bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study EV-103: New randomized cohort testing enfortumab vedotin as monotherapy or in combination with pembrolizumab in locally advanced or metastatic urothelial cancer.
Authors: Mar Nataliya , Friedlander Terence W. , Hoimes Christopher J. , Flaig Thomas W. , Bilen Mehmet Asim , Balar Arjun Vasant , Henry Elizabeth , Srinivas Sandy , Rosenberg Jonathan E. , Petrylak Daniel Peter , Burgess Earle Frederick , Merchan Jaime R. , Tagawa Scott T. , Carret Anne-Sophie , Steinberg Joyce Leta , Chaney Marya F. , Milowsky Matthew I. 
Published: May 2020

TPS5092 Background: Cisplatin-based chemotherapy is the standard for first-line (1L) patients (pts) with locally advanced/metastatic urothelial cancer (LA/mUC). PD-1/PD-L1 inhibitors have promising durability of responses but 1L use is restricted to pts ineligible for cisplatin-containing therapy and whose tumors express PD-L1 (CPS ≥10) or pts ineligible for platinum-containing chemotherapy regardless of PD-L1 status. Enfortumab vedotin (EV), an antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, which is highly expressed in UC. EV recently received FDA accelerated approval based on tumor response rates for adults with LA/mUC who have previously received a PD-1/PD-L1 inhibitor and a platinum-containing chemotherapy. In the ongoing phase 1b/2 study EV-103/KEYNOTE-869 (NCT03288545), the safety and antitumor activity of EV are investigated as monotherapy (mono) (for the first time in the 1L setting) and in combination with PD-1 inhibitor pembrolizumab (P) +/- chemotherapy in UC. An initial analysis of EV (1.25 mg/kg) + P (200 mg) (both drugs in investigational use here) in this study showed a 73.3% confirmed ORR in 45 1L cisplatin-ineligible LA/mUC pts (dose-escalation + expansion Cohort A) (Rosenberg ASCO 2020). Methods: A new Cohort K randomized 1:1 to 1.25 mg/kg EV mono or 1.25 mg/kg EV + 200 mg P provides additional information on EV + P and the contribution of activity from EV in cisplatin-ineligible pts with LA/mUC in the 1L setting. This cohort will enroll 150 adults (≥18 years) with LA/mUC and measurable disease per RECIST v1.1, and exclude pts with prior systemic treatment for LA/mUC, active CNS metastases, ongoing sensory or motor neuropathy (Grade ≥2), or uncontrolled diabetes. Cisplatin-ineligibility in this study is based on ≥1 of the following: ECOG of 2, creatinine clearance of ≥30 and < 60 mL/min, or hearing loss/dysfunction. In each 3-week cycle of this study, EV is administered on days 1 and 8, and P on day 1. The primary endpoint is ORR per RECIST v1.1 by BICR. Secondary endpoints include ORR per RECIST v1.1 by investigator assessment, DOR, DCR, PFS per RECIST v1.1 by BICR and investigator assessment, OS, safety, and tolerability. Sample size is not based on power calculation for formal hypothesis testing but is selected based on ORR estimate precision based on 95% CIs. Efficacy is summarized by treatment arm with no formal statistical comparisons between arms. The study opened in Oct 2017. Cohort K opened in Jan 2020. Clinical trial information: NCT03288545 .
Phase III study of pembrolizumab (pembro) plus chemoradiotherapy (CRT) versus CRT alone for patients (pts) with muscle-invasive bladder cancer (MIBC): KEYNOTE-992.
Authors: Balar Arjun Vasant , James Nicholas D. , Shariat Shahrokh F. , Shore Neal D. , Van Der Heijden Michiel Simon , Weickhardt Andrew James , Fang Xiao , Godwin James Luke , Kapadia Ekta , Michalski Jeff M. 
Published: May 2020

TPS5093 Background: Pembro has shown clinical activity across many stages of bladder cancer (BC), including metastatic BC, MIBC, and NMIBC. Current NCCN and AUA/ASCO/ASTRO/SUO guidelines recommend CRT as a bladder-preserving treatment option for selected pts with MIBC. This phase 3 study was designed to investigate the safety and efficacy of pembro + CRT in pts with MIBC who opt for bladder preservation. Ongoing phase 2 studies (NCT02662062; NCT02621151) have shown that pembro + CRT may be a promising therapeutic option in MIBC. Methods: KEYNOTE-992 (NCT04241185) is a phase 3, global, multicenter, double-blind, placebo-controlled, randomized trial to evaluate the efficacy and safety of pembro + CRT versus placebo + CRT in pts with previously untreated MIBC. Adults (≥18 years) opting for bladder preservation with histologically confirmed cT2-T4a, nonmetastatic (N0M0) MIBC after maximal TURBT are eligible. An estimated 636 pts will be randomly assigned 1:1 to receive CRT + either pembro 400 mg IV every 6 weeks (Q6W) or placebo. Treatment will continue with pembro or placebo Q6W for up to 9 doses. CRT regimens will be decided by the investigator before randomization. Accepted radiotherapy regimens are conventional radiotherapy consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated radiotherapy consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only). Accepted concurrent radiosensitizing chemotherapy regimens are cisplatin monotherapy (35 mg/m2 IV weekly), 5-fluorouracil (500 mg/m2 on days 1-5 and days 22-26) + mitomycin C (12 mg/m2 on day 1), or gemcitabine monotherapy (27 mg/m2 IV twice weekly). Randomization will be stratified by ECOG PS (PS 0/1 vs 2), PD-L1 combined positive score ( < 10 vs ≥10), T stage (T2 vs T3/4), and geographic region (US vs Europe vs rest of world). Pts must provide tissue for biomarker analysis. Efficacy will be assessed by cystoscopy (± biopsy), CT or MRI (with blinded independent central review), and urine cytology at 10 weeks after CRT, then Q12W up to the end of year 2, and then Q24W thereafter. The primary end point is bladder-intact event-free survival, defined as time from randomization to residual/recurrent MIBC, nodal or distant metastasis, radical cystectomy, or death from any cause. Key secondary end points are OS, metastasis-free survival, time to occurrence of NMIBC, and safety. Clinical trial information: NCT04241185 .
Phase III study of the hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 versus everolimus in previously treated patients with advanced clear cell renal cell carcinoma (ccRCC).
Authors: Choueiri Toni K. , Albiges Laurence , Fan Li , Perini Rodolfo F. , Zojwalla Naseem J. , Powles Thomas , Rini Brian I. 
Published: May 2020

TPS5094 Background: In RCC, the Von Hippel-Lindau ( VHL) tumor suppressor gene is inactivated in most cases, resulting in the accumulation and overactivation of HIF-2α. HIF-2α is a key oncogenic driver in RCC and is involved in the activation of genes associated with angiogenesis, tumor progression, and metastasis, such as vascular endothelial growth factor A ( VEGFA), cyclin D1, and CXCR4. MK-6482 is a potent and selective small molecule inhibitor of HIF-2α, and it has shown antitumor activity in a phase 1/2 study in patients with previously treated advanced ccRCC. Methods: The current study (NCT04195750) is a phase 3, open-label, multicenter, randomized, active-controlled trial to compare the efficacy and safety of MK-6482 with everolimus in patients with previously treated advanced ccRCC. Adults aged ≥18 years will be eligible if they have unresectable, locally advanced, or metastatic ccRCC; have measurable disease per RECIST v1.1; and received ≤3 prior systemic regimens, which must include a PD-1/PD-L1 inhibitor (≥2 doses) and a VEGF-targeted therapy, for locally advanced or metastatic RCC. Approximately 736 patients will be randomly assigned 1:1 to receive MK-6482 120 mg orally once daily or everolimus 10 mg orally once daily. At randomization, patients will be stratified by International Metastatic RCC Database prognostic scores (0 vs 1-2 vs 3-6) and by the number of prior anti-VEGF–targeted therapies received for advanced RCC (1 vs 2-3). Responses will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review at week 9 from the date of randomization, then every 8 weeks through week 49, and then every 12 weeks thereafter. Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event. Dual primary endpoints are progression-free survival per RECIST v1.1 and overall survival. Key secondary endpoints include objective response rate, duration of response, patient-reported outcomes, and safety. Clinical trial information: NCT04195750 .
PROOF 302: A randomized, double-blind, placebo-controlled, phase III trial of infigratinib as adjuvant therapy in patients with invasive urothelial carcinoma harboring susceptible FGFR3 alterations.
Authors: Daneshmand Siamak , Grivas Petros , Sridhar Srikala S. , Gupta Shilpa , Bellmunt Joaquim , Sonpavde Guru , Fleming Mark T. , Lerner Seth P. , Loriot Yohann , Wang Hao , Takkele Hiywot , Andresen Corina , Rearden Jessica , Berman Craig , Pal Sumanta K. 
Published: May 2020

TPS5095 Background: Radical surgery ± cisplatin‐based (neo)adjuvant chemotherapy (NAC) is the mainstay of treatment for invasive urothelial carcinoma of the upper urinary tract (UTUC) or bladder (UBC), but recurrence rates are high. Furthermore, many patients are unable to receive NAC due to cisplatin ineligibility. Fibroblast growth factor receptor 3 (FGFR3) genetic alterations occur in up to 70% of UTUC and up to 20% of UBC and may constitute a potential candidate for targeted therapy. Infigratinib (BGJ398), a FGFR1–3 selective oral tyrosine kinase inhibitor, has shown promising clinical activity and tolerability in patients with advanced urothelial carcinoma having FGFR3 alterations [Pal et al. Cancer Discov 2018]. PROOF 302 has been designed to investigate the efficacy and safety of infigratinib versus placebo as adjuvant therapy in patients with high-risk invasive urothelial carcinoma and susceptible FGFR3 alterations. Methods: PROOF 302 is a randomized, double-blind, placebo-controlled, phase III study of approx. 218 patients. Adults with high-risk invasive UTUC or UBC with susceptible FGFR3 genetic alterations (i.e. activating mutations, gene fusions or translocations) who are ≤120 days following surgical resection and ineligible for or refusing cisplatin-based adjuvant chemotherapy or with residual disease after cisplatin-based NAC are eligible. Those who received non cisplatin-based NAC are eligible if they have residual disease and are ineligible for adjuvant cisplatin. Patients receive oral infigratinib 125 mg or placebo (1:1 ratio) once daily on days 1–21 every 28 days for up to 52 weeks or until disease recurrence, unacceptable toxicity or death. Primary endpoint: centrally reviewed disease-free survival (DFS). Secondary endpoints: DFS including intraluminal low-risk recurrence; metastasis-free survival; overall survival; DFS (per investigator); safety and tolerability. Exploratory endpoints include quality of life, pharmacokinetics, cell-free DNA (cfDNA) and/or RNA for resistance mechanisms. The study will involve approximately 120 centers worldwide. The study was initiated in late 2019 and is expected to end in 2024. Clinical trial information: NCT04197986 .
Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO): A single-arm, open-label window-of-opportunity trial of neoadjuvant abemaciclib in platinum-ineligible muscle invasive bladder cancer patients.
Authors: Nauseef Jones , Vlachostergios Panagiotis J. , Molina Ana M. , Nanus David M. , Sternberg Cora N. , McClure Timothy D , Scherr Douglas , Martin M. Laura , Inghirami Giorgio , Elemento Olivier , Tagawa Scott T. , Faltas Bishoy Morris 
Published: May 2020

TPS5096 Background: The standard of care for clinically localized muscle-invasive bladder cancer (MIBC) is neoadjuvant platinum-based combination chemotherapy followed by radical cystectomy (RC). Up to 40% of patients (pts) are ineligible to receive cisplatin and proceed to RC without any neoadjuvant therapy. We and others have demonstrated enrichment of molecular alterations in cell cycle genes in MIBC, including copy number losses of CDKN2A in 41% of pts. Abemaciclib is a unique CDK4/6 inhibitor with single agent activity and a target kinome distinct from other CDK4/6 inhibitors. We have demonstrated that CRISPR knockout of CDKN2A increases susceptibility to abemaciclib in bladder cancer cell lines. Beyond tumor-intrinsic effects, abemaciclib also modulates the tumor microenvironment (TME) via upregulating human endogenous retroviral elements and increasing T cell infiltration. Methods: Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO) is a single arm, window-of-opportunity trial of neoadjuvant abemaciclib which will evaluate tumor cell and TME changes in response to abemaciclib. Enrolled pts must be ineligible for platinum-based neoadjuvant therapy for resectable MIBC. Pts receive abemaciclib (200 mg BID PO) for 4 weeks prior to RC. Tumor tissue collected via transurethral resection of bladder tumor (TURBT) and residual tumor at RC undergo single cell RNA sequencing and whole-exome sequencing. Patient-derived organoids and xenografts are generated for a co-clinical trial of abemaciclib alone or in combination. The primary endpoint is the measurement of changes in cell cycle dynamics. Secondary objectives are assessment of toxicity via NCI CTCAE v 5.0 and pathologic downstaging of MIBC. We will perform targeted sequencing of a panel of cell cycle genes in serial plasma and urine cell free DNA to evaluate changes in the variant allele fractions of somatic alterations. The novel design of this trial allows dynamic in vivo assessment of tumor changes and creates a new paradigm for studying tumor evolution in real time. Clinical trials information: NCT03837821. Clinical trial information: NCT03837821 .
A phase III, randomized, placebo-controlled trial of nivolumab or nivolumab plus ipilimumab in patients with localized renal cell carcinoma at high-risk of relapse after radical or partial nephrectomy (CheckMate 914).
Authors: Bex Axel , Russo Paul , Tomita Yoshihiko , Grünwald Viktor , Ramirez Luz-Margarita , McHenry Brent M. , Motzer Robert J. 
Published: May 2020

TPS5099 Background: Surgery is standard treatment for nonmetastatic renal cell carcinoma (RCC). Unfortunately, patients (pts) with stage II or III RCC have high risk of relapse with 5-year disease-free survival rates of ~51%–56%; prevention of recurrence is an unmet need. In CheckMate 214, first-line nivolumab plus ipilimumab (NIVO+IPI) demonstrated significant overall survival improvements in pts with advanced/metastatic RCC, with a manageable safety profile. Moreover, while not yet confirmed in randomized controlled trials, evidence suggests that anti-PD-(L)1 monotherapy may provide sufficient clinical activity in some pts with advanced RCC. These findings indicate a potential for improved clinical outcomes in the early-stage adjuvant RCC setting. As such, the phase 3, double-blind CheckMate 914 study will evaluate NIVO and NIVO+IPI vs placebo in pts with high risk of relapse after nephrectomy (NCT03138512). Methods: Key inclusion criteria: radical or partial nephrectomy with negative surgical margins > 4 weeks and ≤12 weeks before randomization; predominantly clear cell histology; pathologic TNM staging T2a (grade [G] 3 or 4), T2b (any G), T3 (any G), or T4 (any G) N0M0, or any T (any G) N1M0; Eastern Cooperative Oncology Group performance status ≤1; no clinical/radiological evidence of macroscopic residual disease or distant metastases post-nephrectomy; and tumor tissue obtained ≤3 months pre-enrollment. Key exclusion criteria: conditions requiring corticosteroid or immunosuppressive systemic treatment, autoimmune disease, prior treatment with drugs specifically targeting T-cell co-stimulation or checkpoint pathways, and prior systemic treatment for RCC. In part A, pts are randomized 1:1 to receive NIVO+IPI or placebo infusions; in part B, pts are randomized 1:1:2 to receive NIVO+IPI, placebo infusions, or NIVO with IPI placebo. All treatments are given for 24 weeks or until disease recurrence, unacceptable toxicity, or withdrawal of consent. Stratification factors: TNM staging and type of nephrectomy procedure. Primary endpoint: disease-free survival per blinded independent central review (part A: NIVO+IPI vs placebo; part B: NIVO vs placebo). Secondary endpoints: overall survival (part A: NIVO+IPI vs placebo; part B: NIVO vs placebo and NIVO+IPI vs NIVO), disease-free survival (part B: NIVO+IPI vs NIVO), and safety. Enrollment in the study is ongoing. Total target enrollment across parts A and B is 1600 pts. Clinical trial information: NCT03138512 .
PROSPER: Phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).
Authors: Haas Naomi B. , Puligandla Maneka , Allaf Mohamad E. , McDermott David F. , Drake Charles G. , Signoretti Sabina , Cella David , Gupta Rajan T. , Shuch Brian M. , Lara Primo , Kapoor Anil , Heng Daniel Yick Chin , Leibovich Bradley C. , Michaelson M Dror , Choueiri Toni K. , Jewett Michael A.S. , Maskens Deb , Harshman Lauren C , Master Viraj A. , Carducci Michael Anthony 
Published: May 2020

TPS5101 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ~56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 2020, 396 patients have been enrolled. Clinical trial information: NCT03055013 .
Phase III, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of adagloxad simolenin (OBI-822) and OBI-821 treatment in patients with early-stage triple-negative breast cancer (TNBC) at high risk for recurrence.
Authors: Rugo Hope S. , Chow Louis W. C. , Cortes Javier , Fasching Peter A. , Hsu Pei , Huang Chiun-Sheng , Kim Sung-Bae , Lu Yen-Shen , Melisko Michelle E. , Nanda Rita , Sharma Priyanka , Schwab Richard B. , Xu Binghe 
Published: May 2020

TPS599 Background: Adagloxad simolenin (AS) is a therapeutic vaccine comprising the tumor-associated antigen Globo H linked to the carrier protein keyhole limpet hemocyanin (KLH). The KLH provides antigenic immune recognition and T-cell responses. AS is co-administered with a saponin-based adjuvant OBI-821 to induce a humoral response. A phase 2 trial showed that AS/OBI-821 exhibited a trend for superior progression-free survival vs placebo in patients whose breast cancers have higher Globo H expression. Methods: Patients with TNBC (ER/PR < 5%, and HER2-negative) with nonmetastatic disease and either 1) residual invasive disease of ≥1 cm in the breast or ≥1 positive axillary node following neoadjuvant chemotherapy or 2) ≥4 axillary lymph nodes with invasive carcinoma treated with adjuvant chemotherapy are included. Patients are prescreened for Globo H expression using a validated IHC assay (H-score of ≥15). Patients will receive either AS (30 μg) with OBI-821 (100 μg) or volume-matched placebo (1:1), administered as SC injections. Up to 21 SC injections of study treatment (or placebo), will be administered over 100 weeks, given on the following schedule: weekly for 4 doses; every 2 weeks for 4 doses; every 4 weeks for 4 doses; and then every 8 weeks for 9 doses. Patients may terminate treatment due to disease recurrence or unacceptable toxicity, withdrawal of consent, protocol violation, loss to follow-up or death. The primary objective is to determine the effect of AS/OBI-821 treatment on invasive disease-free survival in patients with TNBC at high risk for recurrence. Secondary objectives are to determine the impact of AS/OBI-821 treatment on overall survival, quality of life (QoL), breast cancer-free interval, distant disease-free survival, safety, and tolerability. Imaging and clinical examination will be performed regularly for 5 years. QoL will be assessed using the EORTC Core Quality of Life Questionnaire (QLQ)-C30 plus the EORTC Breast Cancer-specific QLQ-BR23 questionnaire and the European Quality of Life 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire. Adverse events will be graded/recorded as per National Cancer Institute CTCAE v5.0. An estimated 668 subjects will be enrolled, treated for up to 2 years and followed until occurrence of 187 events (invasive disease recurrence or death) or 3 years from last subject randomized. Survival follow-up is for 5 years from randomization of last subject. Clinical trial information: NTC03562637 .