tbuckley/cabot-search huggingface dataset:
Decade-long insights into transperineal prostate biopsy in a west China population: Temporal trend, targeted and repeat biopsies, and pathological characterization.
Authors: Jinge Zhao, Diming Cai, Yuntian Chen, Jindong Dai, Ni Chen, Pengfei Shen, Hao Zeng
Journal: Journal of Clinical Oncology (2024)

e17004 Background: Despite advances in prostate cancer (PCa) detection, the need for improving diagnostics and in-depth assessment of the latest prostate biopsy (PBx) techniques through extensive, longitudinal studies remains critical. Methods: Data from 10,378 PBx involving 10,038 patients were retrospectively examined. We detailed the yearly changes in PBx numbers and patient diagnoses, the real-world efficacy of PI-RADS scoring, MRI-targeted biopsy (MRI-TBx), and repeat PBx. We also outlined the detection rates and the clinical profiles of non-adenocarcinoma (non-AC) PCa. Results: A consistent annual increase in PBx was witnessed, with the positive rate climbing to approximately 55%. There was a gradual decline in median age, PSA levels, and M1 stage proportion among PCa patients, suggesting an earlier diagnosis trend. However, compared to Western populations, our center's patients had a significantly higher incidence of M1 stage (34% vs. 6%, P&lt;0.001) and, within the M0 category, presented with older age and elevated baseline PSA levels. Integrating MRI-TBx into the 12-core systematic biopsy (SBx) led to a numerical improvement in PCa detection and enhanced ISUP grading accuracy. Merging MRI-TBx with a 6-core SBx achieved a median clinically significant PCa (csPCa) detection rate of 39.76% in men with PSA&lt;20ng/mL, similar to that of MRI-TBx with a 12-core SBx (40.36%). Furthermore, we identified 1,455 men with non-AC PCa, occurring less in localized cases (about 15%) but more in metastatic cases (over 50%), and exhibiting more aggressive characteristics compared to adenocarcinoma-only cases. Besides, among the 305 individuals undergoing repeat PBx, 62 csPCa cases were identified, all of which exhibited lower positive cores, ISUP grading, and M1 stage incidence than men diagnosed by initial PBx. Conclusions: Analyzing a decade's worth of PBx data from one of the largest Asian cohorts offered pivotal insights into the evolving epidemiology and clinical profiles of PBx, which are essential for shaping future diagnostic approaches for PCa.
Preliminary efficacy and safety results from RC48-C017: A phase II study of neoadjuvant treatment with disitamab vedotin plus toripalimab in patients with muscle invasive bladder cancer (MIBC) with HER2 expression.
Authors: Xinan Sheng, Kaiwei Yang, Yongpeng Ji, Li Zhou, Benkui Zou, Hang Huang, Yonghua Wang, Xue Bai, Dan Feng, Yong Yang, Jiasheng Bian, Zhixian Yu, Haitao Niu, Peng Du, Jianmin Fang, Zhisong He, Jun Guo
Journal: Journal of Clinical Oncology (2024)

4568 Background: Disitamab vedotin (DV) is a novel humanized anti-HER2 antibody-drug conjugate. DV plus toripalimab (a recombinant humanized anti-PD-1 monoclonal antibody) showed promising antitumor activity in metastatic urothelial carcinoma (ASCO 2023). This study aimed to evaluate the safety and efficacy of DV plus toripalimab as neoadjuvant therapy in MIBC patients with HER2 expression. Methods: This is a prospective multicenter phase 2 trial which planned to enroll 40 pts. Primary endpoint is pathological CR (pCR) rate; secondary endpoints include pathologic response rate, safety and tolerability. Study enrolled pts who are previously untreated MIBC (cT2-T4aN0-1M0), medically fit for and agree to undergo curative intent RC+PLND. HER2 expression was required to be immunochemistry (IHC) ≥ 1+ tested locally. Pts received DV 2 mg/kg plus toripalimab 3 mg/kg every two weeks for 6 cycles, followed by RC+ PLND within 4 weeks. Here we present preliminary efficacy and safety results. Results: 44 pts were enrolled and clinical stage at diagnosis was: cT2N0 (38.6%), cT3N0 (29.5%), cT4aN0 (13.6%), cT2-4aN1 (18.2%). HER2 expression of IHC 1+, 2+ or 3+ was 11.4%, 56.8%, and 31.8%, respectively. By the data cut-off date (Feb-2024), 29 pts (65.9%) completed RC + PLND. The pCR rate was 62.1% (18/29). The pathologic response rate was 75.9% (22/29). Common treatment-related adverse events (TRAEs) were mostly Grade 1 or 2, including alopecia (36.4%), alanine aminotransferase increased (31.8%), aspartate aminotransferase increased (25.0%), rash (22.7%), gamma-glutamyl transferase increased (22.7%), peripheral sensory neuropathy (22.7%), and asthenia (20.5%). Grade 3-4 TRAEs were reported in 15.9% of pts. No deaths occurred. No surgery was cancelled due to TRAEs. Survival data are not yet mature. Conclusions: Neoadjuvant treatment with DV plus toripalimab showed promising efficacy results and was well tolerated in operable MIBC pts with HER2 expression. These results will support further investigation for DV plus toripalimab in this population. Clinical trial information: NCT05297552 .
Phase 2 randomized study of rintatolimod following FOLFIRINOX in patients with locally advanced pancreatic adenocarcinoma.
Authors: Kelsey Klute, Vincent J. Picozzi, Nashat Gabrail, Michael A. Hollingsworth, Christopher McAleer, Diane Young, David Rodney Strayer
Journal: Journal of Clinical Oncology (2024)

TPS4214 Background: The immunosuppressive microenvironment of pancreatic ductal adenocarcinoma (PDAC) is a driver of its lethality and resistance to immunotherapy. Strategies which modulate the immunosuppressive milieu have the potential to improve the anti-tumor response and improve outcomes in patients with PDAC. Rintatolimod is a synthetic double-stranded RNA molecule that activates the toll-like receptor 3 (TLR3) present on dendritic cells, B-cells, natural killer cells and pancreatic epithelial cells. TLR3 stimulation may increase cytotoxic T-cell activity in PDAC through dendritic cell maturation, antigen priming and downstream proliferation of cytotoxic T-cells. Twenty-seven patients were treated with rintatolimod in a single center Named Patient Program at Erasmus University Medical Center in Rotterdam between January 2017 and February 2019. All had locally advanced or metastatic PDAC which had not progressed on FOLFIRINOX (median 8 cycles). Maintenance rintatolimod, administered intravenously twice weekly for up to 18 weeks, was generally well tolerated. The most common toxicities were grade 1-2 myalgia (30%), chills (52%) and fatigue (30%); no toxicities ≥ grade 3 were observed. Progression-free and overall survival (from cycle 1 FOLFIRINOX) were 13 and 19 months. Methods: This is a phase 2 randomized, open-label, multicenter clinical trial. The primary objective is to assess the efficacy of rintatolimod compared to observation in subjects with locally advanced PDAC which has not progressed after FOLFIRINOX. Eligible patients have completed at least 4 months of FOLFIRINOX, have no evidence of progressive disease, have measurable disease by RECIST v1.1, Karnofsky Performance Status ≥80 and have adequate organ function. Subjects with resected PDAC or metastatic disease are not eligible. Subjects are randomized 2:1 to rintatolimod vs. observation. Rintatolimod is administered intravenously twice weekly until disease progression in the experimental arm. Cross-sectional imaging is performed every 8 weeks in both arms. The primary endpoint is progression-free survival, as assessed by the investigator. Secondary endpoints include overall survival, objective response rate, duration of response and safety, as assessed by CTCAE v5.0. Exploratory endpoints include quality of life and changes in immune cell composition and T-cell response in the peripheral blood to characterize the immunomodulatory effects of rintatolimod. The planned sample size is 90 subjects. The final analysis will be performed after 64 events (disease progression or death) have been observed. The study is powered to detect a hazard ratio of 0.47 for median PFS with 80% power and significance level of 5%. Clinical trial information: NCT05494697 .
Small bowel adenocarcinoma: A SEER database analysis.
Authors: Sangeetha Isaac, Mohammed Afraz Pasha, Ali Hussain, Sumaira Zareef, Aakriti Arora, Srijan Valasapalli, Nayan Mainkar, Azka Tasleem, Munizay Paracha, Mahvish Muzaffar
Journal: Journal of Clinical Oncology (2024)

e16383 Background: Small bowel malignancies (SBM) account for about 3% of all gastrointestinal malignancies. Small bowel adenocarcinoma (SBA) accounts for the majority of the SBM. SBA is associated with poor prognosis and treatment options are limited in patients with advanced cancer. We analyzed SEER data to study the factors that impacted survival in patients with SBA. Methods: We reviewed data on the SEER database (version Stat 8.4). We extracted data to include patients with adenocarcinoma with labeled primary site as small bowel diagnosed between 2000-2019. We excluded other histology. Variables included were age at diagnosis, race, gender, stage at diagnosis, and grade of malignancy. Chi-square test was used to analyze the association between each variable and survival. Results: We identified 3415 cases of SBA that met our inclusion criteria. The number of annual cases increased from 2000-2019. The mean age was 65.3 years (range 57-75 years). The Male to Female ratio was 11:9. 76% were white, 13.7% were black, 13% were others. Duodenum was the most common primary site with 58%, jejunum at 15.5%, ileum at 13%, and 13.5% overlapped sites or unknown. SEER combined summary stage at diagnosis was 32% regional, 18% localized, 29% distant, and 23% unknown. 6% was grade I, 37% grade II, 27% grade III, 1% grade IV, and 28% unknown. Median survival in patients with SBA was 13 months. The median survival for patients less than or equal to 60 years was 24 months compared to 11 months in patients over 60 years of age (p &lt; 0.0001). Median survival in males was 13 months vs 12 months in females, (p = 0.548). There was no significant difference in survival per race (p = 0.5849). In this cohort, jejunal adenocarcinoma had better outcomes with a survival of 27 months (p &lt; 0.0001). Grade I and II were associated with better outcomes with survival of 21.5 months and 24 months (p &lt; 0.0001). Multivariate analysis showed that age less than 60, early-stage disease, jejunal primary site, and low-grade disease were associated with a better outcome. Conclusions: The number of cases of SBA in the SEER database has increased over the last few decades. SBA is associated with poor outcomes and our analysis shows that patients with early-stage disease, and younger age have better outcomes. Management of SBA is based on retrospective data and data extrapolated from management of colon adenocarcinoma, due to sparsity of prospective data. Clinical trials are needed to identify appropriate therapeutic options for the management of SBA.
A phase I/II study of intraperitoneal (IP) paclitaxel (PTX) in patients with metastatic appendiceal adenocarcinoma.
Authors: John Paul Y.C. Shen, Ichiaki Ito, Abdelrahman M.G. Yousef, Michael White, Keith F. Fournier, Beth A Helmink
Journal: Journal of Clinical Oncology (2024)

TPS4215 Background: Appendiceal cancer is a rare, orphan disease, that is unfortunately becoming more common. There is growing data from our lab and others that particular subtypes of AA do not respond to CRC chemotherapy. The use of CRC chemotherapy to treat patients with AA tragically results in many patients enduring side effects from chemotherapy that is ineffective; however, this practice will likely continue unless AA-specific treatments are developed. The Shen lab has recently tested IP paclitaxel (PTX) in orthotopic PDX models of AA. After allowing implanted tumors to grow for four weeks to simulate diffuse peritoneal metastases, baseline MRI was performed and mice were randomly assigned to treatment groups of four mice and intraperitoneally (IP) administered increasing doses of PTX. Marked response was seen in all three models at dose of 25 mg/kg IP weekly, with a near complete response in model AAPDX-10. This dose given IP was well tolerated by the mice, notably this dose exceeds the know lethal IV PTX dose. Methods: The Phase I component of this study will be a prospective single-arm intervention trial giving IP PTX every 2 weeks for a total of 5 doses with primary endpoint of safety and tolerability (MTD determination). Each patient will have an initial diagnostic laparoscopy where PCI score will be calculated and IP catheter placed, dx lap is repeated at the end of study after 5 biweekly doses. For the Phase 1 portion of the trial a Bayesian Optimal Interval (BOIN) approach will be used to determine recommended phase 2 dose (RP2D). All patients treated at that dose or higher will be included in Phase 2 component of the study where the primary objective is response, determined by change in PCI score. With 15 patients Based on historical data, we estimate that the proportion of patients who will demonstrate an objective response without going on trial is 0.05, i.e., the null hypothesis is a 0.05 ORR. Treatment is expected to raise this proportion to 30%. Using an exact binomial test with one-sided type I error of 0.05, we will reject the null if at least 3 patients achieve response. This test has power of 87%. Secondary end points include pathologic, biochemical and radiographic response, PFS, OS, and the influence of KRAS/GNAS/TP53 mutation on response. PK measurements will also be performed during the Phase 1 portion of the trial to determine the degree to which the IP injected PTX enters the blood stream. Patients will be followed for up to 1 year. Adverse events (AEs) will be captured and graded using the National Cancer Institute’s (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) v. 5.0 (or latest version) and will include the event term, grading, duration and attribution. Attribution to the study agent or intervention will be determined by the PI, Co-PI or treating physician. Clinical trial information: NCT06207305 . [Table: see text]
Correlation of therapy-induced neutropenia with survival in patients with metastatic pancreatic cancer treated with GSK-3 inhibitor elraglusib (9-ING-41) in combination with gemcitabine/nab-paclitaxel in the 1801 phase 2 study.
Authors: Andrey Ugolkov, Austin Koukol, Caroline Kellinger, Sheri Lynn Smith, Susan Gallipoli, Suzanne Gagnon, Chris Seifarth, Steven D. Reich, Andrew Paul Mazar
Journal: Journal of Clinical Oncology (2024)

e16311 Background: Previously, elraglusib (9-ING-41), an inhibitor of Glycogen Synthase Kinase-3 (GSK-3), was shown to potentiate the anticancer effects of chemotherapeutic drugs in preclinical models of cancer. The combination of elraglusib and gemcitabine/nab-paclitaxel (GnP) is currently being investigated in a randomized, open-label 1801 phase 2 study as a first-line therapy for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Chemotherapy-induced neutropenia is a common dose-limiting toxicity resulting in dose reductions and/or treatment interruptions. Present evidence shows that therapy-induced neutropenia (TIN) grade 3-4 correlates with survival and is a potential marker for improved clinical outcome in elraglusib/GnP-treated patients. Methods: We correlated overall survival (OS) and time-to-treatment discontinuation (TTD) with TIN grade 3-4 in 72 (GnP arm) and 155 (elraglusib/GnP arm) mPDAC patients previously untreated for advanced disease (1801 Part 3 Arm B study; NCT03678883). TTD was defined as the date of first dose to the date of treatment discontinuation or death. The Kaplan-Meier log-rank test was used for statistical analysis. A p-value &lt; 0.05 was considered statistically significant. Results: The rate of grade 3-4 TIN was 22% (16/72 patients) and 47% (72/155 patients) in the GnP and elraglusib/GnP groups, respectively. Based on 28% of all recorded death events in elraglusib/GnP group and 36% in GnP group, we found that grade 3-4 TIN was significantly associated with improved OS in patients treated with elraglusib/GnP (median OS: 14.4 vs 5.9 months; P &lt; 0.05) but not in patients treated with GnP (median OS: 7.6 vs 7.2 months). In the elraglusib/GnP group, patients with grade 3-4 TIN stayed on treatment significantly longer (median TTD: 7.9 months; P &lt; 0.05) as compared to the patients who did not develop TIN grade 3-4 (median TTD: 1.7 months). Conclusions: Our preliminary results identified grade 3-4 TIN as a potential marker of improved clinical outcome for elraglusib/GnP therapy in previously untreated patients with mPDAC. Recruitment for the 1801 Part 3 Arm B phase 2 trial has been completed. Another interim analysis of OS and its correlation to grade 3-4 TIN will be available by April 2024 and will be included in the final presentation. Clinical trial information: NCT03678883 .
PEMDA-HN, an open-label, phase II, randomized controlled study of danvatirsen plus pembrolizumab compared to pembrolizumab alone in first-line recurrent and/or metastatic head and neck squamous cell carcinoma (RM HNSCC).
Authors: Marshall R. Posner, Deborah J.L. Wong, Kevin Joseph Harrington, Richard Lee O'Neal, Lukas Makris, Morgane Perdomini, Susan MacIntyre, Andrew Denker, Nabil F. Saba
Journal: Journal of Clinical Oncology (2024)

TPS6113 Background: Signal transducer and activator of transcription 3 (STAT3) plays critical roles in promotion of an immune-suppressive tumor microenvironment and survival of tumor cells. Danvatirsen (DANVA) is a 16-nucleotide, generation 2.5 antisense oligonucleotide designed to down-regulate the expression of human STAT3 mRNA. Over 500 patients with hematologic malignancies or solid tumors have been exposed to DANVA monotherapy or in combination. A tolerable safety profile has been demonstrated for DANVA and toxicities are manageable. The SCORES study in recurrent and/or metastatic (RM) HNSCC patients, naïve to programmed cell death (ligand)1 (PD-(L)1) therapy, demonstrated that DANVA in combination with the PD-L1 inhibitory antibody durvalumab administered in the second line setting appeared to result in a higher objective response rate (ORR) (22.6% [12.3-36.2]) compared with the ORRs seen with durvalumab alone in prior studies (Cohen E. et al. Ann. Oncol., 2018). Several patients had complete responses (CR, 9.4%). The ORR was higher in patients with a PD-L1 tumor proportion score (TPS) ≥1 and ≥20, with increasing benefit noted with higher PD-L1 expression compared with historic anti-PD-(L)1 monotherapy data. The current study aims at evaluating the first-line combination of DANVA with pembrolizumab, an anti-PD-1 agent approved as first-line monotherapy for RM HNSCC in patients with PD-L1 positive disease. Methods: PEMDA-HN is a multicenter, open-label, randomized phase 2 study utilizing a Bayesian Optimal design (BOP2). Approximatively 81 RM HNSCC patients with a PD-L1 combined positive score (CPS) score ≥1 will be randomized in a 2:1 ratio stratified based on CPS&lt;20 and CPS≥20 to receive either DANVA (3 mg/kg IV Days 1, 3, and 5 and then weekly starting on Day 8) and pembrolizumab (200 mg IV every 3 weeks) or pembrolizumab alone as a first line therapy for recurrent or metastatic disease. Eligible patients will receive study treatment until disease progression or discontinuation. The primary endpoint of the study is ORR by response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) as assessed by the investigator. Key secondary objectives are safety, additional antitumor activity evaluation (CR rate, duration of response, disease control rate, progression-free and overall survival) and pharmacokinetics. Efficacy (e.g. ORR, CR rate) will be evaluated in all patients and in subsets of patients with CPS&lt;20, CPS≥20 and CPS≥50. Exploratory endpoints include but are not limited to target engagement and biomarker evaluation. The study is being, or will be, conducted at US, South Korea and United-Kingdom study centers. Clinical trial information: NCT05814666 .
A phase I/II open label study to assess safety and preliminary evidence of a therapeutic effect of azeliragon in patients refractory to first-line treatment of metastatic pancreatic cancer.
Authors: Andrew Eugene Hendifar, Stephen Garrett Marcus, Warren S. Brenner, Marc Isamu Uemura, Ki Y. Chung, Donald A. Richards, Nathan Bahary
Journal: Journal of Clinical Oncology (2024)

TPS4212 Background: Azeliragon is an orally administered small molecule, administered once daily, that inhibits RAGE interactions with its natural ligands, including HMGB1 and S100 proteins. Azeliragon was previously under development for Alzheimer’s disease and failed to show efficacy in phase 3 trials. Clinical safety data from these trials, with over 1500 individuals dosed for periods up to 18 months, indicated that azeliragon has a high level of safety and tolerability, virtually indistinguishable from placebo. RAGE, the receptor for advanced glycation end products, is highly expressed in pancreatic ductal adenocarcinoma (PDAC). RAGE interaction with its ligands, including S100 proteins and HMGB1 released from PDAC cells, promotes PDAC invasion, metastasis, and resistance to 5 FU and Gemcitabine. PDAC-secreted S100 proteins can also stimulate fibroblasts surrounding PDAC cells since RAGE is positively expressed in fibroblasts, promoting the desmoplastic response. RAGE has also been implicated in the muscle wasting associated with cancer and with aging, as well as in neuropathic pain, suggesting a potential supportive role in PDAC treatment. Methods: This is an open label study to determine the safety and preliminary evidence of a therapeutic effect of azeliragon in patients refractory to the standard of care treatment of metastatic pancreatic cancer. Azeliragon is administered at three dose levels in a rolling dose escalation strategy with 6 patients at each dose level: 5 mg/day (level 1), 10 mg/day (level 2) and 20 mg/day (level 3). These dose levels have an initial loading dose for 6 days at 15 mg daily, 15 mg twice a day and 30 mg twice a day, respectively. The primary objective is to determine the RP2D, defined as the dose for which &lt;33% patients experience a dose limiting toxicity (DLT) within 28 days from initiation of dosing. Secondary endpoints include disease control, overall survival, changes in pain as determined by the Brief Pain Inventory, and changes in ECOG performance status, weight, and serum albumin. The study received regulatory approval and accrual started in June 2023. Clinical trial information: NCT05766748 .