bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apalutamide and stereotactic body radiation therapy for low-burden, metastatic, hormone-sensitive prostate cancer: A randomized trial (PERSIAN).
Authors: Francolini Giulio , Porreca Angelo , Facchini Gaetano , Santini Daniele , Bruni Alessio , Simoni Nicola , Trovò Marco , Osti Mattia Falchetto , Fornarini Giuseppe , Sisani Michele , Di Cataldo Vanessa , Detti Beatrice , Garlatti Pietro , Bertini Niccolò , Burchini Luca , Frosini Giulio , Bonaparte Ilaria , Serni Sergio , Minervini Andrea , Livi Lorenzo 
Published: January 2024

TPS235 Background: TITAN trial showed that apalutamide + ADT improved OS in patients with metastatic hormone sensitive prostate cancer (mHSPC), both in low and high-volume disease. On the other hand, SABR-COMET trial suggested that stereotactic body radiotherapy (SBRT) improved outcomes in oligometastatic patients if compared to systemic therapy alone. Recently, one trial suggested that SBRT may offer significant benefit in terms of biochemical response and progression free survival within oligometastatic castrate resistant prostate cancer patients undergoing first line abiraterone acetate treatment (ARTO trial, NCT03449719). However, there are no data specifically assessing the benefit offered by SBRT in oligometastatic mHSPC treated with apalutamide. PERSIAN trial is aimed to test the hypothesis that metastases directed SBRT will improve outcomes in select subgroups of pts with oligometastatic mHSPC treated with apalutamide + ADT. Moreover, we implemented baseline blood sample tests at enrollment/randomization, to evaluate the status of PIK3CA/AKT1/PTEN and BRCA1/BRCA2 mutations, and to investigate the predictive value of these alterations on treatment response. Furthermore, oncometabolites expression will be evaluated through metabolomic analysis before and after start of SBRT. Methods: PERSIAN trial is a prospective phase II randomized superiority study. All patients are affected by metachronous oligometastatic HSPC defined as presence of < 5 non-visceral metastatic lesions. Patients with de novo metastatic disease are excluded from the trial. Patients will be randomized to receive standard systemic treatment alone with apalutamide + ADT (Arm A: Control) or the same systemic treatment combined with SBRT on all sites of metastatic spread (Arm B: Treatment). This trial design will allow us to evaluate the benefit of SBRT in a selected cohort of patients with identical systemic treatments. Primary endpoint of the trial is the rate of patients with complete biochemical response (PSA < 0.2 ng/ml) 6 months after apalutamide + ADT start. Assuming a rate of complete biochemical response of 61% in the control arm, a sample size of 180 patients will have 80% statistical power to detect an absolute benefit of 19% in the treatment group, with alpha 0.05. Secondary endpoints are: time to PSA progression, radiologic progression free survival, frequency of treatment severe adverse events, overall and cancer specific survival, quality of life (measured with EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires). Enrollment started in March 2023, 31 patients have been enrolled to date. Clinical trial information: NCT05717660 .
Cohort expansion from the phase 1 JEWEL-101 study investigating the tissue factor–targeting antibody-drug conjugate XB002 in patients with advanced solid tumors: Metastatic castration-resistant prostate cancer cohort.
Authors: Ulahannan Susanna Varkey , Johnson Melissa Lynne , Weiss Mia C. , Vandross Andrae L. , Vidal-Cardenas Sofia Luz , Syed Mustafa , Tolcher Anthony W. 
Published: January 2024

TPS237 Background: There is a high unmet need for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) that has progressed on novel hormonal therapies (NHTs) due to acquired resistance to treatment. Tissue factor (TF) is a transmembrane protein that functions as a factor VIIa receptor and initiates the extrinsic coagulation cascade. Its overexpression has been associated with disease progression and poor prognosis in multiple solid tumor types, including mCRPC. XB002 is a novel antibody-drug conjugate (ADC) composed of a high-affinity TF-directed human monoclonal antibody conjugated to zovodotin, an auristatin-based payload with a protease-cleavable linker. The zovodotin payload of XB002 is designed to have lower off-target payload deconjugation and improved tolerability compared with other auristatin-based ADCs. In preclinical studies, XB002 demonstrated antitumor activity and encouraging safety without affecting coagulation. JEWEL-101 (NCT04925284) is a phase 1, open-label, multicenter, first-in-human study evaluating XB002 alone and in combination regimens. The study consists of a dose-escalation stage to determine the recommended dose and/or maximum tolerated dose of XB002, and a tumor-specific cohort expansion stage to evaluate the safety and preliminary antitumor activity in pts with advanced solid tumors. Preliminary results from the dose-escalation stage showed XB002 was well tolerated at multiple dose levels, with low-grade ocular toxicity and no bleeding events or treatment-related peripheral neuropathy (PN).1 Presented here is the design of the expansion cohort in pts with mCRPC. Methods: Pts with mCRPC and primary histology of adenocarcinoma are eligible; neuroendocrine differentiation and other histological features are also permitted. Pts must have documented progressive disease after 1–3 prior systemic therapies, including at least 1 prior NHT for metastatic castration-sensitive or castration-resistant disease. Prior taxane-based chemotherapy is optional, and bone-only disease without soft-tissue tumor components is allowed. No prior treatment with TF-targeting or auristatin-based ADCs is allowed, and pts with significant ocular disorders are excluded. PN not impacting activities of daily living is acceptable, and concomitant use of anticoagulants is permitted. Pts in the mCRPC cohort will be treated with XB002 single agent. The primary outcome is objective response rate per investigator assessment. Secondary outcomes include safety, pharmacokinetics, immunogenicity, progression-free survival, duration of response, and overall survival. Enrollment is ongoing in the United States, Europe, and the Asia-Pacific region. 1. Ulahannan et al. ENA 2022. Clinical trial information: NCT04925284 .
ProstACT GLOBAL: A phase 3 study of best standard of care with and without 177Lu-DOTA-rosopatamab (TLX591) for patients with PSMA expressing metastatic castration-resistant prostate cancer progressing despite prior treatment with a novel androgen axis drug.
Authors: Hawkins Charlotte , Lenzo Nat , Gibson Julie , Brown Tracey , Patel Neel , Martina Stefanie , Hayward Colin 
Published: January 2024

TPS256 Background: The treatment of advanced prostate cancer (PC) is challenging, with undesirable side effects that impact patient quality of life. Radioimmunotherapy (RIT) can localize therapy to specific tumor cells in multiple organs to reduce or eliminate damage to normal tissue. The cell surface glycoprotein prostate-specific membrane antigen (PSMA) is an ideal therapeutic target as it is highly expressed by malignant prostate cells. There is a strong rationale for further investigation of the 177Lu-labeled, chelator-conjugated antibody, 177Lu-DOTA-rosopatamab, as a potential RIT candidate for the treatment of PC. Methods: In this multinational, multicenter, prospective, randomized, open label phase 3 study (NCT04876651), 387 patients with PSMA-expressing metastatic castration-resistant PC (mCRPC) that have progressed despite prior treatment with a novel androgen axis drug will be enrolled in a 2:1 ratio to receive either the best standard of care (SoC) or 2 single intravenous (IV) injections of 76 milicuries (mCi) each (equivalent to a 45 mCi/m2 dose in a standard 1.7m2 individual) of 177Lu-DOTA- rosopatamab, given 14 days apart, plus best SoC. Eligible patients must have received prior therapy with either enzalutamide or abiraterone plus prednisone, and 1 line of prior taxane therapy or have refused or are ineligible for taxanes. Patients must have adequate organ function including at least 150x109 /L platelets, hemoglobin 10 g/dL, and have PSMA-positive disease on 68Ga-PSMA-11 PET/CT imaging as confirmed by a central reader. Key exclusion criteria include small cell histology, increased risk of hemorrhage or bleeding, known brain or hepatic metastases, or history of stroke, seizure, or treatment with radioisotopes within 6 months prior to randomization. The primary endpoint is radiographic progression-free survival. Secondary endpoints include 5-year overall survival, tumor objective response rate, time to symptomatic skeletal event, progression free survival, and number of participants with treatment-related adverse events. Clinical trial information: NCT04876651 .
Borxpten: A phase II study of bortezomib (B) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with PTEN deletion.
Authors: Mathew Thomas Vinay , Moynier Colin , Boucher Kenneth M. , Nordblad Blake , Clement Susan , Esplin Michelle , Kohli Manish , Gupta Sumati , Maughan Benjamin L. , Agarwal Neeraj , Swami Umang 
Published: January 2024

TPS258 Background: Despite recent therapeutic advancements, there is an unmet need for effective treatment options in mCRPC. The tumor suppressor gene PTEN maps to chromosome region 10q23 and is deleted in 30% of primary and 60% of castration-resistant prostate cancer. Approximately 40 kb upstream of PTEN is ATAD1, which encodes an ATPase involved in mitochondrial protein homeostasis on the outer mitochondrial membrane. ATAD1 is frequently co-deleted with PTEN, with the highest occurrence in prostate cancer (25%). Winter et al. demonstrated that cells harboring a Chr10q23 deletion highly depend on the ubiquitin-proteasome system and were exquisitely sensitive to the proteasome inhibitor, B (PMID: 36409067). Treatment of pts with mCRPC enriched for PTEN and ATAD1 co-deleted tumors with B could lead to an effective treatment approach in mCRPC. Herein we evaluate the efficacy of B in pts with mCRPC with PTEN deletion. Methods: This investigator-initiated, phase II, single-arm, single-center study will enroll 22 pts. Treatment: B will be administered at 1.3 mg/m2 of the body-surface area subcutaneously on days 1, 4, 8, and 11 in a 21-day cycle. Key inclusion criteria: ≥18 years of age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, PTEN deletion on next generation sequencing, prior treatment with one androgen receptor pathway inhibitor (ARPI), no other treatment for mCRPC (except ARPI if not used in castration sensitive stage), ECOG performance status ≤ 2, adequate organ function. Key exclusion criteria: grade ≥ 2 neuropathy, untreated brain metastases or any spinal cord compression. Primary objective: To evaluate the antitumor activity of B in pts with mCRPC with PTEN deletion as assessed by PSA 30% response rate. Simon’s two-stage design will be used. The null hypothesis is that the true response rate is 20% which will be tested against a one-sided alternative. In the first stage, 10 pts will be accrued. If there are ≤2 responses, the study will be stopped. Otherwise, 12 additional pts will be accrued for a total of 22 pts. The null hypothesis will be rejected if ≥8 responses are observed in 22 pts. This design yields a type I error rate of 0.0492 and a power of 0.8065 when the true response rate is 45%. Secondary Objectives: 1) To assess the antitumor activity of bortezomib in pts with mCRPC with PTEN deletion as assessed by PSA 50% response rate, duration of PSA response, PSA progression free survival (PFS), objective response rate, duration of response, radiographic PFS, PFS, and OS 2.) To assess the safety and tolerability of B in pts with mCRPC with PTEN deletion. Exploratory analysis: Concurrent PTEN and ATAD1 loss will be correlated with treatment responses with B. Clinical trial information: NCT06029998 .
Role of 18F-flotufolastat PET/CT imaging in men with high-risk prostate cancer following conventional imaging and associated changes in medical management: A phase 3b investigator-initiated trial.
Authors: Taylor Zachariah , Zeltser Ilia , Stollman Nachum , Belkoff Laurence 
Published: January 2024

TPS347 Background: 18F-Flotufolastat (18F-rhPSMA-7.3) is a prostate-specific membrane antigen (PSMA) ligand for the detection of prostate cancer (PCa). It targets the extracellular epitope of the PSMA molecule and is administered as a single intravenous (IV) bolus microdose. The molecular structure comprises a PSMA binding motif, a peptide spacer, an 18F-radiolabeled silicon fluoride acceptor moiety, and a gallium chelator complex. Recent studies have demonstrated the utilization of 18F-flotufolastat in newly diagnosed PCa is beneficial with high specificity for detecting N1 and M1 disease prior to surgery. While the evidence for utilizing PSMA imaging for staging of newly diagnosed PCa is growing, the impact on clinical management is yet to be examined. Here, we evaluate the sensitivity and specificity of 18F-flotufolastat for detection of N1 and M1 disease, with subsequent evaluation of management changes for patients with extraprostatic disease. Methods: This is a multicenter, prospective, randomized study comparing 18F-flotufolastat PET/CT to conventional imaging for staging men with high-risk PCa and the subsequent change in medical management of these men. High-risk patients are defined as grade group ≥3 (primary Gleason grade 4, or any Gleason grade 5), PSA ≥20, or clinical stage ≥T3. Inclusion criteria include males >18y with untreated biopsy-proven PCa with high-risk features as detailed above, and informed consent. Exclusion criteria are as follows: any prior therapy for PCa, previous imaging for staging of PCa, history of other malignancy, and significant comorbidity. All men will undergo conventional imaging techniques to complete staging. Physicians will then record the patients’ treatment plan (surgery, radiation including planned radiation fields, hormonal therapy, or other). The patients will then undergo PET/CT with a single bolus of 296MBq 18F-flotufolastat IV. Results will be reported to the responsible physician who will provide a final management plan. If treatment is planned post-18F-flotufolastat, the patient will receive treatment as follows: Standard of care surgical treatment of PCa, including PLND; or if the 18F-flotufolastat PET detects M1 lesion(s), a biopsy/surgery and/or additional imaging to confirm M1 lesion(s) will be required prior to treatment. The co-primary objectives of this study are the percentage of men with high-risk PCa upstaged to N1 or M1 disease, and the subsequent change in management. Clinical trial information: NCT05799248 .
Daro-PET: A phase 2 trial of darolutamide as a prostate-specific membrane antigen (PSMA) expression enhancer in patients with localized prostate cancer.
Authors: Mota Jose Mauricio , Mosci Camila , Vasconcellos Jéssica , Hemerly Thiago Souto , Silva Neto Deusdedit Cortêz Vieira , Brandao Luis Felipe , Srougi Victor , Ramos Rodrigo Nalio , Cunha Isabela Werneck 
Published: January 2024

TPS348 Background: Prostate specific membrane antigen (PSMA) has been explored as a target in imaging studies using positron emission tomography (PSMA-PET) to unveil occult prostate cancer metastasis, and as a target for radioligand therapy. Preclinical and retrospective clinical studies suggest that PSMA expression can be rapidly increased by androgen suppression, which might impact the accuracy of disease detection using PSMA-PET scans and radioligand treatment efficacy. Methods: Daro-PET (NCT05900973) is a single-arm phase 2 study to evaluate the efficacy of a limited course of darolutamide as a PSMA expression enhancer in men planned for radical prostatectomy due to high-risk localized prostate cancer as per conventional imaging. PSMA PET/CT scans will be acquired before (PSMA-PET 1) and after (PSMA-PET 2) a 7-day treatment with darolutamide 600 mg PO q12 h. The primary endpoint is the proportion of patients achieving an increase in SUVmax of 20% or greater from PSMA-PET 1 to PSMA-PET 2. Key secondary endpoints include other PSMA PET parameters (e.g. SUVmean, Total lesion PSMA), proportion of planned management changes, detection of pelvic or extrapelvic metastatic disease, and safety. Correlative exploratory studies will include PSMA expression by immunohistochemistry, gene expression, and methylation patterns between tissue samples from prostate biopsy and prostatectomy. The trial will enroll up to 16 patients using a Simon’s two-stage design, with a power of 0.80 and a one-sided alpha error of 0.05. As of September 20th, 1 patient was included in the study. Clinical trial information: NCT05900973 .
Efficacy of perioperative pembrolizumab treatment in patients with resectable metastases from kidney cancer: The PE-PE study.
Authors: Iacovelli Roberto , Fantinel Emanuela , Bimbatti Davide , Buti Sebastiano , Bonomi Lucia , Rizzo Mimma , Accettura Caterina , Buttigliero Consuelo , Massari Francesco , Santoni Matteo , Zucali Paolo Andrea , Zanardi Elisa , Mosca Alessandra , Primi Francesca , Spina Francesco , Procopio Giuseppe , Bracarda Sergio , Calabrò Fabio , Antonuzzo Lorenzo , Ciccarese Chiara 
Published: January 2024

TPS495 Background: Radical metastasectomy and other local treatment strategies (including definitive radiotherapy, RT) can be carried out instead of systemic therapies for selected metastatic renal cell carcinoma (mRCC) patients (pts) with the aim of healing the patient even in an advanced disease stage. Recent data suggests a potential benefit from perioperative immunotherapy with immune checkpoint inhibitors (ICIs), as shown by the significant efficacy of adjuvant pembrolizumab in the M1 NED subgroup of the KEYNOTE-564 trial. Moreover, important activity of a short course of pembrolizumab has been demonstrated also in oligometastatic mRCC pts in combination with stereotactic ablative RT in the RAPPORT study. To date, no randomized trial has evaluated the concomitant use of pembrolizumab with surgery or definitive RT in mRCC compared to local therapy alone, which is the aim of our study. Methods: PE-PE study (NCT05578664) is a randomized, open-label, multicenter, phase 2 study evaluating the efficacy of pembrolizumab in delaying tumor progression in pts with oligometastatic mRCC who are candidates for radical surgery and/or definitive RT of the metastases. Eligible pts should have undergone previous nephrectomy and have maximum three metastases considered eligible for radical metastasis directed therapy (MDT; either metastasectomy or RT) and new disease must have appeared within 5 years from prior nephrectomy or metastasectomy. Pts will be randomized 2:1 to receive pembrolizumab at flat dose of 400 mg every six weeks for a total of 9 cycles (one year of therapy) and MDT from day 21 to day 42 of the cycle 1 (ARM A); or MDT alone within 42 days from randomization (ARM B). The primary endpoint is to assess the relapse free survival (RFS) defined as the length of time from randomization to the appearance of radiological progression in pts who receive pembrolizumab compared to those who do not. Secondary endpoints include: distant RFS (defined as the time from randomization to the appearance of distant metastases other those treated with surgery or RT), overall survival, and safety. Exploratory biomarkers analysis will be performed. The trial is actively recruiting. Clinical trial information: NCT05578664 .
Guiding adjuvant instillation in intermediate-risk non-muscle invasive bladder cancer by drug screens in patient-derived organoids.
Authors: Egger Martin , De Menna Marta , Lyatoshinsky Pavel , Blarer Jennifer , Hösli Raphael , Abt Dominik , Seiler Roland 
Published: January 2024

TPS711 Background: Recurrence rates in intermediate risk non-muscle invasive bladder cancer (NMIBC) are high and therefore, clinical guidelines recommend adjuvant instillations. However, the exact regimen with an exact number of instillations and the chemotherapeutic agent to be used are not clearly defined. During the last years we have established a standardized pipeline to generate patient-derived organoids (PDO) from cold cup biopsies of NMIBC. We showed that the subsequent organoids maintain key features of the parental tumor and share the molecular landscape. Moreover, our pipeline allows to investigate drug response to different agents in a standardized manner. Methods: In this ongoing, open-label, single center phase II trial, we aim to use drug screens in PDO of patients with intermediate risk NMIBC to guide drug selection for intravesical instillation. Patients with diagnosis of intermediate-risk NMIBC are enrolled. PDO are generated from biopsies prior transurethral resection of the bladder tumor. On the generated PDO drug response is determined to four chemotherapeutic agents that have already been used for bladder instillations in the literature (Epirubicin, Mitomycin C, Gemcitabine and Docetaxel). The most effective drug is selected for adjuvant instillation into the bladder once weekly for 6 instillations. The follow-up thereafter is performed according to European guidelines. The primary endpoint of the study is to determine the proportion of patients for which a specific selection of chemotherapeutic agent for intravesical instillation can be determined by using drug screens in PDOs. Secondary endpoints are recurrence- and, progression free survival, quality of life and translational studies. The null hypothesis, that a drug prediction will only be possible in 65% of patients, will be tested against a one-sided alternative. Assuming that the real proportion is 85%, 31 participants should show a statistically significant result at 5% significance and 80% power (exact binomial test). Due to early termination of 10%, a total number of 34 patients will be included. We are successfully conducting a trial to implement drug screens in PDO into daily routine and to guide patient treatment. This is a novel concept to precise treatment selection in patients with intermediate-risk NMIBC. When the primary endpoint is met, a modification of the trial with larger sample size, novel compounds and a focus oncological outcomes is foreseen. Clinical trial information: NCT05024734 .
Chief Topinabee: Using Tribal Memories to Better Understand American (Indian) History—Nwi Yathmomen—We Will Tell Our Story
Authors: Low John 
Published: January 2024

Abstract
Chief Topinabee was born around 1758 in his father’s village on the Saint Joseph River, in what is now southwest Michigan. He probably died on 29 July 1826 near present-day Niles, Michigan. A complicated leader of his village, he may have fought at the Battle of Fallen Timbers in 1794, certainly was a signatory to the Treaty of Greenville the next year, appears to have become an ally of Tecumseh and his intertribal confederacy at Prophetstown, may have been a participant in the Battle of Fort Dearborn in 1812, and served as a leader of strategic resistance to settler domination. The usual narrative is that Topinabee was a great warrior and leader of his people who in the last years of his life degenerated into a hapless drunkard and accommodationist. But is that a fair depiction of him? This essay is a celebration of ethnohistory and the paths it has cleared for the use of nontraditional sources of information. The article is based largely on access to a family archive that provides a counternarrative to the usual biography of Topinabee and allows for a fuller understanding of him as a leader and a person.