bluuebunny/crossref_metadata_2025_split huggingface dataset:
The CONFIDENT-P trial: Clinical implementation of artificial intelligence assistance in prostate cancer pathology.
Authors: Flach Rachel , Stathonikos Nikolas , Nguyen Tri , ter Hoeve Natalie D , van Diest Paul J. , van Dooijeweert Carmen 
Published: March 2023

TPS405 Background: Prostate cancer grading has been subject to variation, putting patients at risk for over- and under-treatment (Flach et al., 2022). As a response, development of artificial intelligence (AI) prostate cancer algorithms has been on the rise in the field of pathology. Despite promising results in retrospective studies, and several FDA-approved and CE-IVD certified algorithms on the market, prospective clinical implementation studies of AI are lacking. Moreover, uptake of digital pathology is currently insufficient due to high implementation costs (Ho et al., 2014). In this trial, we will explore the benefits of an AI-assisted pathology workflow in prostate cancer detection, while maintaining diagnostic safety standards. We will focus on reducing costly immunohistochemistry stains (IHC), which are currently used to aid in the diagnosis of prostate cancer. Methods: CONFIDENT-P is a SPIRIT-AI compliant single-centre, clinical trial, in a fully digital academic pathology laboratory. We will prospectively enroll 80 prostate cancer patients who undergo prostate needle biopsies. The pathology specimens will be pseudo-randomized to be assessed by a pathologist with- or without AI-assistance in a pragmatic (bi-)weekly sequential design, in a 1:1 allocation ratio. Patients are excluded when they are redirected for a second opinion to the UMC Utrecht. In the intervention group, pathologists will assess whole slide images (WSI) of the standard haematoxylin-eosin (HE)-stained sections assisted by the output of a CE-IVD approved prostate cancer detection and grading algorithm. In the control group, pathologists will assess HE WSI according to the current clinical workflow. If no tumour cells are identified or when the pathologist is in doubt, staining by immunohistochemistry (IHC) will be performed. Primary endpoint is the number of saved resources on IHC for detecting tumour cells, since this will clarify tangible cost savings that will help to build the business case for AI. We will compare the proportion of IHC-use in both arms, and calculate adjusted relative risks, using a log-binomial model. The sample size gives at least 80% power to detect a 30% difference in IHC usage, using a one-sided significance level of 5%. Enrolment is set to begin in November 2022. The ethics committee (MREC NedMec) waived the need of official ethical approval, as participants are not subjected to procedures and as they are not required to follow rules. Furthermore, they are not at risk of an inferior diagnosis. Trial registration is therefore applicable nor suitable.
A randomized phase II trial of neoadjuvant chemokine modulation in patients with localized prostate cancer undergoing radical prostatectomy.
Authors: Jatwani Karan , Farmer Bailey , Roy Arya Mariam , Slomba Ronald , Attwood Kristopher , Levine Ellis Glenn , Kauffman Eric , Kalinski Pawel , Guru Khurshid , Gopalakrishnan Dharmesh , Chatta Gurkamal S. 
Published: March 2023

TPS406 Background: Most patients with high or very high risk localized prostate cancer (PCa) experience disease recurrence after radical prostatectomy (RP). Neoadjuvant androgen ablation has not improved high-risk pathological features or recurrence rates after RP.1 We reported the association between high intratumoral CD8+ T lymphocyte (CTL) density and improved survival post-RP, suggesting clinical benefit from neoadjuvant immunomodulation (NI).2 Analysis of the tumor immune microenvironment after NI may also provide key insights into potential therapeutic strategies in PCa. CTL/NK/Th1-recruiting chemokines (CCL5, CXCL9 and CXCL10) are downregulated while MDSC/Treg-attracting chemokines (CCL2, CCL22, and CXCL12) are upregulated in human PCa tissue.3 A large proportion of T cells in PCa are Tregs or dysfunctional CTLs and this immunosuppressive profile may be partly driven by COX-2 upregulation.4,5 A chemokine modulating regimen (CKM) of rintatolimod (TLR-3 ligand), aspirin (COX-2 inhibitor), and IFN-α favorably reprogrammed the chemokine profile and CTL/Treg ratio in human PCa explants.3 This combination has demonstrated safety in phase I/II trials across other tumor types, though it is unclear if IFN-α can be omitted without compromising efficacy.7-8 Methods: This is a three-arm, phase II trial where patients with localized PCa scheduled to undergo RP are randomized in 1:1:1 ratio to a 2-week regimen of neoadjuvant CKM triplet (rintatolimod + aspirin + IFN-α) vs CKM doublet (rintatolimod + aspirin) vs no CKM. Thirty patients will be enrolled to assess CD8+ T cell density in the RP specimen as the primary endpoint. Pathological and PSA responses, surgical margin positivity, and safety/toxicity of the CKM combinations will be secondary endpoints. Pre- and post-treatment density of various infiltrating T cell subtypes, MDSCs, chemokine and chemokine receptor profiles, immune checkpoint expression, immune-regulatory gene expression signatures, and peripheral blood immune cell landscape will be key exploratory endpoints. The trial is currently open with 11 patients enrolled. Clinical trial ID: NCT03899987 . References: 1) Scolieri MJ, J Urol 2000, 2) Clin Oncol 36, 2018: suppl; abstr 5068, 3) Muthuswamy R, Prostate 2016, 4) Sfanos KS, Prostate 2009, 5) Gupta S, Prostate 2000, 6) NCT01545141, 7) NCT02151448, 8) NCT02432378.
A multicenter prospective validation study of the 3-cm cut-off in stage I seminoma (S3MI-PT).
Authors: Fontes-Sousa Mario , Magalhães Helena , Leão Ricardo , Mansinho André , Malheiro Mariana , Rosinha Alina , Carrolo Margarida , Borralho Paula , Mauricio Joaquina , Brito Margarida , Passos-Coelho Jose Luis C. , Quintela Antonio 
Published: March 2023

TPS435 Background: Testicular germ cell tumors (TGCT) are the most common solid malignancy in men aged 15 to 35, and Seminoma histology can account for up to half of the cases. Since the latest edition of the American Joint Committee on Cancer (AJCC) staging manual (8th edition, 2018), it is recommended that, only in pure Seminoma, the pT1 category should be subdivided according to tumor size: pT1a for tumors < 3 cm or T1b for tumors ≥ 3 cm. This change was based on large retrospective data that suggested almost a doubling of the risk of relapse at 3-years in pT1b versus pT1a, with a Hazard Ratio of 1.87, 95% confidence interval (CI) 1.15-3.06. So far, there has been no prospective validation for these staging changes and there are no known implications of its use in clinical practice. Furthermore, these changes are exclusive for AJCC since the Union for International Cancer Control (UICC), another widely used staging system, did not change from previous editions (i.e., no pT1 subdivision in pure Seminoma). Tumor size was already recognized as a risk factor for relapse (if tumor size > 4 cm) but not formally used for staging before. Of concern, these are mostly young patients, and despite exceptionally good long-term survival rates, in stage I Seminoma, the general estimation of relapse is about 15% but can surpass 30% — therefore accurate prognostic information is particularly important. This study aims to validate the 3 cm cut-off in stage I Seminoma introduced by AJCC 8th edition. Additionally, the study will allow for the evaluation for current trends of adjuvant options (namely surveillance vs active treatment). Methods: S3MI-PT, or Seminoma 3 cm cut-off Prospective Trial, is a multicenter prospective observational validation study that aims to include at least 300 patients (the estimate includes a 10% loss to follow-up rate as TGCT studies are historically difficult to accrue). Eligibility criteria: male patients ≥ 18 years old diagnosed with clinical stage I pure Seminoma histology (pT1N0M0S0), whose orchiectomy must have occurred after January 2018, the AJCC 8th ed. implementation date, who are willing to sign the informed consent. Demographic and clinical data will be collected, that includes, age at diagnosis, tumor size, rete testis invasion, values for TGCT markers, adjuvant treatment options (surveillance or active treatment) and relapse, if applicable. Exclusion criteria: non-pure Seminoma TGCT staged pT2-T4, pN1-N3, M1, S1-3. Primary endpoint is relapse-free survival at 3 years in pT1a versus pT1b, with two-sided P < 0.05 used to determine statistical significance with a 95% CI, by Kaplan-Meier method. S3MI-PT has been approved by the Ethics Committee. The study is actively enrolling, and all individuals and institutions interested in collaborating can do so by request.
A phase II study of risk-based stratification after chemotherapy combined with PD-1 antibody: Two various bladder-sparing modalities for muscle invasive bladder cancer therapy (ReBirth).
Authors: Shen Yijun , Lu Xiaolin , Ma Xuejun , Liu Wei , Ye Dingwei 
Published: March 2023

TPS580 Background: Neoadjuvant chemotherapy plus radical cystectomy is the standard for cisplatin-eligible patients with cT2-4aN0M0 muscle invasive bladder cancer, however, some of them desperately need innate bladder. Developments in the last two decades suggest that well-documented Trimodal therapy(TMT) demonstrated durable oncologic control and long-term survival in selected patients. Nevertheless, personalized treatment based on responses of systematic treatment and biomarker are currently lacking. Additionally, concerning a balance between non-inferiority of hypofractionated radiation therapy in local control and late toxicity, the specified dose regimen combined with immunotherapy is worth exploring. "ReBirth" study was designed to evaluate the efficacy and tolerability of two various bladder-sparing modalities with risk-based stratification after chemotherapy combined with PD-1 antibody. Methods: This is a single-arm, phase II trial that includes cT2-4aN0-1M0 patients who aged 18-85 years and histologically confirmed bladder urothelial carcinoma. Other key inclusion criteria: no prior anti PD-(L)1 therapy; ECOG 0-2 and cisplatin eligible. The trial consists of two stages. In the first stage, eligible patients will receive tislelizumab 200 mg in day 1 (D1), cisplatin 70 mg/m2 D1, and gemcitabine 1000 mg/m2 D1 and D8 every 21 days for four cycles. Patients will then be divided into two cohorts in the second stage based on the cystoscopy, urine cytology, and imaging combined with utDNA (urine tumor DNA). Patients who achieve clinical complete response (cT0, cTa) will enter into cohort 1 and treated with tislelizumab 200 mg IV Q3 for up to 6 months, while patients who did not achieve clinical complete response will enter into cohort 2 and treated with tislelizumab 200 mg IV Q3W for up to 6 months and chemoradiotherapy for whole bladder 44Gy/16 fractionation, if lymph node is positive, it can be dosed to the maximum tolerable dose, such as tumor boost 11Gy/4fractionation, combined with DDP as radiosensitizer. The primary endpoint is BIDFS (bladder intact disease-free survival) at one year, which is defined as time from initiation of protocol therapy until the development of muscle-invasive bladder cancer recurrence, regional pelvic recurrence, distant metastases, bladder cancer-related death, or cystectomy. Secondary endpoints include metastatic free survival rate at two years, BIDFS at two years and safety graded according to CTCAE V5.0. Tissue samples will be collected for genomic profiling and utDNA will be collected and examined for biomarker exploring in this bladder preservation therapy. Till Sep.2022, 5 of planned 30 patients have been enrolled. Clinical trial information: NCT05531123 .
Phase 3 KEYNOTE-905/EV-303: Perioperative pembrolizumab (pembro) or pembro + enfortumab vedotin (EV) for muscle-invasive bladder cancer (MIBC).
Authors: Necchi Andrea , Bedke Jens , Galsky Matt D. , Shore Neal D. , Plimack Elizabeth R. , Xylinas Evanguelos , Jia Calvin , Hennika Tammy , Homet Moreno Blanca , Witjes Alfred Alfred 
Published: March 2023

TPS585 Background: Standard of care for MIBC is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy + pelvic lymph node dissection (RC + PLND). However, a substantial proportion of patients (pts) with MIBC are ineligible to receive cisplatin-based chemotherapy. In the phase 1b/2 KEYNOTE-869/EV-103 study, promising antitumor activity was shown in cisplatin-ineligible pts with metastatic urothelial carcinoma treated with the PD-1 inhibitor pembro combined with the nectin-4–directed antibody-drug conjugate EV. This multicenter, open-label, randomized, phase 3 KEYNOTE-905/EV-303 study (NCT03924895) is designed to evaluate the efficacy and safety of perioperative pembro alone or in combination with EV compared with RC + PLND alone in pts with MIBC who are ineligible for or decline cisplatin-based treatment. Methods: Approximately 857 adults who are cisplatin ineligible or decline cisplatin-based treatment with treatment-naive MIBC (T2-T4aN0M0 or T1-T4aN1M0), have an Eastern Cooperative Oncology Group performance status score of 0-2, and have a predominant (≥50%) urothelial histology will be randomly assigned to arm A (neoadjuvant pembro 200 mg intravenously [IV] every 3 weeks [Q3W] up to 3 cycles followed by RC + PLND and adjuvant pembro 200 mg IV Q3W up to 14 cycles), arm B (RC + PLND followed by observation), or arm C (neoadjuvant EV 1.25 mg/kg + pembro 200 mg IV Q3W up to 3 cycles followed by RC + PLND and adjuvant EV + pembro up to 6 cycles and adjuvant pembro 200 mg IV Q3W up to 8 cycles). In both the neoadjuvant and adjuvant phases of arm C, pembro will be administered on day 1 and EV will be administered on days 1 and 8 of each cycle. Dual primary end points are pathologic complete response as assessed by central pathologic review and event-free survival. Secondary end points include overall survival, disease-free survival, pathologic downstaging rates, and safety and tolerability. Enrollment is ongoing in Africa, Asia, Europe, and North America. Clinical trial information: NCT03924895 .
First in human (FIH) phase 1/1b study evaluating KIN-3248, a next-generation, irreversible pan-FGFR inhibitor (FGFRi), in patients (pts) with advanced urothelial carcinoma (UC) and other solid tumors harboring FGFR2 and/or FGFR3 gene alterations.
Authors: Garmezy Benjamin , Perez Cesar Augusto , Kato Shumei , Sharma Manish , Quah Cheng Seok , Tam Betty , Severson Paul 
Published: March 2023

TPS593 Background: FGFR1-4 gene alterations are infrequent across solid tumors though preclinical and clinical evidence indicate activating alterations drive oncogenesis and tumor growth. They can be found in up to 20% of patients with UC and up to 35% of upper tract UC. Reversible FGFRi are approved for the treatment of pts with locally advanced or metastatic urothelial carcinoma (UC) with susceptible FGFR2 or FGFR3 genetic alterations (erdafitinib) or metastatic CCA harboring FGFR2 gene fusions or rearrangements (pemigatinib and infigratinib). A critical limitation of current clinical-stage FGFRi is the emergence of secondary, on-target resistance mutations (mutn) that reduce duration of response, and indeed, about 70% of CCA patients pre-treated with FGFRi exhibit secondary FGFR2 kinase domain resistance mutn at the time of relapse. KIN-3248 is a next-generation, selective, irreversible, small molecule pan-FGFRi, structurally designed to inhibit primary FGFR oncogenic alterations as well as secondary kinase domain mutn associated with disease progression. Preclinically, KIN-3248 has favorable pharmaceutical properties, is well-tolerated with continuous, daily oral administration in GLP toxicology studies and is efficacious against primary FGFR2 and FGFR3 oncogenic driver alterations as well as secondary FGFR2 resistance mutn (e.g., gatekeeper and molecular brake) in human cancer cell and PDX models. Methods: This is a FIH, multicenter, non-randomized Ph1 study of KIN-3248 in adult pts with advanced and metastatic solid tumors (AMST) harboring FGFR2 and/or FGFR3 gene alterations. KIN-3248 is given PO QD continuously in 28-day cycles until drug intolerance or disease progression. Part A is a dose-escalation assessing single agent KIN-3248 via a BOIN design to determine the MTD/RP2D. Part B will evaluate a selected dose of KIN-3248 in 3 cohorts of pts (UC, CCA, or other AMST), each driven by specified FGFR alterations—FGFRi-naïve and -pretreated pts are eligible in both parts. Enrollment criteria include ECOG PS 0-1, intact organ function, prior receipt of standard treatment or medical judgment that such is not appropriate. Pts may have measurable or evaluable disease. Key exclusion criteria include known active brain metastases and active/uncontrolled HBV/HCV. Planned sample size is ~120 pts. Primary endpoints are safety/tolerability (Part A), and preliminary antitumor activity: objective response rate, disease control rate, duration of response, & duration of stable disease (Part B). Secondary objectives include pharmacokinetic and pharmacodynamic assessments including measures of FGFR pathway modulation. The study is actively enrolling patients in the US and globally. Clinical trial information: NCT05242822 .
Neutralizing GDF-15 in muscle-invasive bladder cancer (MIBC): A neoadjuvant immunotherapy trial of visugromab (CTL-002) in combination with the anti-PD1 antibody nivolumab (NEO-GDFATHER).
Authors: Necchi Andrea , Iacovelli Roberto , Di Maio Massimo , Gontero Paolo , Fettes Petra , Klar Kathrin , Hermann Frank , Leo Eugen 
Published: March 2023

TPS595 Background: Neoadjuvant chemotherapy (NACT) is a well-established treatment modality in MIBC but suffers from limited activity and significant toxicity. Recently, neoadjuvant immunotherapy (I/O) has demonstrated clinical safety and efficacy in various solid tumor indications including MIBC, with potentially less toxicity. Results from previous studies of single-agent I/O indicated a proportion of pathologic complete responses (ypT0N0) similar to that reported with NACT. Therefore, improving ypT0N0 responses remains a major task for successful treatment of MIBC in the future. Increasing evidence has emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical local immunosuppressive. Apart from blocking immune-cell entry into tissues GDF-15 also has major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block I/O therapy success. Various translational research efforts have indicated that GDF-15 may play a significant role for immunosuppression and T-cell exclusion in urothelial carcinoma (UC). Visugromab (CTL-002) is a GDF-15 neutralizing IgG4 monoclonal antibody that has demonstrated in Phase 1 a favorable safety profile and promising clinical activity with durable and deep responses in PD-1/PD-L1 relapsed/refractory metastatic solid tumors in combination with the anti-PD1 antibody Nivolumab (Nivo)*. This clinical trial is intended to investigate the combination of Visugromab with Nivo vs. Nivo monotherapy as neoadjuvant therapy for MIBC in patients (pts) who are ineligible for or elect not to undergo NACT. Primary endpoints are the complete pathologic response rate and radiologic response. Methods: This is a multi-center, parallel-cohorts and single-blinded Phase 2 study of neoadjuvant therapy in pts planned for radical cystectomy (RC). A total number of 30 subjects with stage T2-T4N0M0 MIBC will be enrolled and assigned 1:1 to receive either Nivo + Visugromab or Nivo + Placebo after stratification for CPS PD-L1 expression and cT-stage. No statistical assumptions have been undertaken at this stage. Treatment consists of three 4-week cycles [i.v., Q4Wk], and RC is planned 4-8 weeks after last dose of study drug. After RC, pts will follow standard recommendations according to EAU guidelines. Primary endpoints are the proportion of ypT0N0 response and radiologic response rate. Secondary endpoints comprise additional efficacy parameter, surgical and medical safety, PK and PD assessments. Translational research includes evaluation of immunologic parameters in the tumor, other immune-correlates and molecular profiles, as well as evaluation of treatment-emergent cytokine and chemokine profiles in peripheral blood. * Melero et al., Annals of Oncology (2022) 33 (suppl_7): S331-S355.
A phase 1, open-label trial to evaluate feasibility and safety of intramural injection of belzupacap sarotalocan (AU-011) in non-muscle–invasive bladder cancer (NMIBC).
Authors: Lerner Seth P. , Bivalacqua Trinity , Kim Isaac Yi , Murray Carrie , Rich Cadmus Collins , Agarwal Piyush K. , Shore Neal D. 
Published: March 2023

TPS596 Background: A high unmet medical need exists for new therapies in NMIBC to reduce common risks of recurrence, progression and, ultimately, cystectomy. Belzupacap sarotalocan, a novel investigational virus-like drug conjugate (VDC), has a dual mechanism of action designed to provide 1) selective binding to malignant cells, causing acute necrosis upon light activation, and 2) long-term anti-tumor immunity as demonstrated in pre-clinical models. This Phase 1 trial is designed to evaluate the feasibility and safety of intramural injection with or without intratumoral injection of belzupacap sarotalocan for treatment of NMIBC. The hypothesis is that after near infrared light activation, targeted distribution of belzupacap sarotalocan at high concentrations at the tumor base could necrose the tumor where it is most likely to be invasive. In turn, the tumor targeted pro-immunogenic cell death could potentially lead to an anti-tumor immune response preventing the risk for recurrence, progression and metastasis. Methods: This is an actively enrolling “window of opportunity” trial (NCT05483868) in low, medium or high risk NMIBC subjects scheduled to undergo TURBT or cystectomy per standard of care. A pre-treatment biopsy will be performed in up to 23 adult subjects enrolled in 4 cohorts, who will be given belzupacap sarotalocan +/- laser as shown in the table. The primary endpoint is incidence and severity of treatment-related adverse events, serious adverse events regardless of attribution, and incidence of dose-limiting toxicities. Each cohort will have a safety review for the injection procedure and laser (as needed), after 3 subjects have been treated and followed for 28 days. Secondary endpoints are based on histopathology and include assessment of local biodistribution of belzupacap sarotalocan measured via immunohistochemical staining, tumor necrosis, and evidence of an immune response via comparison of pre-treatment biopsy to TURBT/cystectomy samples after treatment. Statistical analysis plan includes descriptive statistics for the above endpoints. Clinical trial information: NCT05483868 . [Table: see text]