twice daily until pain resolution or Day 14. The primary endpoint was local tolerability and systemic safety. Key secondary endpoints were diclofenac plasma concentrations and analgesic efficacy.Results104 patients were enrolled; 52 were 6–11 years old, and 52 were 12–16 years old (mean age 11.6 years). The maximum tolerability score experienced by any patient was 1 (faint redness). Fourteen adverse events (none serious) in nine patients (8.7%) were considered possibly treatment-related. Reduction in pain during the study was somewhat greater for patients aged 6–11 versus 12–16 years (p < 0.011). The diclofenac plasma concentration tended to be higher in the younger age group compared with older patients: 1.83 versus 1.46 ng/mL at the first assessment and 2.49 versus 1.11 ng/mL at the last assessment (p = 0.002).ConclusionThe FLECTOR topical system safely and effectively provided pain relief for minor soft tissue injuries in the pediatric population, with minimal systemic nonsteroidal anti-inflammatory drug exposure and low potential risk of local or systemic adverse events.Clinical Trial RegistrationClinicalTrials.gov identifier NCT02132247.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40261-021-01101-x.