Citations

Abstract Introduction Delirium occurrence is common and preventive strategies are resource intensive. Screening tools can prioritize patients at risk. Using machine learning, we can capture time and treatment effects that pose a challenge to delirium prediction. We aim to develop a delirium prediction model that can be used as a screening tool. Methods From the eICU Collaborative Research Database (eICU-CRD) and the Medical Information Mart for Intensive Care version III (MIMIC-III) database, patients with one or more Confusion Assessment Method-Intensive Care Unit (CAM-ICU) values and intensive care unit (ICU) length of stay greater than 24 h were included in our study. We validated our model using 21 quantitative clinical parameters and assessed performance across a range of observation and prediction windows, using different thresholds and applied interpretation techniques. We evaluate our models based on stratified repeated cross-validation using 3 algorithms, namely Logistic Regression, Random Forest, and Bidirectional Long Short-Term Memory (BiLSTM). BiLSTM represents an evolution from recurrent neural network-based Long Short-Term Memory, and with a backward input, preserves information from both past and future. Model performance is measured using Area Under Receiver Operating Characteristic, Area Under Precision Recall Curve, Recall, Precision (Positive Predictive Value), and Negative Predictive Value metrics. Results We evaluated our results on 16 546 patients (47% female) and 6294 patients (44% female) from eICU-CRD and MIMIC-III databases, respectively. Performance was best in BiLSTM models where, precision and recall changed from 37.52% (95% confidence interval [CI], 36.00%–39.05%) to 17.45 (95% CI, 15.83%–19.08%) and 86.1% (95% CI, 82.49%–89.71%) to 75.58% (95% CI, 68.33%–82.83%), respectively as prediction window increased from 12 to 96 h. After optimizing for higher recall, precision and recall changed from 26.96% (95% CI, 24.99%–28.94%) to 11.34% (95% CI, 10.71%–11.98%) and 93.73% (95% CI, 93.1%–94.37%) to 92.57% (95% CI, 88.19%–96.95%), respectively. Comparable results were obtained in the MIMIC-III cohort. Conclusions Our model performed comparably to contemporary models using fewer variables. Using techniques like sliding windows, modification of threshold to augment recall and feature ranking for interpretability, we addressed shortcomings of current models.

PURPOSE Biliary tract cancers (BTCs) are aggressive cancers that carry a poor prognosis. An enhanced understanding of the immune landscape of anatomically and molecularly defined subsets of BTC may improve patient selection for immunotherapy and inform immune-based combination treatment strategies. METHODS We analyzed deidentified clinical, genomic, and transcriptomic data from the Tempus database to determine the mutational frequency and mutational clustering across the three major BTC subtypes (intrahepatic cholangiocarcinoma [IHC], extrahepatic cholangiocarcinoma, and gallbladder cancer). We subsequently determined the relationship between specific molecular alterations and anatomical subsets and features of the BTC immune microenvironment. RESULTS We analyzed 454 samples of BTC, of which the most commonly detected alterations were TP53 (42.5%), CDKN2A (23.4%), ARID1A (19.6%), BAP1 (15.5%), KRAS (15%), CDKN2B (14.2%), PBRM1 (11.7%), IDH1 (11.7%), TERT (8.4%), KMT2C (10.4%) and LRP1B (8.4%), and FGFR2 fusions (8.7%). Potentially actionable molecular alterations were identified in 30.5% of BTCs including 39.1% of IHC. Integrative cluster analysis revealed four distinct molecular clusters, with cluster 4 predominately associated with FGFR2 rearrangements and BAP1 mutations in IHC. Immune-related biomarkers indicative of an inflamed tumor-immune microenvironment were elevated in gallbladder cancers and in cluster 1, which was enriched for TP53, KRAS, and ATM mutations. Multiple common driver genes, including TP53, FGFR2, IDH1, TERT, BRAF, and BAP1, were individually associated with unique BTC immune microenvironments. CONCLUSION BTC subtypes exhibit diverse DNA alterations, RNA inflammatory signatures, and immune biomarkers. The association between specific BTC anatomical subsets, molecular alterations, and immunophenotypes highlights new opportunities for therapeutic development.

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 <90 days prior to registration, and no prior systemic therapy (adjuvant radiation allowed), ECOG 0/1, no uncontrolled significant autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. Results: From 9/17 to 8/21, 44 patients were approached at 6 centers. Of these 9 were ineligible, and 35 were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) had adjuvant radiation prior to enrollment. As of Dec 2021, 31 patients have completed the treatment phase. Of the 35 patients treated on study, 20 patients have recurred (7 local, 5 distant, 3 regional, 5 sites unconfirmed), 6 stopped therapy due to adverse effects, and 8 have died. The mean age of patients was 65.8 years and 21 (60.0%) were female. The primary site of disease was vulvovaginal N=12 (32.4%) patients, sinonasal N= 11 (29.7%), anorectal N= 9 (24.3%) and other site N= 5 (13.5%). Adjuvant radiation had been given in 7 pts. Driver mutations were rare, with only 3 (8.6%) patients having a KIT mutation, and one patient (2.9%) each having a NRAS or BRAF mutation. RFS rates at 1 and 2 years were 50% (95% CI 31-66%) and 37% (95% CI 19-55%), with OS rates at 1 and 2 years of 87% (95% CI 68-95%) and 68% (95% CI 46-83%). Median RFS was 10.3 m (95% CI5.7-25.8). Most common grade 3 adverse events were diarrhea (14%), hypertension (14%), hyponatremia (11%), with no grade 4/5 toxicities. Conclusions: Flip dose ipilimumab and nivolumab after resection is associated with outcomes improved over previously reported outcomes in the absence of therapy. Long term follow up is ongoing as are subgroup analyses and correlative studies. Clinical trial information: NCT03241186.

e21134 Background: Therapies with monoclonal antibodies targeting PD-1 and its ligands are associated with remarkable outcomes and have revolutionized cancer treatment (Honey 2017). However, patients treated with PD-1/PD-L1 blockade may develop “a primary or secondary resistance” to therapy (Sharma, Hu-Lieskovan et al. 2017). Contrary to monoclonal antibodies, chimeric B-cell cancer vaccines have the advantage of producing polyclonal B-cell antibodies that can potentially induce memory B- and T-cell responses, while reducing immune evasion and suppression. The hypothesis is that a polyclonal induced B-cell antibody response will be more effective or as effective with improved safety over current monoclonal antibody therapy. IMU-201 (PD1-Vaxx) is being developed using an active immunization approach to treat cancers that overexpress PD-L1 by inducing the production of anti-PD-1 antibodies with a peptide epitope designed to stimulate polyclonal antibodies against PD-1 (Kaumaya et al. 2020). Methods: The IMPRINTER study is an ongoing open-label dose escalation study of IMU-201 as monotherapy (Phase 1) or in combination with atezolizumab (Phase 1b) for patients with PD-L1 expressing non-small cell lung cancer (NSCLC). All patients enrolled in Phase 1 of the study must have previously received an immune checkpoint inhibitor and experienced disease progression. The primary objective is to evaluate the safety and tolerability of IMU-201 and identify the optimal biological dose (OBD). The secondary objective is to evaluate the efficacy of IMU-201 as monotherapy and in combination with atezolizumab. Humoral and cellular immunogenicity data will be evaluated, including IMU-201 and PD-1 specific antibodies (IgG, IgM), vaccine-specific cytokine levels, and regulatory and effector T and B cells. IMU-201 is administered by intramuscular (IM) injection on Day 1, Day 15, and Day 29. Dose-limiting toxicity (DLT) assessment is completed after 29 days on treatment. Tumor progression is evaluated according to RECIST 1.1 at Day 43 then every 42 days until progression or withdrawal. Results: In Phase 1, four patients were enrolled into each of the three cohorts at 10 μg/dose, 50 μg/dose and 100 μg/dose IMU-201 with no DLTs observed. In the 10 μg/dose cohort, one patient achieved CR and one patient SD; in the 50 μg/dose cohort, four patients achieved SD; and in the 100 μg/dose cohort, one patient achieved PR and two patients achieved SD. Within the 100 μg/dose cohort, one patient experienced an immune related pneumonitis after two IMU-201 administrations and discontinued from study treatment. Conclusions: IMU-201 had no observed DLT and demonstrated preliminary signs of efficacy. The study will therefore move into Phase 1b with IMU-201 being assessed in combination with atezolizumab. Clinical trial information: NCT04432207.

e16200 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Indoleamine-2,3-dioxygenase (IDO) is an intracellular enzyme expressed by HCC which helps to orchestrate immune suppression within the tumor microenvironment (TME) and may contribute to primary and acquired resistance of PD-(L)1 inhibitors. BMS-986205 is a novel oral drug that potently and selectively inhibits IDO1. This Phase I/II study is evaluating the safety and tolerability of the combination of BMS-986205 and nivolumab as first-line therapy in HCC. Methods: Patients (pts) ≥18y with untreated, unresectable/metastatic HCC received BMS-986205 in combination with nivolumab. A fixed dose of Nivolumab 240mg/m2 IV was administered on Day 1 of each 14-day cycle. BMS-986205 was an oral tablet administered daily; a total of two dose levels (50-100mg) were given to determine dose limiting toxicities (DLT) during the dose-escalation Phase I of the study. Safety was assessed using CTCAE v5.0 criteria, and efficacy was assessed by objective response rate (ORR) using RECIST v1.1 criteria. Secondary objectives included preliminary data on disease control rate (DCR), duration of response (DOR), ORR using immune RECIST criteria (iRECIST), progression free survival (PFS) and overall survival (OS). Results: Here we report the results of the dose escalation cohort. Eight pts were treated with median age 69y [60-76]; 75% male; and PS 0 (3 pts) or 1 (5 pts). Pts were White (62.5%), Asian (25%), and African American (12.5%). Six of 8 pts had underlying viral hepatitis (5 hepatitis C, 1 hepatitis B), and all pts were Child Pugh A at enrollment with median baseline alpha-fetoprotein (AFP) level 41.8 [3.8–917.2]; 4 pts received prior local therapies. A total of 91 cycles of therapy were administered; 2 pts received 27 and 43 cycles of treatment each. Six pts were evaluable for DLT; 2 pts were replaced for DLT assessment due to insufficient dose administered, unrelated to toxicity. No DLTs were observed at either the 50 or 100mg dose of BMS-986205. There were 24 treatment-related adverse events (TRAEs), 4 of which were Grade 3 events; there were no Grade 4-5 events. The most common TRAEs of all grades were AST elevation and ALT elevation in 3 pts, and diarrhea, maculopapular rash and increased alkaline phosphatase in 2 pts each. Grade 3 events were diarrhea and AST elevation (1 pt), and hyperglycemia and pancreatitis requiring treatment discontinuation (1 pt). Eight pts were evaluable for efficacy with best response of partial response in 1 pt (12.5%) and stable disease in 3 pts (37.5%), yielding a DCR of 50%. Median PFS was 8.5 weeks; median OS has not been reached. Conclusions: Combination BMS-986205 and nivolumab showed a manageable safety profile with durable benefit as 1st line therapy in a meaningful subset of patients with unresectable/metastatic HCC. Clinical trial information: NCT03695250.

TPS3158 Background: ELU001 is a novel, first-in-class, new molecular entity described as a C’Dot Drug Conjugate (CDC). ELU001 consists of ̃12 folic acid targeting moieties and ̃22 exatecan topoisomerase-1 inhibitor payloads on Cathepsin-B cleavable linkers covalently bound to the surface of each silicon core/polyethylene glycol C’Dot nanoparticle. CDCs are small in size (̃6 nm), have a greater ability to penetrate into and through tumors as compared to ADCs, and are rapidly eliminated by the kidneys. The rapid systemic elimination is expected to lead to less toxicity than is observed with targeting platforms like ADCs that have a longer half-life in circulation. ELU001’s high avidity is believed to promote internalization into FRα overexpressing cancer cells, selectively delivering it’s ̃22 molecules of payload. The first-in-human clinical trial, ELU-FRα-1, is currently recruiting patients that have advanced, recurrent or refractory FRα overexpressing tumors considered to be topoisomerase 1 inhibitor-sensitive based on the literature, and, in the opinion of the Investigator, have no satisfactory therapeutic options available. Methods: This is a Phase 1 / 2 multicenter, open label clinical trial with two parts: Part 1 Dose Escalation and Part 2 Tumor Group Expansion Cohort(s). In Part 1, patients with cancer types with a high likelihood of having FRα overexpressing tumors based on historical data, (specifically, ovarian, endometrial, colorectal, gastric, gastroesophageal junction, triple negative breast, or non-small cell lung cancers, or cholangiocarcinoma), will be enrolled to the study. Patients will receive ELU001 on a weekly dose regimen (QW) (once a week for 3 weeks, 1 week rest) or every other week dose regimen (Q2W, with no rest between cycles). Retrospective analysis of FRα expression will be determined. Part 2 uses a Simon’s Two-Stage design to evaluate 4-6 tumor group expansion cohorts, each consisting of patients with specific tumor types (to be identified based on emerging data) that overexpress FRα (prospectively determined prior to enrollment). The primary objective for Part 1 is to identify the MTD/RP2D and for Part 2 is ORR. Dose Escalation will recruit about 25 patients per dose regimen (QW or Q2W). Dose Expansion will recruit about 15 patients per tumor group expansion cohort. Secondary objectives are anti-tumor activity (DOR, PFS, TFST, PFS2, OS), frequency, severity and tolerability of adverse events, PK, ADA, and FRα expression assessments. The study is actively enrolling in the US – Cohorts 1-2 have been completed without DLT. Enrollment to Cohort 3 began in December 2021. Clinical trial information: NCT05001282 .

3084 Background: Homologous recombination (HR) is an essential, high-fidelity mechanism to repair DNA double strand breaks (DSBs) in cancer cells. CYT-0851 inhibits HR leading to an accumulation of unrepaired DSBs and tumor cell death. We are reporting the completed Phase 1 dose-escalation results and RP2D selection to support ongoing development of CYT-0851. Methods: Patients (pts) with advanced hematologic and solid tumors were treated with continuous 28-day cycles of increasing doses of CYT-0851 following a 3+3 design. The primary objective was determining the maximum tolerated dose. Secondary objectives included safety, pharmacokinetics, and anti-tumor activity. Results: As of a 15 Nov 2021 data cutoff (DCO), 73 pts with advanced cancers (NHL n = 18; Sarcoma n = 16; Pancreas n = 11; Breast n = 8; HNSCC n = 6; Ovarian n = 4; SCLC n = 4; Other n = 4; Myeloma n = 2) were treated in 12 cohorts (total daily doses: 30 mg to 1200 mg). One pt experienced a dose-limiting toxicity (DLT) of reversible metabolic acidosis at 1200 mg. Two of 3 pts at 800 mg experienced reversible DLT-like events in Cycle 2 of Gr3 dry skin and Gr3 myalgia and polyarthritis, respectively. Three of 10 pts treated at 600 mg experienced DLT-like events in Cycle 1: 1 pt experienced an SAE of Gr3 anorexia with Gr3 stomatitis, vomiting, and dehydration and 2 pts had Gr3 fatigue. No DLTs occurred at 400 mg daily which was selected as the RP2D. 42 pts (57.5%) experienced a CYT-0851-related adverse event (AE), including 12 (16.4%) with a Gr3/4 AE. There were no treatment-related deaths. AE leading to CYT-0851 withdrawal were reported in 2 pts (2.7%) treated with 600 and 800 mg. The most common CYT-0851-related AEs were primarily Gr1/2 and included fatigue (20.5%), hyperuricemia (11%), nausea (11%), alopecia (9.6%), constipation (8.2%) and headache (8.2%). CYT-0851 exposure was approximately dose-proportional across the evaluated doses with an effective half-life of ̃3 days. Exposure at 400 mg daily was consistent with efficacy in preclinical models. 46 pts were evaluable for response at the DCO. 12 pts with NHL were evaluable by Lugano and included 1 CR in FL and 1 PR in DLBCL treated for 393+ and 244 days respectively. 34 pts with solid tumors were evaluable by RECIST v1.1 with 1 PR in a pt with myxofibrosarcoma treated for 313 days and 16 pts with stable disease. Fifteen pts were treated for 100+ days and 5 for 180+ days. Conclusions: CYT-0851 has demonstrated promising and broad clinical activity in a Ph 1 population of pts with advanced cancers. The safety profile is favorable as characterized by events that were infrequent, primarily Gr1/2, and reversible. Six expansion cohorts (DLBCL, Follicular Lymphoma, Myeloma, Pancreatic, Ovarian and Sarcoma) are enrolling to characterize activity at the RP2D. Ph 1 evaluation of CYT-0851 in combination with 3 chemotherapy backbones is also ongoing. Clinical trial information: NCT03997968.

TPS2670 Background: Tumor necrosis factor receptor-2 (TNFR2) is expressed on effector CD8+ T cells, CD4+ T cells, T regulatory cells, natural killer cells, and myeloid cells. Targeting TNFR2 is anticipated to yield effective anti-tumor immunity by stimulating T-cell and NK-cell activation and proliferation in the tumor microenvironment. HFB200301 is a first-in-class anti-TNFR2 agonistic monoclonal antibody that triggers both innate and adaptive immune stimulation by binding to a specific epitope on TNFR2. HFB200301 has demonstrated dose-dependent anti-tumor activity in human TNFR2 knock-in mice bearing MC38 and Hepa1-6 syngeneic tumors. Methods: HFB200301 is being evaluated in a first-in-human, open-label, multi-center, dose escalation and expansion study in adult patients with advanced solid tumors. A single-cell immune profiling platform, DIS, was deployed to identify unique tumor-infiltrating T cell signatures that could help optimize patient selection for HFB200301 treatment. It is hypothesized that the presence of an effector T cell subpopulation that express both TNFR2 and CD8A in solid tumors may represent a tumor microenvironment favorable to TNFR2 agonism. The following cancer indications have been identified based on the prevalence of a TNFR2 high/CD8 high signature: Epstein-Barr Virus positive (EBV+) gastric cancer, clear cell renal cell carcinoma (ccRCC), cutaneous melanoma, testicular germ cell tumor (TGCT), soft tissue sarcoma (STS), and PD-L1+ cancers: cervical cancer, pleural mesothelioma, lung adenocarcinoma, and head and neck squamous cell carcinoma (HNSCC). The escalation portion of the study explores increasing doses in cohorts of up to six patients, utilizing mTPI-2 design to determine recommended dose(s) for expansion (RDE(s)). Based on pharmacokinetic modeling to maximize HFB200301 activity, 60-minute intravenous infusions of HFB200301 are administered every 4 weeks. Once RDE(s) is determined, expansion into three indication-specific cohorts is planned to determine the recommended phase 2 dose (RP2D). Key eligibility criteria include histologically documented advanced or metastatic solid tumors in the above listed indications. Patient enrollment opened in February 2022 in the USA, with plans for additional clinical sites in Spain and China. The primary objective is to identify the RDE, characterize safety and tolerability of HFB200301, and determine RP2D. Secondary objectives include pharmacokinetic parameters, preliminary evidence of anti-tumor efficacy (e.g., ORR, DCR, DOR) and pharmacodynamic evaluation (e.g., T cell subsets) in the blood and in the tumor. Furthermore, a potential predictive biomarker signature derived based on the DIS single-cell immune profiling approach will be investigated retrospectively. Clinical trial information: NCT05238883.

TPS9595 Background: There is a need for novel immunotherapies to address the patient population that never or no longer responds to immune checkpoint inhibitors (CPI). VV1 is an oncolytic vesicular stomatitis virus engineered to express human interferon beta (IFNβ) to enhance cellular anti-tumor immune responses and tumor selectivity. Phase 1 studies demonstrated VV1 anti-tumor activity in several malignancies with or without a CPI. We are exploring ways to optimize VV1 efficacy in combination with cemiplimab, an anti-PD1 antibody approved for lung, basal and squamous cell skin cancers. Recent clinical data support a 5-fold higher dose of VV1 than was previously explored, and pre-clinical data show synergy between the oncolytic and an anti-CTLA4 antibody, in addition to cemiplimab, supporting exploration of a triplet. What was originally a five-arm study of intravenous (IV) VV1 in combination with IV cemiplimab has been amended to focus on 2 means of optimizing efficacy: use of a higher dose of VV1 and triplet combination in proof-of-concept populations. Methods: We are now enrolling pts with advanced melanoma (after progression on anti-PD1) and plan to include 1 st -line NSCLC pts with PD-L1 expression ≥50%. The study is first exploring the preliminary anti-tumor activity, safety, and immunogenic activity of the combination of IV VV1 at a dose of 1.0 x 10 11 TCID 50 once on D1 followed by IV cemiplimab Q3W starting on D8, or the same regimen with an additional intratumoral injection of VV1 1.0 x 10 9 TCID 50 once on D1 for pts with accessible lesions. Pts receive IV cemiplimab Q3W until confirmed disease progression or intolerable toxicity. Once at least 6 pts have been treated with acceptable safety across the 2 melanoma doublet cohorts using this higher dose of VV1, a 3 rd melanoma cohort will open to add a single dose of ipilimumab 50 mg on D1 (all IV triplet). Once 6 melanoma pts have received the triplet safely, the 1 st -line NSCLC cohort will open. All cohort decisions are guided by a Data Review Committee. Cohorts will be expanded based on a Simon 2-stage design using a type I error rate of 0.05 and power of 85%. Null ORR is 10% with a target of 35% for 2 nd line melanoma and null ORR is 40% in 1 st line NSCLC with a target of 70%. Each melanoma cohort will require a response in ≥2 of 10 pts in the 1 st stage to add 11 more in the 2 nd stage, while NSCLC will first need 5/9 evaluable pts to respond, then an additional 13 to complete the design. Response is assessed at week 7 then Q9W per RECIST v1.1. The study includes serial biopsies in ≥3/10 pts in Stage 1 of each of the IV melanoma cohorts (doublet and triplet therapy), all pts in Stage 2 of these IV melanoma cohorts, and all pts in both Stage 1 and Stage 2 of the IV/IT melanoma cohort, to permit a thorough investigation of the impact of the 3 immunotherapies under investigation. The study is currently ongoing in the USA. Clinical trial information: NCT04291105.