bluuebunny/crossref_metadata_2025_split huggingface dataset:
The study of immune-related adverse events in a community-based centre.
Authors: Cautha Sandhya , Jain Kevin R. , Budhathoki Pravash , Okobi Tobechukwu Joseph , Bhatt Tanushree , Moirangthem Valentina , Gupta Sorab , Luong Thanh-Ha T. , Hanif Ahmad 
Published: June 2023

2642 Background: The effectiveness of immunotherapy is often hindered by the development of immune-related adverse events (IrAE). Racial minorities were under-represented in the key clinical trials that led to the approval of different immune checkpoint inhibitors (ICI). In this study, we explore the side effect profile of immune checkpoint inhibitors in our patient population that comprises almost entirely of minorities, mostly African Americans (AA) and Hispanics. We hypothesize that due to race-based differences in immune milieu of the body and disease susceptibility, the timing and severity of immunotherapy-related IrAE would be different in AA and Hispanics compared to Caucasians. This can translate into a difference in clinical outcomes as well. There have been some suggestions of a positive association of the development of IrAE with cancer survival, although the data is limited and heterogeneous. The purpose of our study is to study the frequency and severity of IrAEs in racial minority groups, compare them with previous clinical trials population, and add valuable real-world data in this underrepresented group of patients. Methods: A retrospective chart review was performed on adult patients with solid malignancies treated with any ICI between January 1, 2015 and April 30, 2022. Patients were classified according to age (greater/equal to 65y or younger), sex, race (self-identified), primary cancer, and type of immunotherapy received. Outcome data using type and severity of IrAE, time to development of IrAE, and any association with clinical outcomes was collected and analyzed using descriptive statistics as well as univariate analysis. Results: A total of 78 patients were included in the final analysis. The mean age was 68 years; 51% were males; 42.3% were Hispanics, 37% were AA, 19.7% were others, and 1% were Whites. Most common malignancy was lung cancer (65.5%). Most common ICI agent used was Pembrolizumab (n = 52) and 2 patients were treated with combination therapy using Ipilimumab and Nivolumab. 41 (52.5%) patients had IrAE of any grade while 9 (11.5%) patients experienced grade 3 side effects. None of the patients experienced grade 4 side effects. Most common IrAE of any grade was hypothyroidism (n = 14) while most common grade 3 side effect was colitis (n = 6). 31 patients were less than 65y of age. There was no significant difference in IrAE in patients less than 65 years of age vs ≥ 65 years (51.6% vs 53.1%) or grade 3 IrAE (9.6% vs 12.7%). Conclusions: In our study population consisting mostly of AA and Hispanics, the rate of IrAE of any grade as well as grade 3 or 4 IrAE with ICI therapy was comparable to what was seen in clinical trials involving these drugs. This data and its potential effects on survival outcomes need to be analyzed in prospective studies involving a larger number of patients.
Immune related adverse events (irAEs) in patients with solid tumors and advanced chronic kidney disease (CKD) receiving checkpoint inhibitors (CPIs).
Authors: Kaakour Dalia , Vosoughi Elham , Warnecke Brian , Yazdanpanah Omid , Rezazadeh Arash , Valerin Jennifer Brooke , Mar Nataliya 
Published: June 2023

2650 Background: Randomized controlled trials evaluating CPIs in the management of solid tumors have typically excluded patients with advanced CKD and end-stage renal disease (ESRD). Limited available data evaluating the safety of CPI use in this patient population demonstrated a similar incidence of irAEs in patients with advanced CKD compared to those with normal or mildly impaired renal function, with majority of irAEs being grade 1 or 2. CPIs are not modified by dialysis due to their molecular size and, as such, do not require renal dosing. Methods: We performed a retrospective analysis of patients over 18 years of age with solid tumors and advanced CKD, who received CPIs at the University of California Irvine from 1/2015 to 6/2021. Advanced CKD was defined as glomerular filtration rate (GFR) less than 60 ml/min. Patients must have received at least one dose of a PD-1/PD-L1 or CTLA-4 inhibitor as a single-agent or in combination with another therapy. Patients were stratified by severity of CKD, including CKD3 (GFR of 30-59 ml/min), CKD4 (GFR of 15-29 ml/min), and CKD 5/ESRD (GFR less than 15 ml/min). Results: A total of 32 patients were included, 24 (75.00%) with CKD3, 6 (18.25%) with CKD4, and 2 (6.25%) with CKD5/ESRD. 10 (31.25%) patients were female and 22 (68.75%) were male. Median age was 73.5 years [range: 26 to 98]. 22 (68.75%) received CPI monotherapy and 10 (31.25%) received a combination of CPI with another agent. After initiation of CPI therapy, 16 (50.00%) patients experienced an irAE, with a total of 23 unique irAEs due to some patients experiencing multiple irAEs. In patients with irAEs, 13 (81.25%) received CPI monotherapy and 3 (18.75%) received CPI combined with another agent. In patients with CKD3, CKD4, and CKD5/ESRD, 14 (87.50%), 2 (12.60%), and 0 (0.00%) experienced irAEs, respectively. Types of irAEs observed are listed, with the most common being colitis in 6 (26.1%) patients, endocrinopathies in 4 (17.39%) patients, and dermatologic in 4 (17.39%) patients. 18 (78.26%) of unique irAEs were grade 1 or 2, while 5 (21.74%) were grade 3 or higher. 10 (43.48%) of irAEs were managed with steroids as per physician discretion, 8 (80.00%) with CKD3 and 2 (20.00%) with CKD4. Conclusions: The safety of CPIs in patients with solid tumors and advanced CKD has not been rigorously evaluated. Recognizing the small sample size and retrospective nature of this dataset, the incidence and type of irAEs in patients with advanced CKD appears similar to that of patients with normal renal function or mild renal impairment. More prospective data in this population is needed, particularly in patients with CKD5/ESRD. Types of irAEs in patients with advanced CKD. [Table: see text]
Frequency of delayed immune-related adverse events (irAEs) in hospitalized patients treated with immune checkpoint inhibitors (ICIs).
Authors: Durbin Sienna , Zubiri Leyre , Perlman Katherine , Molina Gabriel , Jacoby Ted , Shah Nishi , Reynolds Kerry Lynn 
Published: June 2023

2652 Background: Across cancer types and indications, the use of ICIs is increasing. Guidelines indicate that most irAEs occur in the months immediately following receipt of ICI. Little is known about the frequency of delayed irAEs following ICI administration. Methods: Patients who received ICIs and were hospitalized following ICI initiation between January 2011 and October 2022 were identified using pharmacy and hospital admission databases. Patient demographics, and oncologic and irAE history were extracted from the medical record. All admissions were reviewed by two physicians to evaluate for irAEs, which were defined as suspected or confirmed using published disease-specific criteria. We examined the number of irAEs hospitalizations at < 6 months, 6-12 months, 1-2 years, 2-5 years, and >5 years from the first dose of the most recent line of ICI to date of admission. Results: Among the 930 patients hospitalized with irAEs, average age was 66.0 years (range 18.3 - 96.2) and 61.2% were male. Most common tumor types were melanoma (42.0%), lung (24.1%), and gastrointestinal (12.7%). Median time from start of last line of ICI to hospitalization was 98 days (IQR 37-244.3). One hundred sixty-six patients (19.4%) had been treated with >1 prior line of ICI and 102 (11.0%) were diagnosed with multiple irAEs during the same admission. Of all patients admitted, 147 (15.7%) presented 6 months – 1 year after start of ICI line, 79 (8.4%) presented after 1-2 years, 35 (3.7%) presented after 2-5 years, and 2 (0.2%) presented after >5 years. Rates of irAEs by time from start of ICI line are demonstrated. Conclusions: Although irAEs occur in a time-dependent fashion, delayed, serious irAEs in hospitalized patients are common (28% at 6+ months), with a subset presenting two years or more after start of ICI. Providers must remain vigilant for potential irAEs regardless of elapsed time from ICI, especially as patients live longer and ICIs become widely used in different settings. Future work is needed to define potential triggers of and patients at risk for delayed irAEs. [Table: see text]
Tumor fraction to improve patient selection for oncology early phase clinical trials: Analysis of two precision medicine studies.
Authors: Cousin Sophie , Belcaid Laila , Trin Kilian , Bayle Arnaud , Alame Melissa , Rouleau Etienne , Soubeyran Isabelle , Lacroix Ludovic , Blouin Laura , Vasseur Damien , Mathoulin-Pélissier Simone , Bellera Carine A. , Italiano Antoine 
Published: June 2023

3005 Background: Typical entry criteria in early phase studies include expected life expectancy greater than 3 months. However, this evaluation is quite subjective and more objective and reproducible tools are needed to improve patients (pts) selection. The quantification of ctDNA shed by measuring tumor fraction (TF) has been associated with prognosis in solid tumors pts. However, prognostic implications of TF quantification have been evaluated primarily in retrospective studies and in a limited number of cancer types. We report here the first prospective evaluation of the prognostic impact of TF in 2 independent precision medicine studies enrolling pts referred to consider their eligibility to early phase trials. Methods: All consecutive adult pts with an advanced solid tumor included between December 2020 and December 2021 in 2 precision medicine studies: BIP (NCT02534649, sponsor: Institut Bergonié, Bordeaux, France) and STING (NCT04932525, sponsor: Institut Gustave Roussy, Villejuif, France). All pts underwent comprehensive genomic profiling with the 324-gene FoundationOne. TF was analyzed as a binary variable, indicating whether a specimen had TF ≥10% or TF <10%. Multivariate analysis included previously validated prognostic scores: the Royal Marsden Hospital (albumin, LDH, number of metastatic sites) and the GRIm (LDH, neutrophil/lymphocyte ratio (NLR), albumin) scores as well as their individual components. Results: 1912 pts: N=965 in BIP and N=947 in STING were included. Their characteristics are described. High TF was associated with significantly worse overall survival (OS) in both BIP and STING studies. On multivariate analysis, TF was associated with worse OS (HR:2.49 [CI95%: 2.11 - 2.95, p<0.001] and HR:2.52 [CI95%: 2.06 - 3.08, p<0.001] in BIP and STING studies respectively) independently of the RMH and GRIM scores as well as their individual components. Conclusions: This is the first prospective analysis confirming that TF is a strong prognostic factor in pts with advanced solid tumors and represent an helpful tool in the process of patient selection for phase I trial entry. [Table: see text]
Debio 0123-101: A phase 1 trial of Debio 0123 in combination with carboplatin in advanced solid tumors—Safety, pharmacokinetic, and preliminary antitumor activity data.
Authors: Gelderblom Hans , Jalving Mathilde , Desar Ingrid , Saavedra Omar , Gietema Jourik A. , van Ravensteijn Stefan , Ajmone Marsan Nina , Bellon Anne , Micallef Sandrine , Luong Noemie , Piggott Luke , Frederiksen Franzen Rikke , Rodrigo Imedio Esteban 
Published: June 2023

3012 Background: Cell cycle faults are typical in cancer, with tumor cells depending on G2 checkpoints to avoid excess DNA damage. WEE1, a DNA damage-activated kinase, governs G2 by phosphorylating cyclin-dependent kinase 1 (CDK1) to arrest the cell cycle and permit DNA repair. Via CDK1 inhibition, WEE1 also blocks replication initiation, limiting oncogene-induced replication stress. WEE1 inhibition, with accumulating DNA damage, can induce mitotic catastrophe and apoptosis. Debio 0123, an orally available, ATP-competitive WEE1 inhibitor, is being studied as monotherapy and in combination with carboplatin (CP) in patients (pts) with solid tumors. Here, we report safety, pharmacokinetic (PK), pharmacodynamic, and antitumor activity data for the combination. Methods: Debio 0123-101 (NCT03968653) is a two-arm dose-escalation study in pts with advanced solid tumors that recurred or progressed after receiving platinum-containing therapy, where no standard therapy of proven benefit is available. In Arm A, Debio 0123 was given as monotherapy in cycle (C) 1 (as a single dose on day [D] -3 and once daily over D1–3) and in combination with CP from C2 until end of treatment (EOT). In Arm B, Debio 0123 was given in combination with CP on D1–3 and D8–10, from C1 to EOT. CP was given on D1 of each 21-day cycle in both arms. Skin biopsies were taken at baseline and C1D3 to assess target engagement (TE). Results: Arm A data (cut-off 31.12.2022) is shown. Overall, 38 pts were treated (78.9% female, mean age 58.5 years), with two pts ongoing. Using a continual reassessment method-guided dose escalation, tested Debio 0123 doses ranged from 30–520 mg. The maximum tolerated dose was declared at 520 mg. At this dose level, 2/6 pts experienced a dose-limiting toxicity. The treatment was deemed well tolerated, with a manageable safety profile in line with that expected for CP monotherapy. Most Debio 0123-related toxicities were grade 1/2. Preliminary PK data indicate that Debio 0123 plasma levels rise proportionally with dose. TE was seen from the 150 mg dose, becoming more pronounced with increasing dose levels. Confirmed partial responses (PR) occurred in 5/30 evaluable pts; 4/12 pts with platinum-resistant ovarian cancer achieved a PR (one ongoing). Conclusions: Debio 0123, combined with CP, has a manageable safety profile and is well tolerated up to 520 mg; this combination led to observable antitumor activity in pts with platinum-resistant cancer. Further study of Debio 0123 as a therapeutic agent is warranted. Clinical trial information: NCT03968653 . [Table: see text]
Phase 1 trial evaluating TTI-101, a first-in-class, orally bioavailable, small molecule, inhibitor of STAT3, in patients with advanced solid tumors.
Authors: Tsimberidou Apostolia Maria , Vining David J. , Arora Sukeshi Patel , de Achaval Sofia , Larson Jeffrey , Cartwright Carrie , Avritscher Rony , Alibhai Imran , Kaseb Ahmed Omar 
Published: June 2023

3018 Background: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor at the critical intersection of signaling pathways controlling gene networks integral to the survival and immune sequestration of cancer cells. Given the integral role of STAT3 in tumorigenesis and immune suppression, STAT3 signaling inhibition may have dual antitumor activity. TTI-101 is a first-in-class, orally bioavailable, selective small molecule that binds to STAT3 and prevents STAT3-mediated transcriptional activation. A first-in-human, Phase 1, dose escalation and expansion study of TTI-101 monotherapy was conducted in patients with advanced/refractory solid tumors (NCT03195699). Methods: Patients with advanced metastatic cancer who had failed standard therapy were treated with TTI-101 twice daily in 28-day cycles at dose levels (DL) 1-4: 3.2 (DL1), 6.4 (DL2), 12.8 (DL3), and 25.6 (DL4) mg/kg/d (“3+3” design). Three different formulations of TTI-101 were used stepwise, beginning with formulation 1 (F1). A second-generation formulation (F2) was introduced at DL3 during dose escalation and patients were stratified into two cohorts: hepatocellular carcinoma (HCC) and other solid tumors. A third-generation formulation (F3) was evaluated once the recommended phase 2 dose (RP2D) was determined. Treatment continued until disease progression, unacceptable toxicity, or study withdrawal. Results: Key patient characteristics included a median age of 63 years (range, 33-78), 52% male, and a median number of 3 (range, 1-9) prior systemic therapies. No dose limiting toxicities (DLTs), or fatal treatment-related adverse events (TRAEs) were observed. Diarrhea was the only TRAE observed in ≥30% of the safety population (n=64) with events being mostly Grade 1/2. F3 was better tolerated than F1 and F2 with no events ≥Grade 3. One patient experienced transient Grade 4 hyperglycemia which resolved with insulin and metformin. Five patients had serious TRAEs (all Grade 3), which resolved. TTI-101 showed linear pharmacokinetics from DL1-3 plateauing at DL3. The RP2D was determined to be 12.8mg/kg/d (DL3) for both the HCC and other solid tumor cohorts. Of the 39 patients evaluable for response, 5 (13%) patients had confirmed partial responses (cPR) and 16 (41%) stable disease (SD). Of the 15 patients with HCC, 3 (20%) had a cPR with a median duration of 10.5 months. The other two cPRs were in ovarian cancer (n=1) and gastric cancer (n=1). Conclusions: TTI-101 was well-tolerated and no DLTs were noted. cPRs were observed across tumor types. The antitumor activity of TTI-101 monotherapy in the relapsed/refractory setting is promising, particularly in HCC. Two Phase 2 oncology studies of TTI-101 in STAT3-driven cancers (HCC and metastatic breast cancer) are underway. Clinical trial information: NCT03195699 .
SGN-B6A, an integrin beta-6 (ITGB6)-targeted antibody-drug conjugate (ADC), in patients with advanced solid tumors: Updated results from a phase 1 study (SGNB6A-001).
Authors: Hollebecque Antoine , Lopez Juanita Suzanne , Piha-Paul Sarina A. , Dowlati Afshin , Patnaik Amita , Galvao Vladimir , Bockorny Bruno , Sehgal Kartik , Kingsley Ed , Sanborn Rachel E. , Perez Cesar Augusto , Peters Solange , Yan Mingjin , Nazarenko Natalya N. , Calvo Emiliano 
Published: June 2023

3024 Background: The receptor ITGB6 plays a role in tumor pathogenesis and invasiveness, and its overexpression is correlated with poor outcomes. Non-small cell lung cancer (NSCLC), head and neck (HNSCC), and esophageal cancer (EC) are among tumors with high ITGB6 expression (Lyon 2021). SGN-B6A is an ITGB6-directed vedotin ADC with a monomethyl auristatin E (MMAE) payload. SGN-B6A elicits antitumor activity via MMAE-mediated cytotoxicity, bystander effect, and immunogenic cell death. Here, we present updated results of an ongoing phase 1 study with a focus on NSCLC, HNSCC, and EC (Hollebecque SITC 2022). Methods: SGNB6A-001 (NCT04389632) is an open-label, multicenter, dose-escalation/expansion study evaluating the safety, pharmacokinetics, and antitumor activity of SGN-B6A (per RECIST v1.1) in patients (pts) with advanced solid tumors. Dose escalation (Part A) explored continuous weekly and intermittent dosing regimens. Dose was calculated using total body weight (TBW) or adjusted ideal body weight. Dose expansion (Part B) is enrolling pts with NSCLC, HNSCC, and EC. Results: As of 14 December 2022, 148 pts received SGN-B6A, 88 pts in Part A and 60 pts in Part B; enrollment for Part A is complete. In all cohorts (N=148), treatment-emergent adverse events (TEAEs) were observed in 88.5% of pts: 50.7% were Grade ≥ 3 (21.6% related), and 37.2% were serious (8.1% related); 6.1% of pts discontinued treatment due to TEAEs. 3 pts (2.0%) died due to TEAEs; none of the deaths were considered treatment-related. The most common TEAE was fatigue (35.1%); the most common Grade ≥ 3 TEAE was neutropenia (8.1%); the most common TEAEs leading to treatment discontinuation were peripheral sensory neuropathy and pneumonia (1.4% each). Prior lines of therapy and efficacy data for Part A (NSCLC, EC, and HNSCC) and Part B (HNSCC) subsets are summarized. Conclusions: SGN-B6A demonstrated a manageable safety profile, and showed encouraging preliminary antitumor activity and response durability in dose escalation in a heavily pretreated population. Part B dose expansion cohorts in NSCLC, esophageal squamous cell carcinoma (ESCC), and HNSCC are ongoing. Clinical trial information: NCT04389632 . [Table: see text]
Plasma lipidomic profiling of chemotherapy-induced peripheral neuropathy.
Authors: Yeung Nicole , Lin Hui-Ming , Timmins Hannah , Li Tiffany , Goldstein David , Friedlander Michael , Harrison Michelle L. , Mahon Kate Lynette , Meikle Peter , Park Susanna , Horvath Lisa 
Published: June 2023

3031 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of cytotoxic cancer treatment. This may result in dose reduction (DR) or chemotherapy discontinuation (CD) and ultimately decrease the efficacy of therapy. There is a lack of studies examining the role of lipids in relation to CIPN, despite the association of obesity with worse CIPN, and hyperlipidaemia with diabetic neuropathy. The aim of this study is to determine if circulating lipids are associated with CIPN severity. Methods: Pre-chemotherapy plasma samples from 137 patients with CIPN from docetaxel or paclitaxel-based treatment underwent lipidomic analysis (788 lipids). CIPN severity was measured using the neurological grading scale Total Neuropathy Score-clinical version (TNSc score; John Hopkins University) and patient-reported outcome measure EORTC QLQ-CIPN20. The association of baseline lipid levels with severe CIPN, as defined by high TNSc and CIPN20 scores, was performed using linear modelling (LIMMA). Baseline lipids associated with shorter time to dose reduction (DR) or chemotherapy discontinuation (CD) due to CIPN was determined by Cox regression, with adjustment for body mass index (BMI), age and diabetes. Lipid profiles were identified using latent class analysis (LCA) of significant lipids from the Cox regression. Results: Higher TNSc or CIPN20 scores were associated with 107 and 43 lipid species respectively (LIMMA p<0.05), of which only 3 species were in common. Triacylglycerols (TG) represented a significant proportion of lipids with elevated levels associated with higher TNSc (32.5%) or CIPN20 (9.1%) scores (Fisher’s exact test p<0.001). 70 lipid species were associated with shorter time to DR/CD (Cox regression p<0.05), which included 15 TG with higher levels associated with shorter time to DR/CD. Unsupervised LCA identified a specific lipid profile associated with worse CIPN [Hazard ratio 2.61 (95% CI 1.40 – 4.84, p=0.002)]. This lipid profile also had higher levels of TG (t-test p<0.05). The high risk CIPN lipid profile was independently associated with shorter time to DR/CD when modelled with clinical factors (diabetes, age, BMI or prior numbness/tingling; Cox regression p<0.006); however, these clinical factors were not associated with time to DR/CD in the multivariable models (p>0.08). Conclusions: Higher levels of baseline plasma TG are associated with increased CIPN severity and shorter time to DR/CD in taxane-treated patients. These findings are consistent with other reports regarding the association of hyperlipidaemia with neuropathy. Further research is required to determine if TG-lowering medication can reduce the risk of CIPN development.