bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I-II study to evaluate safety and efficacy of niraparib plus cabozantinib in patients with advanced urothelial/kidney cancer (NICARAGUA trial): Preliminary data of phase I study.
Authors: Castellano Daniel E. , Duran Ignacio , Mellado Begona , Climent Duran Miguel Angel A. , Garcia del Muro Xavier , Sala González Nuria , Alonso Gordoa Teresa , Sevillano Elena , Domenech Montserrat , Paramio Jesus , Real Francisco X. , Malats Nuria , Sanz Juan Luis , Font Albert ,   Fundación CRIS
Published: February 2022

490 Background: Niraparib (N) is a (PARP)-1/-2 inhibitor and Cabozantinib (C) is a tyrosine kinase (TK) inhibitor that targets VEGF signalling via inhibition of multiple TK receptors including c-MET and TAM kinases (TYRO3, AXL, MER). The c-Met receptor TK is abnormally activated and could be decrease response to PARP inhibitors. Preclinical data reveals that treatment with c-Met inhibitors renders cells more sensitive to PARP inhibition. A phase (Ph) I-II study was designed to explore the safety and efficacy of the combination of N + C in genitourinary cancers. Methods: Multicenter, open-label Ph I-II study (NCT03425201). Confirmed histopathological diagnosis of either metastatic urothelial carcinoma (mUC) or advanced clear cell renal cell carcinoma previously treated with a maximum of two previous regimens. Adequate bone marrow, liver and renal functions were required. The Ph I portion aimed to identify the maximum tolerated dose (MTD) and recommended ph II dose (RP2D). Pt received N and C p.o. once daily in 28-day cycles: Dose level 1 (DL1) N/C 100/20 mg; DL2 200/20 mg; DL3 200/40 mg; DL4 200/60 mg. A further amendment developed DL1.1 100/40 mg. Pt were accrued to each dose level in cohorts of 6 pt until the MTD was achieved (defined as highest dose at which ≤1 out of 6 pt experience a DLT, evaluated during the first 2 cycles). Results: Nineteen evaluable pt for DLT were included, 14 of them had UC. There was no DLT at DL1. Two out of the first 6 evaluable pt in DL2 had DLT (G3 thrombopenia and anemia and G3 diarrhea respectively). Upon analysis of these pt it was agreed to include 3 additional new pt for evaluation. Two pt were included with one presenting a DLT (G3 hepatic toxicity). Enrolment then continued in a new DL 1.1 cohort and 1 of 6 pts had DLT (G3 mucositis), being then considered the RP2D. No toxic deaths were reported. Six pt (32%) received at least 10 cycles and 9 pt (47%) received at least 6 cycles. Three patients (16%) achieved partial response (all of them with mUC disease) and 14 (74%) stable disease. Conclusions: N plus C combination can be safely administered with a manageable toxicity profile and preliminary efficacy was reported in mUC heavily pretreated pts. The RP2D is N 100 mg plus C 40 mg qd. Ph II study is now recruiting mUC patients. Clinical trial information: NCT03425201. [Table: see text]
Gemcitabine and carboplatin versus gemcitabine and paclitaxel chemotherapy in cisplatin ineligible advanced-stage urothelial cancers: A prospective randomized control study.
Authors: Kumar Parmod , Sehrawat Amit , sundriyal Deepak , Sharma Pankaj , Mittal Ankur , Gupta Manoj Kumar 
Published: February 2022

500 Background: Cisplatin ineligibility in metastatic urinary bladder cancer patients poses a major therapeutic challenge. The reported incidence was approximately 20-30% of metastatic urinary bladder cancer. In the absence of insurance, "the immunotherapy" can be economically draining at the current cost. Moreover, there are patients in whom immunotherapy might not be feasible due to comorbid conditions. Therefore, there persists a need to optimize chemotherapy options for gemcitabine combination with either Paclitaxel or Carboplatin are recommended chemotherapy options. However, limited prospective studies are comparing the two options. Methods: This was a non-funded, prospective, randomized, single-center study among treatment naïve cisplatin-ineligible metastatic urothelial cancer from a tertiary care institute from India. The study enrollment duration was 18 months. Patients were randomized in one of the two treatment arms. The "Arm A" received (Gemcitabine and Carboplatin) and "Arm B" received the (Gemcitabine and Paclitaxel) combination chemotherapy, respectively. The two treatment arms were compared prospectively for disease control, survival, and adverse events in an Intention to treat analysis. Results: A total of 32 eligible participants were randomized in the study. "Arm A" vs. "Arm B" had an 18.7% vs. 25% drops out rate, respectively. The ORR was 40% vs. 88.4%; median PFS and OS were 3.7 vs. 3.8 months and 7.3 vs. 14.0 months, respectively. The serious adverse events were nonoverlapping. Hospitalization was needed for the care of adverse events among 37.5% vs. 12.5% patients, respectively. Conclusions: Both groups reported that similar PFS. However, better ORR, OS (though not statically significant), and lower hospitalizations for adverse event management favor the Gemcitabine with paclitaxel combination over Gemcitabine with Carboplatin. Clinical trial information: CTRI/2020/02/023402.
Targeting urothelial neoplasia using an investigational virus-like drug conjugate.
Authors: Kines Rhonda , Railkar Reema S. , Agarwal Piyush K. , Schiller John T 
Published: February 2022

514 Background: Human papillomavirus virus-like particles (HPV VLP) preferentially target tumor cells via cell surface modified heparan-sulfate proteoglycans (HSPG). The investigational virus-like drug conjugate, belzupacap sarotalocan (AU-011), is currently in phase 2 clinical trials for treatment of primary choroidal melanoma. We previously demonstrated AU-011’s in vivo tumor acute cytotoxicity upon activation with near-infrared light (nIR), resulting in tumor-free survival for at least 100 days and protection from tumor re-challenge in the MB49 murine flank model of bladder cancer. Here we provide additional data supporting further clinical development in urothelial neoplasia as an additional oncology indication. Methods: We examined the cytotoxicity of AU-011 in a panel of six human bladder cancer cell lines in vitro and binding and distribution in human tumor biopsy samples ex vivo. Tumor distribution of AU-011 was also assessed in vivo after intravesical instillation in the orthotopic MB49 murine model. In consideration of the glycocalyx layer often found coating the interior of the bladder wall and the surface of bladder tumors, pre-treatment with hyauronidase was tested both on human biopsy samples and in the murine orthotopic model. Lastly, tumor distribution of AU-011 was evaluated when formulated with the polyamide Syn3. Results: When tested in vitro on a panel of human bladder tumor cell lines representing grades I-IV carcinomas, we found AU-011’s potency to be in the picomolar range (EC50 range 16.6 pM – 62.75 pM). We assessed the VLPs ability to bind ex vivo to a panel of human urothelial tumor biopsies and observed binding in samples representing both invasive T2 and non-invasive Ta papillary tumors. Tumor biopsy samples were pre-treated with hyaluronidase to break down the glycocalyx layer surrounding the tumor, and an increase in signal was observed in the Ta biopsy sample. Similarly, using the orthotopic MB49 murine tumor model with intravesical delivery of AU-011, we observed an enhancement of AU-011 distribution into the tumor when the bladders were pre-treated with hyaluronidase. Additionally, when formulated with Syn3, AU-011 distribution throughout the tumors was augmented without the need for hyaluronidase pre-treatment. Conclusions: We have demonstrated AU-011 targeted cytotoxicity in vitro using a panel of human bladder cancer cell lines indicating that its binding to bladder cancer cells is tumor grade and genetic mutation agnostic. Additionally, tumor binding and distribution was observed ex vivo using human bladder cancer biopsy samples and in vivo in the murine MB49 orthotopic model. Human and murine tumor distribution was improved with a pre-treatment of hyaluronidase or when formulated with Syn3. Collectively, these data support the further investigation of the use of AU-011 for the indication of uroepithelial cancer.
Characterizing molecular subtypes of high-risk nonmuscle-invasive bladder cancer in African American patients.
Authors: Williams Stephen B. , You Sungyong , Kim Minhyung , Widen Steven G. , Yu Alexander , Eyzaguirre Eduardo J. , Dyrskjøt Lars , McConkey David , Choi Woonyoung , Theodorescu Dan , Chan Keith S. , Shan Yong , Tyler Douglas S. , De Hoedt Amanda M. , Freedland Stephen J. 
Published: February 2022

527 Background: Patients with high-risk non-muscle-invasive bladder cancer (NMIBC) have heterogeneous outcomes with African Americans (AAs) having worse survival than European Americans (EAs). It is unknown whether race-based biological differences contribute to this disparity. Methods: We performed a retrospective cohort study including patients from the University of Texas Medical Branch (UTMB) and the Durham VA Health Care System (DVAHCS) from 2010-2020 among treatment naïve, high-risk NMIBC. Profiled gene expressions of high-risk NMIBC by race were performed using the UROMOL classification system. Results: A total of 26 patients (14 AAs and 12 EAs) matched on age and sex were included with no significant difference in clinical stage group (CIS +/- T1 or TaHG vs. TaHG or T1, no CIS), smoking status, or progression. We found a similar racial UROMOL subtype distribution with class 2a being most common. A total of 10 genes were discovered to be commonly upregulated differentially expressed genes (up-DEGs) in AAs vs EAs. EFEMP1, which has been associated with progression to muscle-invasive bladder cancer (MIBC) in vitro, and S100A16 gene expression, which has been implicated with mitomycin C resistance in bladder cancer in vitro, was significantly more common among AAs. We used single nuclei analysis to map the malignant cell heterogeneity in urothelial cancer which five distinct malignant epithelial subtypes whose presence has been associated with different therapeutic response prediction ability. We mapped the expression of the 10 genes commonly up-DEGs by race as a function of the five malignant subtypes. This showed borderline (p = 0.056) differences among the subtypes suggesting AA and EA patients may be expected to have different therapeutic responses to treatments for BC. AAs were enriched with immune-related, inflammatory, and cellular regulation pathways compared to EAs, yet appeared to have reduced levels of the aggressive C3 bladder tumor cell population. Conclusions: In this small sample, we found similar subtype distribution among high-risk NMIBC patients according to race. However, gene expression differs by race, supporting potential novel race-based etiologies for differences in muscle-invasion, response to treatments, and transcriptome pathway regulations. Further biological studies in NMIBC molecular sub-stratification, associated treatment(s), and prognoses in a larger cohort are needed to support these hypotheses.
Biomarkers predictive of response to enfortumab vedotin (EV) treatment in advanced urothelial cancer (aUC).
Authors: Jindal Tanya , Zhang Li , Chou Jonathan , Shui David , Porten Sima P. , Wong Anthony C. , Chan Emily , Stohr Bradley A. , de Kouchkovsky Ivan , Borno Hala , Bose Rohit , Kwon Daniel H , Desai Arpita , Huang Franklin W. , Aggarwal Rahul Raj , Small Eric Jay , Fong Lawrence , Friedlander Terence W. , Koshkin Vadim S 
Published: February 2022

531 Background: EV is an antibody-drug conjugate which recently received full FDA approval for treatment-refractory aUC. Molecular biomarkers and characteristics of patients (pts) most likely to respond to EV therapy have not been well defined. Methods: We retrospectively identified all aUC pts treated with EV at our institution. Clinicopathologic, treatment and response data were abstracted from pt charts. Pts were considered responders to EV if they had a complete response on initial scans after 2-3 months of treatment, or were treated with EV for ≥ 6 months. Responders and non-responders were compared in terms of their molecular and clinical characteristics using Chi-squared test. Most common somatic alterations present in ≥10 pts ( TERTp, TP53, CDKN2A, CDKN2B) were also used to divide pts with available next-generation sequencing (NGS) results into groups with and without these alterations. Log rank test was used to determine differences in overall survival (OS) and progression free survival (PFS) among these groups. Results: Between 1/2020 and 8/2021 a total of 32 pts received EV and 28 had NGS data available with either FoundationOne (14 pts), UCSF500 (13 pts) or Strata (1). Median age was 69.5 years, 24 (75%) were male, 22 (69%) Caucasian, 22 (69%) had pure urothelial histology and 22 (69%) primary tumor location in the bladder. At EV start, 24 (75%) had visceral metastases (mets), 8 (25%) had liver mets, and 13 (41%) had bone mets. Median follow-up from EV start was 12.5 months (range 0.5-36); 20 (63%) pts received EV monotherapy, and 12 (37%) received EV as part of a combination regimen. Non-responders were more likely to have bone metastases (69% vs 21%, p<0.01), but were otherwise similar in baseline clinical characteristics to responders. TP53 alterations were enriched in responders relative to non-responders, whereas non-responders had more CDKN2B alterations (Table). Similar findings were seen in the subset of pts treated with EV monotherapy. Pts with TP53 alterations had longer OS (NR vs 17.0 months, p=0.06) and PFS (NR vs 6.6 months, p=0.04) relative to wild-type pts. Shorter PFS was seen in pts with CDKN2A (4.4 months vs NR, p=0.05) and CDKN2B (4.3 months vs NR, p=0.02) alterations, but no differences in OS were observed. Conclusions: In this retrospective cohort of aUC pts with available NGS data, presence of TP53 and absence of CDKN2A and CDKN2B alterations were associated with favorable responses and improved clinical outcomes with EV, suggesting they may be biomarkers of response to EV. These preliminary findings should be validated in larger cohorts.[Table: see text]
A randomized, controlled trial of group exercise training for fall prevention and functional improvements during and after treatment for prostate cancer.
Authors: Winters-Stone Kerri M. , Li Fuzhong , Horak Fay B. , Dieckmann Nathan , Hung Arthur , Amling Christopher L. , Beer Tomasz M. 
Published: February 2022

TPS193 Background: Many prostate cancer survivors are treated with androgen deprivation therapy (ADT), but these therapies may increase frailty, worsen physical functioning, and increase fall risk. While exercise may counter functional declines associated with ADT, no studies have tested whether and which type of exercise may reduce falls and frailty. The purpose of this trial is to compare the relative efficacy of strength training versus tai ji quan training against each other and to a stretching control group on falls, frailty and physical functioning in men expose to ADT for prostate cancer. Methods: Prostate cancer survivors treated with ADT (n = 360) will be recruited to participate in this single-blind, parallel group, randomized trial. To be eligible men must meet the following criteria: 1) histologically confirmed prostate cancer, 2) received at least 6 months of ADT within the past 10 years, 3) report >1 fall in the past year OR have a score on one of two physical performance tests that is associated with increased fall risk (i.e. ≥ 12.0 seconds to complete the 3 meter timed up and go (TUG), or ≥ 10.0 seconds to complete 5 chair stands), 4) completed any other treatment at least 6 weeks prior to enrollment and not be on any concurrent prostate cancer therapy besides ADT, 5) not currently participating in moderate-vigorous intensity lower-body strength training or tai ji quan training ≥ 2 times/week for ≥ 30 minutes per session, 6) no cognitive difficulties that limit ability to answer survey questions or participate in exercise classes and performance tests, 7) no medical condition, disorder, or take medication that contraindicates participation in moderate intensity exercise, and 8) are able to communicate in English. Participants will be randomized to one of three supervised, group training programs: i) strength training, ii) tai ji quan training, or iii) stretching (control), that train 3x/week for 6 months. Outcomes are assessed at baseline, 3 (mid-intervention), 6 (immediately post-intervention) and 12 (follow-up) months. The primary outcome is falls assessed by monthly self-report. Secondary outcomes include the following: Frailty (low lean body mass (by bioelectrical impedance analysis), exhaustion (by SF-36 vitality scale), low activity (by CHAMPS physical activity survey), slowness (by 4m usual walk speed), and weakness (by chair stand time)); Objective and subjective measures of physical function will also be collected. Negative binomial regression models will be used to assess differences in falls between groups, while mixed-effects modeling will be used to compare the relative efficacy of training group on secondary outcomes. Registered November 18, 2018. Clinical trial information: NCT03741335.
TiNivo-2: A phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following one or two lines of therapy where one line has an immune checkpoint inhibitor.
Authors: Choueiri Toni K. , Albiges Laurence , Hammers Hans J. , McKay Rana R. , Heng Daniel Yick Chin , Beckermann Katy , Kasturi Vijay , Motzer Robert J. 
Published: February 2022

TPS405 Background: Tivozanib, a highly selective and potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, has demonstrated single-agent efficacy in advanced renal cell carcinoma (aRCC) along with minimal off-target toxicities and a favorable adverse event (AE) profile (Rini et al. Lancet Oncol 2020; 21:95-104). Tivozanib was approved by the FDA on March 10, 2021, for the treatment of patients with aRCC who had progressed on 2 or more prior lines of therapy. Tivozanib was combined with Nivolumab in the TiNivo trial (NCT03136627), showing an objective response rate of 56%, disease control rate of 96%, median PFS of 18.9 months and a favorable safety profile (Albiges et al. Ann Oncol. 2021 Jan;32(1):97-102). Methods: TiNivo-2 (NCT04987203) is a phase 3, randomized, controlled, multicenter, open-label study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma who have progressed following 1-2 lines of therapy including an immune checkpoint inhibitor. Eligibility criteria include age >18 years, clear cell RCC, ECOG PS 0-1, and disease progression during or following at least 6 weeks of treatment with ICI for RCC. Subjects will be stratified by IMDC risk category and whether ICI was received in most recent line of treatment or not. On both arms, subjects will receive Tivozanib 1.34 mg orally once daily for 21 consecutive days followed by 7 days off. In the combination arm, subjects will also receive Nivolumab 480mg intravenously every 4 weeks. Study assessments include CT scan or MRI of the chest, abdomen, and pelvis every 8 weeks following Cycle 1 Day 1 for 2 years and every 12 weeks thereafter until disease progression is confirmed by independent radiology review. The primary objective is to compare the progression-free survival (PFS) of tivozanib in combination with nivolumab to tivozanib. A sample size of 326 subjects, with 191 events will provide at least 80% power to detect a 50% improvement in PFS, 12 mos v. 8 mos, as assessed by an IRR. Secondary endpoints include assessment of overall survival (OS), objective response rate (ORR), and duration of response (DoR), as well as safety and tolerability. Exploratory endpoints are to assess the quality of life (FKSI-DRS and EORTC QLQ C-30) and to investigate the pharmacokinetics of tivozanib. TiNivo-2 is actively enrolling and planning to open at 190 sites in the United States, and the European Union. Clinical trial information: NCT04987203.
A phase 3, single-arm study of CG0070 in subjects with nonmuscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG).
Authors: Uchio Edward M. , Lamm Donald L. , Shore Neal D. , Kamat Ashish M. , Tyson Mark , Tran Ben , Anderson Paul , Grandi Paola , Burke James M. 
Published: February 2022

TPS598 Background: CG0070 is a serotype 5 adenovirus engineered to express GM-CSF and replicate in cells with mutated or deficient RB, with response rates (RR) of approximately 45% observed in patients with recurrent NMIBC after BCG (J Urol. 2012;188:2391–7; Urol Oncol. 2018;36(10):440–7). This single arm phase 3 study (NCT04452591) was launched to confirm the clinical activity of CG0070 in patients with BCG Unresponsive NMIBC. Methods: 110 patients with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravesical (IVe) CG0070 at a dose of 1x1012 vp. CG0070 will be administered as follows: induction weekly x 6 followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Patients with persistent CIS or HG Ta at 3 months (m) may receive re-induction with weekly x 6 CG0070. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping at 12 m. Detection of high grade disease within the bladder will be enumerated as recurrence or non-response. The primary endpoint of the study is CR at any time on study as assessed by biopsy (directed to cystoscopic abnormalities and mandatory mapping at 12 m), urine cytology, and radiography, as above. Secondary endpoints include CR at 12 m, duration of response, progression free survival, cystectomy free survival and safety. Correlative assessments include changes in the tumor immune microenvironment, systemic immune induction as reflected in the peripheral blood and urine, as well as viral replication and transgene expression. Baseline expression of coxsackie adenovirus receptor, E2F transcription factor as well as anti-adenovirus antibody titer will be correlated with tumor response. Study enrollment globally is ongoing including in North America, Taiwan, Japan, and South Korea. Refs. Burke JM, Lamm DL, Meng MV, Nemunaitis JJ, Stephenson JJ, Arseneau JC, Aimi J, Lerner S, Yeung AW, Kazarian T, Maslyar DJ, McKiernan JM. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. Clinical trial information: NCT04452591.