bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I open-label study of a novel IL-2Rβ/γ cytokine agonist, LTC004, in patients with advanced or metastatic solid tumors.
Authors: Gong Jifang , Shen Lin , Zang Aimin , Zhou Huan , Tang Jie , Liu Dan , Jia Youchao , Wang Beibei 
Published: June 2024

2652 Background: LTC004, a novel IL-2Rβ/γ cytokine agonist, designed to minimize toxicity with improved potency. It has selective affinity for the receptor IL-2Rβγ subunits, preferentially stimulates CD8+ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells. LTC004 has shown significant in vitro and in vivo anti-tumor activity in multiple cell lines and murine models respectively. Methods: This is a first-in-human, multicenter, open-label, dose-escalation and dose-expansion phase I study of LTC004 in advanced solid tumors. Dose escalation part assessed safety and tolerability of intravenous LTC004 with doses ranging from 3.0 to 360 µg/kg. The dose escalation schedule utilized an accelerated titration and Bayesian Optimal Interval (BOIN) design. Eligible pts with advanced solid tumor were required to have received prior standard therapy. LTC004 is administrated intravenously once every 3 weeks. Results: The study completed dose-escalation part (3.0 to 360 µg/kg) as of cutoff date (Jan 10, 2024). 17 pts of multiple tumor types (including non-small cell lung, cervical, colorectal, sarcoma, melanoma, parotid adenocarcinoma, thymic adenocarcinoma, gastric and ovarian cancers) were enrolled and received ≥1 dose of LTC004. At baseline, 12 pts (70.6%) had received ≥2 prior lines therapy, 11 pts (64.7%) had received prior targeted therapy, 10 pts (58.8%) had received prior immune checkpoint inhibitor (ICI) therapy. LTC004 generally well tolerated and no dose-limiting toxicities (DLTs) up to and including 360 µg/kg was observed. The most common TEAEs overall in ≥30% of pts were fever, white blood cell decreased, anemia, AST/ALT increased, neutrophil count decreased, GGT increased, nausea and hypotension. Most of the reported AEs were G1 and G2, all drug related events reversible and responsive to supportive care therapy. Fever can be resolved with standard anti-pyretic treatment or steroids, transient hypotension can be preventable with prophylactic fluid infusion. Of 17 pts enrolled evaluable for efficacy per RECIST v1.1, the ORR were 5.9% (1/17), DCR were 58.8% (10/17). A confirmed PR was achieved in a pMMR/MSS CRC patient with prior therapies including fluoropyrimidines, irinotecan, oxaliplatin, targeted therapy and TKI. The starting dose was 45µg/kg, titration to 90µg/kg after 4 consecutive doses at 45µg/kg Q3W. As of cutoff date, the patient sustained PR for 4.8 months with follow-up ongoing. Conclusions: LTC004 demonstrated encouraging anti-tumor efficacy including cold tumor, and well tolerated in patients with advanced or metastatic solid tumors. The further dose expansion in selected tumor types is ongoing, and evaluations in combination with other agents are being planned. Clinical trial information: NCT05666635 .
A multi-centre, single arm, phase 2 trial of pembrolizumab in treatment-naïve patients with carcinoma of unknown primary site.
Authors: Monzon Jose Gerard , Karachiwala Hatim , Walker John WT , Goel Rakesh , Wheatley-Price Paul , Asmis Timothy R. , Navani Vishal , Tang Patricia A. , Vickers Michael M. 
Published: June 2024

2659 Background: Cancer of unknown primary (CUP) represents a heterogeneous group of cancers that present with metastatic epithelial disease with no identifiable primary lesion at the time of diagnosis. Patients with poor prognostic features have limited effective systemic therapy options. Researchers hypothesize that these primary lesions are occult, in part, due to anti-cancer immune surveillance. We hypothesize, pembrolizumab will have activity in this setting. Methods: This single arm phase 2 study evaluated the use of pembrolizumab in treatment naïve patients with poor prognosis CUP. Patients ≥18 years of age with ECOG PS 0-1 and histologically proven, measurable metastatic carcinoma with no primary site identified were eligible. Pembrolizumab was administered at 200 mg intravenously every 3-weeks for up to 24 months. The primary endpoint was safety and objective response rate (ORR) per RECIST 1.1. Secondary objectives included progression free survival (PFS) and overall survival (OS). The study used a Simon’s two stage design based on a one-sided test with a type 1 error rate of 0.1, null hypothesis for ORR ≤ 20% yielding a power of 0.8 with an alternate hypothesis of ≥40%. The null hypothesis will be rejected if 8 or more responses are observed in 25 patients. Mismatch repair (MMR) and microsatellite instability (MSI) testing was not mandatory for patients. Results: There were 27 evaluable and 6 unevaluable (no response assessment, included in adverse event analysis) patients. The median age was 64 (range 21-80) and the majority were male (57.6%) and ECOG 1 (84.8%). Four patients experienced grade 3 treatment related adverse events (pain, anorexia, fatigue, confusion, and anemia). There were no treatment related deaths or new signals of toxicity. Of the evaluable patients, the ORR was 18.5% (4 partial responses and 1 complete response), disease control rate was 51.9% (9 stable disease) and thus the null hypothesis could not be rejected. For evaluable patients, the median PFS and OS were 2.56 (95% CI 2.10 – 7.46) and 9.79 (95% CI 3.84 – 16.03) months respectively. The one patient who developed a CR had MMR deficiency and has completed 2 years of therapy. Of the 4 patients with a partial response, one had an MMR proficient tumour, while the remaining 3 had unknown MMR status. Conclusions: Although not meeting the primary endpoint, pembrolizumab has some activity in CUP patients. Patients with CUP should be screened for MMR or MSI. Future studies should evaluate combination therapies with the addition of pembrolizumab. Clinical trial information: NCT03391973 .
A phase I study of irinotecan combined with BAY1895344 (ATR inhibitor) in advanced solid tumors: Results of ETCTN 10402 dose escalation.
Authors: Heumann Thatcher Ross , Stockton Shannon , Cecchini Michael , Aljumaily Raid , Shyr Cathy , Whisenant Jennifer , Starr Jason S. , Dayyani Farshid , Baranda Joaquina Celebre , Trikalinos Nikolaos , Ivy S. Percy , LoRusso Patricia , Das Satya , Gore Steven , Beumer Jan Hendrik , Berlin Jordan 
Published: June 2024

3077 Background: ATR protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA defects in various cancers. The topoisomerase-I (Top1) inhibitor irinotecan induces DNA damage. The ATR inhibitor BAY1895344 (elimusertib) has demonstrated cytotoxic potential in SCLC and GI cancer xenografts when combined with Top1 inhibitors . Methods: This phase Ia trial assessed elimusertib in combination with irinotecan in adult patients with refractory advanced solid tumors for whom irinotecan can be considered standard care. Patients with previous irinotecan exposure were excluded. Two dosing schedules were used: 1) Biweekly - irinotecan IV (starting at 150 mg/m2) D1 + elimusertib (starting dose 20 mg PO BID) D1,D2 (cycle=14 days); 2) Weekly - irinotecan (starting at 50 mg/m2) IV on D1,8,15 with elimusertib (starting at 20 mg PO daily) on D2,D3,D9,D10 and D16,D17 (cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity. Results: A total of 21 patients were enrolled in dose escalation (N=9 [Biweekly] and N=12 [Weekly], median age 58 and 2 lines of prior therapy. For the Biweekly cohort: 3/3 patients enrolled at dose level (DL) 1 experienced hematologic dose-limiting toxicity (DLT); 6 patients received DL-1 without any DLTs. The weekly regimen escalation comprised of 12 patients: 6 enrolled in DL1 with 2/6 having hematologic DLT and 5/6 unable to complete ≥75% of cycle 1 dosing; 6 enrolled in DL-1 with no DLTs observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized (Table 1). The majority of evaluable patients in both schedules had initial disease control (56% [biweekly] and 67% [weekly]). One confirmed partial response was seen in the biweekly RP2D. Median progression-free survival was 2.1 mo [biweekly] and 2.5 mo [weekly]. PK results will be presented at time of meeting. Conclusions: Both RP2D and MTD of elimusertib in combination with irinotecan were reached for both dosing schedules: irinotecan 150 mg/m2 IV D1 + elimusertib 10 mg BID PO D1,D2 (biweekly) and irinotecan 25 mg/m2 IV on D1 + elimusertib (20 mg PO daily) on D2,D3 (weekly). Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansion but the concept of ATR + topo I combination remains scientifically relevant. Clinical trial information: NCT04514497 . [Table: see text]
Diversity in B7-H3/CD276 expression across cancer types: Exploring a dynamic novel immune checkpoint.
Authors: Larkin Brigid , Nishizaki Daisuke , Miyashita Hirotaka , Lee Suzanna , Nikanjam Mina , Nesline Mary K , Pabla Sarabjot , Conroy Jeffrey M , DePietro Paul , Sicklick Jason K. , Kurzrock Razelle , Kato Shumei 
Published: June 2024

3133 Background: The resistance encountered in immune checkpoint blockade has persistently impaired the achievement of robust, durable antitumor immune responses in most cancer patients, prompting the search for additional immune targets. B7 homolog 3 (B7-H3)/CD276 is an emerging immune biomarker whose contrasting immune functions challenge conventional immune marker classifications, making it a compelling target. The present study aimed to characterize the expression of B7-H3/CD276 in a pan-cancer setting, analyze its co-expression patterns with potentially co-targetable immune checkpoints, and discuss implications for ongoing clinical trials. Methods: We conducted a focused analysis of B7-H3/CD276 expression in 514 cancer patients with diverse tumor histologies evaluated under the PREDICT protocol at the University of California San Diego. RNA sequencing of tissue specimens was performed, and results were used to characterize the RNA expression levels of B7-H3/CD276 and its correlation with key cancer immunity markers including PD-1, PD-L1, PD-L2, CTLA4, LAG3, BTLA, TIM3, VISTA, ADORA2A and IDO1. Results: Elevated expression levels of B7-H3/CD276 were observed in 41.6% [214/514] of the 514 tumor samples analyzed. When stratified by cancer type, the highest rates of elevated expression were found in sarcomas (58.30%, 14/24), followed by pancreatic (58.20%, 32/55) and liver and bile duct cancers (52.60%, 10/19). The independent association with pancreatic cancers was statistically significant on multivariate analysis (odds ratio 2.20, 95% confidence interval 1.09 – 4.45, p = 0.027). Ninety-three unique patterns of immune co-expression were observed among the 214 patients with high B7-H3/CD276 expression levels. Among them, the most commonly observed pattern was high expression of B7-H3/CD276 alone (26.2%, 56/214) followed by co-expression with high VISTA (7.0%, [15/214]) and high ADORA2A (5.6%, [12/214]). Of note, there was significant heterogeneity observed in the patterns of co-expression in cancer immunity markers, with 72.04% (67/93) in the cohort being unique to one patient. Conclusions: We have observed immunomic diversity in our analysis of B7-H3/CD276 expression levels across varied tumor types as well as in its co-expression patterns with other immune markers. Our findings suggest that leveraging immune profiling to build customized therapeutic regimens may be pertinent to optimizing response rates and minimizing toxicity to B7-H3/CD276 targeting therapies.
Comprehensive molecular profiling of newly diagnosed advanced, high-grade ovarian cancer: Unveiling BRCA1/2 mutations and genomic instability scores to advocate for public insurance coverage of genetic testing—Insights from the Hellenic Society of Medical Oncology (HeSMO) national program.
Authors: Saloustros Emmanouil S. , Liontos Michael , Timotheadou Eleni , Andreadis Charalampos , Skafida Efthymia , Syrios John , Kalykaki Antonia , Koutsoukos Konstantinos , Kesisis Georgios , Boukovinas Ioannis , Boutis Anastasios L. , Papakotoulas Pavlos , Ziogas Dimitrios C. , Karageorgopoulou Sofia , Giassas Stylianos , Lianos Evangelos , Chatzifoti Natalia , Papageorgiou Fotini , Saridaki Zacharenia (Zenia) 
Published: June 2024

3146 Background: Homologous recombination deficiency (HRD) in ovarian cancer, indicative of impaired DNA repair, contributes to genomic instability (GIS). Beyond mutations in BRCA1/2 genes, GIS is particularly significant for identifying patients who may benefit from PARP inhibitors. Equivalence between Myriad Genetics' myChoice CDx and the standard diagnostic tests OncoScan and Amoy Diagnostics has been published, prompting HeSMO to launch a national program addressing GIS and BRCA 1/2 mutations in newly diagnosed advanced high grade ovarian cancer patients, with the utilization of these more economically advantageous tests, in order to guide effective therapeutic strategies, since official reimbursement is not yet applicable in our country. Methods: Patients with locally advanced or metastatic high-grade stage III/IV ovarian cancer were eligible for the HeSMO program, submitting an FFPE tissue tumor sample. The evaluation focused on HRD detection (positive or negative) and GIS assessment (high or low), combining results from OncoScan and Amoy Diagnostics. Results: Between August 2022 and December 2023, 511 patients from Greece underwent testing. 48.14% (n=246) tested HRD positive, 46.58% (n=238) HRD negative. High GIS score was observed in 44.81% (n=229), low GIS in 49.71% (n=254). Potential pathogenic mutations in BRCA1/2 genes were found in 19.96% (n=102). BRCA1 mutations (13.70%, n=70) included key mutations: c.190T>C p.(Cys64Arg), c.3700_3704delGTAAA p.(Val1234GlnfsTer8), c.4065_4068del p.(Asn1355LysfsTer10). BRCA2 mutations (6.26%, n=32) comprised of c.1129G>T p.(Glu377Ter), c.3650_3659del p.(Arg1217IlefsTer8), c.7150C>T p.(Gln2384Ter). In 27 samples (5.28%) no result was produced. Conclusions: HRD and GIS are vital genomic instability biomarkers in high-grade ovarian cancer. These metrics provide valuable insights into tumor aggressiveness, guiding therapeutic decisions, including the use of PARP inhibitors. In this study of 511 patients from 50 centers across Greece, 48.14% tested positive for HRD, emphasizing PARP inhibitors' significance and suggesting hereditary implications. Our commitment to enhance patient access to reliable diagnostic biomarker testing in Greece is unquestionable. Furthermore, we believe, our results will strengthen our efforts towards official state reimbursement, paving the way for local HRD testing solutions. [Table: see text]
The role of metastasectomy in patients with early onset metastatic colorectal cancer.
Authors: Pretta Andrea , Ziranu Pina , Perissinotto Eleonora , Scalia Raimondo , Marmorino Federica , De Grandis Maria Caterina , Ciracì Paolo , Russo Alessandra , Cerma Krisida , Cavalli Chiara , Chiaramonte Anna , Taravella Ada , Giampieri Riccardo , Berardi Rossana , Lonardi Sara , Bergamo Francesca , Pietrantonio Filippo , Cremolini Chiara , Scartozzi Mario 
Published: June 2024

3541 Background: According to the literature, metastasectomies in colorectal cancer patients can lead to a significant increase in outcomes. However, the behavior of early-onset CRC (EO-CRC), which refers to cancer occurring in adults between 18 and 49 years, when subjected to metastasectomy, remains unclear. Clinical and prognostic data on this setting are limited and conflicting. Our study aimed to evaluate clinical, prognostic, and molecular differences in early-onset colorectal cancer (EO-CRC) patients undergoing metastasectomy to identify potentially relevant differences compared to a control group of late-onset CRC (LO-CRC). Methods: We retrospectively collected data from 1123 metastatic colorectal cancer patients from 5 different Italian Institutions. 673 (59.9%) EO-CRC and 450 (40.1%) LO-CRC as a control group. All patients had one or more metastatic sites, molecular profiling available (including RAS, BRAF, and MSI status), and underwent at least one line of treatment for metastatic disease. The main objective of the study was to evaluate clinical outcomes for the EO-CRC patients undergoing metastasectomy in comparison to patients included in the control group according to molecular profile. Results: In the EO-CRC group, the median age was 44.1 (20.0-50.9), while in the control group, it was 64.4 (51.0-86.2). Among EO-CRCs patients, 388 out of 673 (57.6%) underwent metastasectomy, whereas, in LO-CRCs patients, only 181 out of 450 (40.2%) had the procedure. In the general population, patients who underwent metastasectomy demonstrated a higher median overall survival (mOS) compared to those who did not undergo the procedure. However, within the metastasectomy group, EO-CRCs patients exhibited a lower mOS compared to LO-CRCs patients (46.0 versus 60.0 months, p < 0.0001). Similar results were obtained when evaluating subgroups of RAS-BRAF wild type patients (53.0 months versus 81.0 months, p < 0.0001) and RAS-BRAF mutated patients (42.0 months versus 45.0 months, p < 0.0001). Conclusions: Although EO-CRC patients seem more likely to undergo surgical resection for metastatic disease, our findings suggest a worse overall prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly, this seems to occur regardless of the molecular status. These observations could have a considerable impact on clinical practice and research. Further investigations will be necessary to better understand the specific clinical and molecular characteristics of this growing group of patients to better define the most appropriate therapeutic strategy.
Robotic versus laparoscopic surgery for middle and low rectal cancer (REAL): Primary outcome of a multicenter randomized controlled trial.
Authors: Xu Jianmin , Yuan Weitang , Li Taiyuan , Tang Bo , Jia Baoqing , Zhou Yanbing , Zhang Wei , Zhao Ren , Zhang Cheng , Cheng Longwei , Zhang Xiaoqiao , Liang Fei , He Guodong , Wei Ye , Feng Qingyang 
Published: June 2024

3617 Background: Robotic surgery for rectal cancer is gaining popularity, but persuasive evidence on long-term oncological outcomes is lacking. This multicenter randomized controlled trial compared robotic and conventional laparoscopic surgery regarding surgical quality and long-term oncological outcomes among patients with middle and low rectal cancer. Previously the short-term outcomes of this trial had been reported that robotic surgery had significantly lower circumferential resection margin positivity rate, lower postoperative complication rate, and better postoperative recovery. Now the long-term oncological outcomes were reported. Methods: This superiority trial was undertaken at 11 hospitals in 8 Chinese provinces. Patients with middle (> 5–10 cm from anal verge) or low (0–5 cm from anal verge) rectal adenocarcinoma, cT1–T3 N0–1 or ycT1–T3 Nx after preoperative radio-/chemoradiotherapy, and no evidence of distant metastasis were enrolled and randomly assigned in a 1:1 ratio to receive robotic or conventional laparoscopic surgery. The 3-year locoregional recurrence rate was the primary outcome and was compared using modified intention-to-treat (mITT) analysis. Secondary outcomes included disease-free survival and overall survival. All time-to-event outcomes were calculated using Kaplan-Meier method with log-rank test. This trial was registered with ClinicalTrials.gov (NCT02817126). Results: Between July 2016 and December 2020, 1240 patients were enrolled, and 1171 were included in the mITT analysis (586 in robotic and 585 in laparoscopic group). The pathological TNM stage of the mITT population was 73 (6.2%) patients with complete response, 346 (29.5%) with stage I, 368 (31.4%) with stage II, 384 (32.8%) with stage III. And the median follow-up time was 43.0 months (interquartile range = 36.7 to 60.0), with 34 (2.9%) patients lost to follow-up. The 3-year locoregional recurrence rate in robotic group (1.5%) was significantly lower than in laparoscopic group (4.0%, log-rank p=0.025, hazard ratio = 0.451, 95% confidence interval = 0.221 to 0.921). Robotic group also had significantly higher 3-year disease-free survival rate (87.3% vs. 83.6%, log-rank p=0.035). No significant difference was observed in 3-year overall survival rate (94.8% vs. 93.1%, log-rank p=0.155). Conclusions: Robotic surgery for middle and low rectal cancer significantly reduced locoregional recurrence and improved disease-free survival, compared with conventional laparoscopic surgery. Clinical trial information: NCT02817126 .
Phase I study of C-CAR031, a GPC3-specific TGFβRIIDN armored autologous CAR-T, in patients with advanced hepatocellular carcinoma (HCC).
Authors: Zhang Qi , Fu Qihan , Cao Wanyue , Wang Hongkan , Xu Xingyuan , Huang Jiaqi , Zou Andy , Zhu Judy , Wan Hui , Yao Yihong , Tu Eric , Stone John , Bondanza Attilio , Farsaci Benedetto , Liang Tingbo 
Published: June 2024

4019 Background: GPC3 is a surface antigen overexpressed in HCC and virtually absent on healthy tissues. Chimeric antigen receptor (CAR) T cells targeting GPC3 offer a promising option for advanced unresectable HCC treatment. C-CAR031 is an autologous GPC3-directed CAR-T armored with dominant negative TGF-b receptor II. Here we report the safety and preliminary efficacy of C-CAR031 in advanced HCC patients (pts). Methods: The first-in-human, open-label dose-escalation trial employs an accelerated titration plus i3+3 design. GPC3+ advanced HCC pts who failed ≥ 1 line systemic treatments received a single i.v. infusion of C-CAR031 post standard lymphodepletion. Primary endpoints are safety and tolerability, others include pharmacokinetics and preliminary efficacy. Adverse events (AEs) were graded by CTCAE 5.0, and cytokine release syndrome (CRS) / immune effector cell-associated neurotoxicity syndrome (ICANS) were assessed per ASTCT 2019 criteria. Objective response was assessed by investigator per RECIST 1.1. Results: As of Jan 5th, 2024, a total of 24 pts received C-CAR031 infusion at 4 dose levels (DLs). All pts had BCLC stage C HCC, 83.3% (20/24) had extrahepatic metastasis. The median number of prior lines of therapy was 3.5 (range 1-6), 23 (95.8%) pts received ICIs (immune checkpoint inhibitors) and TKIs (tyrosine kinase inhibitors). All pts were evaluable for safety. No dose-limiting toxicity and ICANS was observed. CRS was observed in 22 (91.7%) pts with only 1 (4.2%) grade (G) 3 CRS. The most common ≥G3 AEs were lymphocytopenia (100%), neutropenia (70.8%), thrombocytopenia (37.5%) and transaminase elevation (16.7%). One pt (4.2%) had G4 myelosuppression and 1 pt (4.2%) had G3 interstitial pneumonitis at DL4 caused by G3 CRS. All AEs were reversible. 22 pts were evaluable for efficacy. Tumor reductions were observed in 90.9% pts, not only in intrahepatic lesions but also extrahepatic ones with a median reduction of 44.0% (range, 3.4%-94.4%). The disease control rate was 90.9% and the objective response rate (ORR) was 50.0% for pts of all DLs. In DL4, the ORR was 57.1%. Conclusions: The study showed a manageable safety profile and encouraging anti-tumor activity of C-CAR031 in heavily treated advanced HCC patients. Clinical trial information: NCT05155189 . [Table: see text]