bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prospective phase II trial of pembrolizumab plus lenvatinib in advanced adrenal cortical carcinoma after failure of platinum- and mitotane-based chemotherapy (ACCOMPLISH).
Authors: Park Inkeun , Kwon Minsuk , Park Kwonoh , Park Se Hoon , Park Joo-Hwan , Shin Sang Joon , Shim Hyun-Jeong , Yun Tak , Lee Jae-Lyun , Lee Hyo Jin , Choi Wonyoung 
Published: March 2023

TPS3 Background: Adrenal cortical carcinoma (ACC) is a very rare cancer with poor prognosis. For advanced ACC, systemic treatment options are limited. There has been only one randomized phase III clinical trial in which etoposide, doxorubicin, cisplatin, and mitotane (EDP-M) achieved statistically significant improvement in terms of objective response rate (ORR) and progression-free survival (PFS). However, after failure of EDP-M regimen, no universally accepted treatment option exists. In human ACC sample, vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) expression were higher than adrenal adenoma, and 10-20% of tumor cells and 70% of tumor infiltrating monocyte are PD-L1 positive. In retrospective review of cabozantinib in advanced ACC, cabozantinib demonstrated 19% of ORR and 16.2 weeks of median PFS. Also, in phase II clinical trial of pembrolizumab in advanced ACC, ORR of 14-23% were shown. Considering synergism of VEGFR tyrosine kinase inhibitors (TKIs) and immune check point inhibitors (ICIs) in other cancers, combination of VEGFR TKI and ICI is an attractive approach in advanced ACC. Methods: This is an open-label,single-arm,multi-center,investigator-initiated phase II trial of lenvatinib plus pembrolizumab in patients with advanced ACC who failed previous platinum and mitotane therapy (NCT 05036434). Using Simon’s optimal two-stage design, 10 patients will be enrolled initially in the first stage. If at least 2 or more patients achieve complete response or partial response, the trial will continue until enrollment of a total of 30 patients. Patients will receive 200 mg of pembrolizumab every 3 weeks intravenously and 20 mg of daily lenvatinib orally until disease progression, intolerable toxicity, or patients’ withdrawal of consent. Key eligibility criteria are age ≥ 19 years, ECOG PS 0-1, biopsy-proven ACC, disease progression despite cisplatin- and mitotane-based chemotherapy, measurable disease according to RECIST v1.1, no uncontrolled hypertension, adequate kidney, liver, and bone marrow function. Primary endpoint is ORR, and secondary endpoints include PFS, safety profile, overall survival, duration of response. Exploratory evaluation of tumor genomics and immune microenvironment by whole exome sequencing, single-cell RNA sequencing, and T cell receptor sequencing in correlation with response will be performed. Enrollment began in June 2022 and projected enrollment goal is 3 years. Clinical trial information: NCT05036434 .
P3BEP (ANZUP 1302): An international randomized phase 3 trial of accelerated versus standard BEP chemotherapy for male and female adults and children with intermediate- and poor-risk metastatic germ cell tumours (GCTs).
Authors: Zebic Danka , Stockler Martin R. , Martin Andrew James , Pashankar Farzana D. , Tran Ben , Mazhar Danish , Huddart Robert A , Wheater Matthew , Walpole Euan Thomas , Dunwoodie Elaine , Feldman Darren R. , Birtle Alison Jane , Stevanovic Amanda Gwendolyn , Wyld David , Hanning Fritha J. , Grimison Peter S. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: March 2023

TPS431 Background: Bleomycin, etoposide, and cisplatin (BEP) given 3-weekly x 4 remains standard 1st line chemotherapy for intermediate or poor risk metastatic GCT. Accelerating standard regimens by shortening the cycle length to 2-weekly improved cure rates in other cancers. P3BEP will determine effects of accelerated versus standard BEP in this setting. This is a first international, randomized trial of chemotherapy for intermediate and poor-risk metastatic GCT to include adults and children of both sexes. Methods: This open label, randomized, phase 3 trial is conducted seamlessly in 2-stages. The primary endpoint for stage I (n=150) was complete response (CR); and for stage 2 (n=500) is progression free survival at 2 years (PFS2y). These sample sizes provide >80% power with a two-sided type I error rate of 5% to detect an absolute improvement of 25% in the CR rate (stage 1) and of 7% in the PFS2y (stage 2). The target population is males and females aged 11 to 45 with intermediate-or poor-risk metastatic GCT of the testis, ovary, retroperitoneum, or mediastinum. Participants are randomized (1:1) to 4 cycles of standard BEP (q3w) or accelerated-BEP (q2w) with cisplatin 20mg/m2 D1-5, etoposide 100mg/m2 D1-5, bleomycin 30 KIU weekly x 12, and pegylated G-CSF D6 or filgrastim daily. Study assessments occur at 30 days after completing chemotherapy, 6 months from randomization, and after completion of all post-chemotherapy treatments (e.g. surgery). Tumour and baseline blood samples are collected for translational substudies. Progress: As of Sept 2022, 226 participants have been recruited from 24 ANZ sites, 17 UK sites (led by Cambridge Clinical Trials Unit), and 149 USA sites (led by Children’s Oncology Group). The first planned interim analysis for safety (n=76) identified no safety concerns. Stage I analysis (n=150) showed sufficiently favorable results with no futility concerns, supporting ongoing trial recruitment. Clinical trial information: NCT02582697 .
Trial in progress: PRESTIGE—Primary retroperitoneal lymph node dissection (RPLND) for clinical stage II (CSII) testicular germ cell tumour (TGCT) and its impact on health-related quality of life (HRQoL) compared to chemotherapy or radiotherapy.
Authors: Conduit Ciara , Lewin Jeremy Howard , Liow Elizabeth Chien Hern , Dhillon Haryana M. , Hong Wei , De Abreu Lourenço Richard , Lawrentschuk Nathan , Thomas Benjamin , Grimison Peter S. , Ahmadi Nariman , Sengupta Shomik , Tran Ben 
Published: March 2023

TPS433 Background: As cure rates for patients with advanced TGCT improve, there is increasing focus on quality of survival. Increasingly, primary RPLND is being used as an alternative to chemotherapy (and radiotherapy) as primary treatment for selected individuals, due to the development of low morbidity surgical techniques (robot-assisted and extraperitoneal approaches), and recognition of acute and long-term toxicity of chemotherapy and radiotherapy. We hypothesise that primary RPLND compared to chemotherapy and radiotherapy will have less detrimental impact on HRQoL with comparable oncological outcomes. Methods: PRESTIGE is a prospective cohort study among adults with histologically confirmed advanced TGCT planned for primary RPLND, chemotherapy or radiotherapy. Eligible patients may have de novo advanced disease, or relapse within two- (NSGCT) or three-years (seminoma) following orchidectomy, without prior chemotherapy or radiotherapy (including adjuvant), and able to complete HRQoL questionnaires in English. See table for cohort-specific eligibility. Surgical approach (modality, template, adjuvant chemotherapy), chemotherapy regimen and radiotherapy dose will be administered at physician discretion and captured in Australia’s national multi-centre TGCT registry, iTestis, with clinical data in follow-up. Participants will complete HRQoL questionnaires focusing on physical, social, emotional, and functional domains commencing prior to treatment and continuing for 24 months. Questionnaires include EORTC QLQ-C30, EORTC QLQ-TC26, Brief Male Sexual Function Inventory and specific questions focusing on retrograde ejaculation and fertility. Patients undergoing RPLND will also have miR-371 evaluation pre-operatively and serially for 12 months after surgery. The primary outcome is change in EORTC QLQ-C30 global health status over 24 months for participants undergoing primary RPLND. Key secondary outcomes are changes in HRQoL, patterns of recurrence, surgical complications, retrograde ejaculation, and infertility. A sample size of 90 participants (30 for RPLND, 60 for chemotherapy) provides >80% power to detect a mean difference of 28% in global health status at 0.05 significance favouring RPLND. Up to 30 individuals receiving radiotherapy may also be enrolled. The first site was activated 4-Aug-22; 2 of 3 study sites are active and 5 out of a planned 120 (4%) participants have enrolled. [Table: see text]
Phase 2 clinical study evaluating the efficacy and safety of disitamab vedotin with or without pembrolizumab in patients with HER2-expressing urothelial carcinoma (RC48G001).
Authors: Powles Thomas , Yu Evan Y. , Iyer Gopa , Campbell Matthew T , Loriot Yohann , De Santis Maria , O'Donnell Peter H. , Burgess Earle F , Necchi Andrea , Krieger Laurence E. M. , Matsubara Nobuaki , Koshkin Vadim S , Zhang Wei , Ichimaru Mari , Galsky Matt D. 
Published: March 2023

TPS594 Background: Urothelial carcinoma (UC) is the 10th most diagnosed cancer worldwide, and nearly 50% of patients cannot tolerate the current first-line (1L) standard of care. There is a need to improve outcomes in 1L and later lines of therapy. HER2 is overexpressed in UC and may be associated with poor outcomes. Despite this, no HER2-directed therapies are currently approved for UC. Disitamab vedotin (DV; RC48-ADC) is an investigational antibody-drug conjugate comprising a novel HER2-directed monoclonal antibody, disitamab, conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. DV elicits antitumor activity through multimodal mechanisms of action including MMAE-mediated direct cytotoxicity, bystander effect, and immunogenic cell death. Methods: RC48G001 (NCT04879329) is a phase 2, multi-cohort, open-label, multicenter trial to evaluate DV in patients with HER2-expressing locally advanced/metastatic UC (LA/mUC). Patients are enrolled in 3 cohorts based on prior treatment and tumor HER2 expression by immunohistochemistry (IHC) and gene amplification (via in situ hybridization [ISH]), assessed centrally. Cohorts A and B are enrolling patients who have received prior systemic therapy (1 or 2 lines, including platinum-containing chemotherapy) and whose tumors are HER2-positive (IHC 3+, or 2+ and ISH-positive) or HER2-low (IHC 2+ and ISH-negative, or IHC 1+), respectively. Cohort C is enrolling 1L treatment-naive patients in the LA/mUC setting, whose tumors have HER2-positive or HER2-low expression. Cohorts A and B will evaluate DV as monotherapy (intravenous [IV] administration, once every 2 weeks [Q2W]). Cohort C will evaluate DV (IV, Q2W) +/– pembrolizumab (IV, Day 1 of each 6-week cycle). Patients in all cohorts must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group Performance Status of 0–1 in Cohorts A and B, and 0–2 in Cohort C. The primary endpoint is confirmed objective response rate (cORR) per blinded independent central review (BICR). Secondary endpoints include cORR by investigator assessment, overall survival, duration of response, progression-free survival, disease control rate per RECIST v1.1 by BICR and investigator, safety, and pharmacokinetic parameters. Enrollment for all cohorts is ongoing in North America and Europe, and planned in Latin America, Asia-Pacific, and Israel. Clinical trial information: NCT04879329 .
Optimal treatment by invoking biologic clusters in renal cell carcinoma (OPTIC RCC).
Authors: Chen Yu-Wei , Beckermann Katy , Haake Scott Mattox , Reddy Anupama , Shyr Yu , Atkins Michael B. , Mar Nataliya , Ornstein Moshe Chaim , Pal Sumanta Monty , Zhang Tian , Rathmell Wendy Kimryn , Rini Brian I. 
Published: March 2023

TPS742 Background: The first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC) includes an immuno-oncology (IO) based combination. The current standard regimens include a PD-1 inhibitor plus either (1) an anti-CTLA-4 inhibitor (IO/IO), or (2) an anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) (IO/TKI). Currently, there is no level 1 evidence to guide physician’s choice between an IO/IO versus IO/TKI combination. The phase III IMmotion 151 trial performed RNA-seq from 823 ccRCC tumors and established seven biologically distinct gene expression clusters of ccRCC (Motzer and Rini et al., Cancer Cell 2020). The seven clusters showed differential responses to immune checkpoint inhibitor and may serve as a predictive biomarker to select frontline treatment. Methods: This trial is a phase II, multicenter study using the established biologic clusters to assign patients with mccRCC to either an IO/IO (ipilimumab/nivolumab) or an IO/TKI (nivolumab/cabozantinib) regimen. Patients diagnosed with mccRCC without prior systemic therapy (including in the neoadjuvant or adjuvant setting) and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. RNA-seq will be performed on metastatic tumor specimens and used to assign tumor clusters. Patients with cluster 1/2 tumors will be assigned to the nivolumab/cabozantinib arm; patients with cluster 4/5 tumors will be assigned to the ipilimumab/nivolumab arm. Cluster 3/6/7 will be excluded. The primary endpoint is overall response rate (ORR) per RECIST 1.1. The hypothesis is that use of tumor clusters to assign front-line therapy to either nivolumab/cabozantinib or ipilimumab/nivolumab will lead to a 20% greater ORR compared to unselected historical controls in CheckMate 9ER (ORR: 55%) or CheckMate 214 (ORR: 40%). This trial adopts Simon’s MiniMax two-stage design (power: 80%, one-sided α: 0.1). For the nivolumab/cabozantinib arm, stage I will enroll 12 eligible patients. If there are 7 or more responders in the first 12 patients, the trial will continue for stage II to enroll additional 14 patients (total n=26). The primary endpoint will be met if there are 18 or more responders (ORR ≥75%). For the ipilimumab/nivolumab arm, stage I will enroll 16 eligible patients. If there are 7 or more responders in the first 16 patients, the trial will continue for stage II to enroll additional 12 patients (total n=28). The primary endpoint will be met if there are 15 or more responders (ORR ≥60%). Key secondary endpoints include progression-free survival (PFS), depth of response>80%, and rate of immune-related adverse events (irAEs). This trial is funded by the Department of Defense Kidney Cancer Research Program Clinical Trial Award (W81XWH-22-1-1033) (NCT05361720). Clinical trial information: NCT05361720 .
A phase II study of nivolumab with ipilimumab and cabozantinib in patients with untreated renal cell carcinoma brain metastases.
Authors: Wang Jianbo , Campbell Matthew T , Shah Amishi Yogesh , Goswami Sangeeta , Msaouel Pavlos , Alhalabi Omar , Hahn Andrew Warren , Kovitz Craig A. , Jana Bagi RP , Araujo John C. , Gao Jianjun , Zurita Amado J. , Jonasch Eric , Corn Paul Gettys , Tannir Nizar M. 
Published: March 2023

TPS745 Background: A SEER analysis from 2010 to 2013 demonstrated that the incidence of brain metastases(mets) at the diagnosis of renal cell carcinoma(RCC) is 1.51%, and around 12% of patients(pts) with advanced RCC (aRCC) also had mets to the brain. Brain mets confer a poor prognosis. Local management strategies for brain mets from RCC include surgical resection, stereotactic radiosurgery and whole brain radiation therapy. Although systemic therapies including tyrosine kinase inhibitors and immune checkpoint inhibitors have been explored in aRCC pts with brain mets, prospective data is lacking. Cabozantinib is a potent small molecule inhibitor of multiple tyrosine kinases that was approved by FDA for pts with aRCC alone or in combination with nivolumab. Cabozantinib has demonstrated activity in patients with intracranial tumors. A phase III trial (COSMIC-313) recently evaluated cabozantinib in combination with nivolumab and ipilimumab compared to nivolumab plus ipilimumab and demonstrated significantly improved progression-free survival (PFS) in previously untreated pts with aRCC. The combination was found to be safe as frontline systemic treatment. The role of this combination in patients with aRCC with brain mets remains undefined. As such, we propose a study to assess the safety and efficacy of cabozantinib in combination with nivolumab/ipilimumab in RCC pts with untreated brain mets. We believe the results from this trial could provide additional treatment options for pts with RCC brain mets who are typically excluded from clinical trials. Methods: This is a phase II study to assess the safety and efficacy of the combination of nivolumab with ipilimumab and cabozantinib in pts with untreated brain mets from RCC until disease progression or intolerable toxicities or patient withdrawal. Planned accrual is 40 pts. Pts will be treated with nivolumab (3mg/kg) and ipilimumab (1mg/kg) IV every 3 weeks for 4 doses and cabozantinib 40mg daily. Then pts will be treated with nivolumab 480mg IV Q 4 weeks and cabozantinib 40mg daily until progression or intolerable toxicities or patient’s withdrawal. A lead-in group of 6 pts will be closely monitored for dose limiting toxicities(DLT). If stopping criteria (>3 patients develop DLTs) is met, then treatment will be switched to nivolumab plus cabozantinib omitting ipilimumab. The primary objective is intracranial progression free survival(PFS). Secondary objectives include intracranial safety, objective response rate (intracranial + extracranial) by modified RECIST v1.1 and RECIST v1.1, extracranial PFS and overall survival. This phase II trial is currently enrolling pts. Clinical trial information: NCT05048212 .
Mortality in Acromegaly Diagnosed in Older Individuals in Spain Is Higher in Women Compared to the General Spanish Population
Authors: Biagetti Betina , Iglesias Pedro , Villar-Taibo Rocío , Moure María-Dolores , Paja Miguel , Araujo-Castro Marta , Ares Jessica , Álvarez-Escola Cristina , Vicente Almudena , Guivernau Èlia Álvarez , Novoa-Testa Iria , Perez Fernando Guerrero , Cámara Rosa , Lecumberri Beatriz , Gómez Carlos García , Bernabéu Ignacio , Manjón Laura , Gaztambide Sonia , Cordido Fernando , Webb Susan M , Menéndez-Torre Edelmiro Luis , Díez Juan J , Simó Rafael , Puig-Domingo Manel 
Published: March 2023

Abstract

Context
There are no data on mortality of acromegaly diagnosed in older individuals.

Objective
This work aimed to compare clinical characteristics, growth hormone–related comorbidities, therapeutic approaches, and mortality rate of patients diagnosed before or after 2010 and to assess overall mortality rate compared with the general Spanish population.

Methods
A retrospective evaluation was conducted among Spanish tertiary care centers of 118 patients diagnosed with acromegaly at age 65 or older. Kaplan-Meier curves were constructed to trace survival, and Cox proportional hazard models were used to assess the risk factors associated with mortality. We also compared mortality with that of the Spanish population by using age- and sex-adjusted standardized mortality ratios (SMRs).

Results
No differences were found in first-line treatment or biochemical control, between both periods except for faster biochemical control after 2010. Twenty-nine (24.6%) patients died, without differences between groups, and had a median of follow-up 8.6 years (103, [72.3] months). Overall SMR was 1.02 (95% CI, 0.57-1.54), (0.60; 95% CI, 0.35-1.06) for men and (1.80; 95% CI, 1.07-2.94) for women. The most common cause of death was cardiovascular disease (CVD).

Conclusion
The mortality in patients with acromegaly diagnosed in older individuals was no different between both periods, and there was no overall SMR difference compared with the general Spanish population. However, the SMR was higher in women. As CVD is the leading cause of mortality, it seems advisable to initiate an intense CVD protective treatment as soon as acromegaly is diagnosed, particularly in women, in addition to tight acromegaly control to prevent excess mortality.
Efficacy and Safety of Low-dose Spironolactone for Chronic Kidney Disease in Type 2 Diabetes
Authors: Oiwa Ako , Hiwatashi Dai , Takeda Teiji , Miyamoto Takahide , Kawata Iori , Koinuma Masayoshi , Yamazaki Masanori , Komatsu Mitsuhisa 
Published: March 2023

Abstract

Context
Although adding spironolactone to renin-angiotensin system blockers reduces albuminuria in adults with chronic kidney disease and type 2 diabetes, it increases the risk of hyperkalemia.

Objective
To assess whether a lower dose of spironolactone (12.5 mg/d) reduces the risk of hyperkalemia while maintaining its effect on reducing albuminemia.

Design
Multicenter, open-label, randomized controlled trial.

Setting
This study was conducted from July 2016 to November 2020 in ambulatory care at 3 diabetes medical institutions in Japan.

Patients
We enrolled 130 Japanese adults with type 2 diabetes and albuminuria (≥30 mg/gCre), estimated glomerular filtration rate ≥30 mL/min/1.73 m2, and serum potassium level &lt;5.0 mEq/L.

Interventions
The participants were randomly assigned to the spironolactone-administered and control groups.

Main outcome measures
Changes in urine albumin-to-creatinine ratio (UACR) from baseline over the 24-week interventional period.

Results
The spironolactone group showed a significant reduction in UACR from baseline (mean decrease, 103.47 ± 340.80 mg/gCre) compared with the control group, which showed an increased UACR (mean increase, 63.93 ± 310.14 mg/gCre; P = .0007, Wilcoxon rank-sum test and t test). Although the spironolactone group had a statistically significant increase in serum potassium levels, none of the participants had a potassium level ≥5.5 mEq/L at 24 weeks. Further, participants with a higher initial serum potassium level tended to have a smaller increase (estimate, −0.37, analysis of covariance).

Conclusions
Low-dose spironolactone administration reduced albuminuria without causing hyperkalemia. Spironolactone administration, the oldest known and most cost-effective mineralocorticoid receptor antagonist, at lower doses should be reconsidered.