bluuebunny/crossref_metadata_2025_split huggingface dataset:
PROTEUS: A randomized, double-blind, placebo (PBO)-controlled, phase 3 trial of apalutamide (APA) plus androgen deprivation therapy (ADT) versus PBO plus ADT prior to radical prostatectomy (RP) in patients (pts) with localized or locally advanced high-risk prostate cancer (PC).
Authors: Kibel Adam S. , Gleave Martin , Brookman-May Sabine D. , Kim Won , Evans Christopher P. , Efstathiou Eleni , Kantoff Philip W. , Ross Ashley , Shore Neal D. , Briganti Alberto , Hadaschik Boris A. , Heidenreich Axel , Rooney Oliver Brendan , Tian Shaozhou Ken , Wetherhold Lisa , Xu Weichun , Parsons J. Kellogg , Yeruva Kesav , Taplin Mary-Ellen 
Published: February 2022

TPS285 Background: In pts with localized high-risk PC, disease recurrence rate following RP is ̃50% (Kane et al. J Urol. 2007). Treatment (tx) with androgen blockade before RP can reduce tumor burden post RP (Taplin et al. J Clin Oncol. 2014; McKay et al. Prostate Cancer Prostatic Dis. 2018; Efstathiou et al. Eur Urol. 2019). This study examines if 12 months of perioperative APA + ADT tx before and after RP with pelvic lymph node dissection (pLND) in localized/locally advanced high-risk PC improves pathologic complete response (pCR) rate and metastasis-free survival (MFS) vs PBO + ADT. Methods: PROTEUS, an international multicenter study, is enrolling ̃2000 pts with localized/locally advanced high-risk/very high-risk PC who are candidates for RP with pLND over 3 years at > 203 sites in 18 countries. Stratification variables: Gleason score (7 vs ≥ 8), pelvic node status (N0 vs N1), international region. Randomization: 1:1 to APA (240 mg/d) + ADT or PBO + ADT. Pts receive 6-month neoadjuvant tx followed by RP and then 6 months’ adjuvant tx. Primary end points: pCR rate and MFS. In addition to MFS based on conventional imaging, MFS based on PSMA PET or conventional imaging will be assessed as a separate end point. Both pCR and MFS are assessed by blinded independent central review. Conventional imaging by CT or MRI and bone scan are done at screening, within 4 weeks after RP, at biochemical failure (BCF), and then every 6 months after BCF until distant metastasis or death. During the direct perioperative period, APA/PBO is stopped 2 weeks prior to planned RP and then resumed 4 weeks after RP if post-RP imaging has been conducted to assess for lymphocele and disease progression and resolution to grade ≤ 1 of any clinically significant adverse events considered related to RP. To reflect evolving standard of care, the following protocol amendments were added: PSMA-PET imaging at 3 months post adjuvant tx, at BCF, and every 6 months until distant metastasis or death; cardiovascular and thrombotic risk assessment at screening, prior to, and after RP; and guidance for standard thrombotic prophylaxis in the perioperative setting. An independent data monitoring committee will review trial data. Clinical trial information: NCT03767244.
Evaluation of safety and effectiveness of cryoablation in the treatment of renal angiomyolipoma related to tuberous sclerosis complex: The Cryo-TSC study.
Authors: Kashiwagi Eiji , Asayama Yoshiki , Hatano Takashi , Miki Jun , Egawa Shin , Takamoto Atsushi , Nasu Yasutomo , Osawa Takahiro , Shinohara Nobuo , Hongo Fumiya , Ukimura Osamu , Nishie Akihiro , Ushijima Yasuhiro , Kiyomi Fumiaki , Nakano Shuji , Arai Yasuaki , Eto Masatoshi 
Published: February 2022

TPS397 Background: Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disease that causes benign tumors called hamartoma all over the body as well as neuropsychiatric symptoms such as epilepsy. One-third of patients have a family history of the disease, but the remaining two-thirds are solitary cases and are caused by newly arising mutations. The TSC1 gene on chromosome 9 and TSC2 on chromosome 16 have been identified as the causative genes. Approximately 60%–80% of patients with TSC have renal lesions, and angiomyolipoma (AML) occurs bilaterally. The frequency of TSC-associated AML (TSC-AML) increases with age, reaching 60%–80% in adults, and the rate of death from renal disease increases with age in TSC patients. The current standard of care for AML is arterial embolization or surgery (partial nephrectomy or nephrectomy), but TSC is a hereditary disease and AMLs occur one after another with age. Repeated surgical procedures are technically difficult, and arterial embolization has a high recurrence rate. Under these circumstances, an mTOR inhibitor, everolimus, has shown a marked reduction of TSC-AML and is widely used. However, everolimus must be administered permanently because AML re-occurs after discontinuation of everolimus. Cryotherapy has been used as a treatment for renal tumors, and there have been some reports of cryotherapy for solitary AML, but the safety and efficacy of cryotherapy for TSC-AML have not been established. Therefore, we planned this study to establish the safety and efficacy of cryotherapy for TSC-AML. Methods: This is an open-label, single-arm, phase II study to evaluate the safety and efficacy of cryotherapy for TSC-AML of 4 cm or less in patients with 16 years of age or older. The exclusion criteria are an inability to withdraw from mTOR inhibitor and failure to maintain rest during cryotherapy. mTOR inhibitor medication should be withdrawn at least 7 days prior to cryotherapy and discontinued during the study period. Cryotherapy will be performed using Cryohit (GALIL MEDICAL LTD, Israel). Safety will be assessed at 1, 2, 6, and 9 months after cryotherapy, and efficacy will be assessed at 3 and 9 months after cryotherapy. The efficacy of cryotherapy will be evaluated according to modified RECIST or RECIST criteria. The primary endpoint will be the disease control rate of AML treated with cryotherapy, and secondary endpoints will be the overall response rate, safety, renal function, quality of life, and whether additional treatment is required. Clinical trial information: jRCTs072200039.
Phase 3 study of first-line treatment with pembrolizumab + belzutifan + lenvatinib or pembrolizumab/quavonlimab + lenvatinib versus pembrolizumab + lenvatinib for advanced renal cell carcinoma (RCC).
Authors: Choueiri Toni K. , Plimack Elizabeth R. , Powles Thomas , Voss Martin H , Gurney Howard , Silverman Rachel Kloss , Perini Rodolfo F. , Rodriguez-Lopez Karla , Rini Brian I. 
Published: February 2022

TPS399 Background: Combination therapy with the PD-1 inhibitor pembrolizumab and the vascular endothelial growth factor (VEGF) inhibitor lenvatinib showed antitumor activity as first-line treatment for advanced clear cell RCC (ccRCC) in the phase 3 KEYNOTE-581/CLEAR study (NCT02811861). Antitumor activity has also been shown with the hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (MK-6482) in ccRCC and with MK-1308A (coformulation of pembrolizumab and the CTLA-4 inhibitor quavonlimab) in non–small cell lung cancer. Therefore, HIF-2α or CTLA-4 inhibition with a PD-1 and VEGF inhibition backbone combination may provide additional benefit as first-line treatment in ccRCC. This open-label, randomized, phase 3 study (NCT04736706) will compare first-line treatment with the novel combination therapies pembrolizumab + belzutifan + lenvatinib (arm A) or MK-1308A + lenvatinib (arm B) with pembrolizumab + lenvatinib (arm C) for advanced RCC. Methods: Approximately 1,431 adults with metastatic ccRCC, measurable disease per RECIST v1.1, and KPS score ≥70% who had not previously undergone systemic therapy for advanced ccRCC will be enrolled. Patients will be randomly assigned 1:1:1 to arm A (belzutifan 120 mg + lenvatinib 20 mg orally once daily [QD] + pembrolizumab 400 mg IV every 6 weeks [Q6W]), arm B (MK-1308A [quavonlimab 25 mg + pembrolizumab 400 mg] IV [Q6W] and lenvatinib 20 mg orally QD), or arm C (pembrolizumab 400 mg IV [Q6W] + lenvatinib 20 mg orally QD). Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event; patients will receive pembrolizumab and MK-1308A for up to 18 cycles (̃2 years). Stratification factors are International mRCC Database Consortium (IMDC) score (favorable vs intermediate vs poor), region of the world (North America vs Western Europe vs rest of world), and sarcomatoid features (yes vs no). Response will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review (BICR) at week 12 from randomization, Q6W through week 78, and every 12 weeks thereafter. Adverse events and serious adverse events will be monitored throughout the study and for 90 days after treatment. Dual primary end points are progression-free survival per RECIST v1.1 by BICR and overall survival for arm A or arm B versus arm C in patients with IMDC intermediate/poor status and in all patients regardless of IMDC status. Secondary end points are objective response rate and duration of response per RECIST v1.1 by BICR, patient-reported outcomes, and safety. The study is recruiting patients at sites across, Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT04736706.
SWOG S1931 (PROBE): Phase III randomized trial of immune checkpoint inhibitor (ICI) combination regimen with or without cytoreductive nephrectomy (CN) in advanced renal cancer.
Authors: Vaishampayan Ulka N. , Tangen Catherine , Tripathi Abhishek , Shuch Brian M. , Pal Sumanta K. , Barata Pedro C. , Tan Alan , Zuckerman Peggy , Mayerson Edward , Lara Primo "Lucky" N. , Agarwal Neeraj , Vogelzang Nicholas J. , Kim Hyung Lae , Thompson Ian Murchie 
Published: February 2022

TPS402 Background: Kidney cancer presenting with synchronous primary tumor and metastases has demonstrated shorter survival outcome, as compared to the patients relapsing later with metastases after nephrectomy. CARMENA trial demonstrated no change in overall survival with addition of nephrectomy to sunitinib therapy. Immune checkpoint based combination therapy has now become the standard of care in frontline setting for RCC. The role of cytoreductive nephrectomy (CN) or primary resection has not been evaluated in the setting of immune checkpoint based systemic therapy. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in advanced RCC within the context of immune checkpoint based combination regimens. The underlying mechanism is that the broader antigen spread and higher neoantigen load enabled by the primary tumor would enhance the efficacy of the immune therapy. CN after initial systemic therapy will potentially enable eradication of the immune resistant clones within the primary. Methods: Eligible patients with primary tumor and metastases are treated with one of the FDA approved ICI based combinations: ipililumab and nivolumab, axitinib and pembrolizumab, or axitinib and avelumab. Cabozantinib + nivolumab and lenvatinib + pembrolizumab combinations are being added into the next amendment. Urology evaluation and response assessment is required. Randomization occurs between 10-14 weeks of therapy; 1:1 to receive CN followed by systemic therapy or to continue on systemic therapy. The primary endpoint is overall survival. We estimate the median survival from time of randomization for the non-surgical arm will be 25 months. The study hypothesis is that CN will result in improvement in OS outcomes in advanced synchronous RCC post-initial systemic immune checkpoint based combination therapy. With a sample size of 302 eligible, randomized participants (151 per arm) and a one-sided alpha = 0.025, the study has 85% power to detect a 47% improvement in median survival (HR = 0.68; 1/0.68 = 1.47) Clinical trial information: NCT04510597.
A phase II trial evaluating the efficacy of cabozantinib in the treatment of patients with refractory germ-cell tumors (GCT).
Authors: King Jennifer , Dropcho S , Beeler Sherry , Sastre Jessica , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil 
Published: February 2022

TPS428 Background: While the majority of patients with metastatic testicular cancer are cured with first-line cisplatin-based chemotherapy, 20-30% of patients will relapse following initial treatment. Many will still be cured with second and even third-line chemotherapy options, but there remains a need for new therapeutic approaches for patients with relapsed/refractory disease. Cabozantinib is an oral tyrosine-kinase inhibitor (TKI) with multiple targets including c-MET, VEGF, RET, and AXL. Testicular GCT have low rates of somatic mutations, though have been shown to be associated with a gain of chromosome 7, a portion of which encodes c-MET. When hepatocyte growth factor (HGF) binds to its c-MET receptor, cell proliferation, migration, invasion, and apoptosis escape occurs. In addition, compared to normal testicular tissue, testicular GCT have been shown to have higher rates of VEGF expression. Based on these findings, we proposed a phase 2 trial with cabozantinib in patients with relapsed/refractory GCT. Methods: This phase II, single arm, open label trial with a Simon two-stage design is evaluating cabozantinib 60mg daily in patients with relapsed/refractory GCT. Eligible patients are adult men and women with GCT (seminoma, non-seminoma, or ovarian GCT) that have progressed after first-line cisplatin-based combination chemotherapy in addition to at least 1 salvage regimen and are considered incurable with standard therapies. Patients with primary mediastinal non-seminoma, late relapse, and treated stable brain metastases are eligible. 12 patients will be enrolled initially in the first stage of the Simon two-stage design. If at least one complete response (CR), partial response (PR), or stable disease (SD) for ≥3 months is achieved, the trial will be deemed worthy of further investigation and 9 additional patients will be enrolled. Patients will be treated daily with cabozantinib until time of progression or unacceptable toxicity. Primary outcome is clinical benefit rate (proportion of CR, PR, and SD for ≥3 months using RECIST 1.1, modified to include tumor markers, AFP and hCG). Secondary outcomes include objective response rate, progression-free survival, overall survival, and tolerability and toxicity of cabozantinib. Exploratory evaluation of MET overexpression by IHC and amplification by next generation sequencing in correlation with response will be performed. This study is currently enrolling patients. As of September 20, 2021, the prespecified goal for the Simon stage 1 has been met, and 7 of planned 21 patients have enrolled. Clinical trial information: NCT04876456.
TROPiCS-04: Study of sacituzumab govitecan (SG) in patients (pts) with locally advanced (LA) unresectable or metastatic urothelial cancer (mUC) that has progressed after prior platinum (PLT) and checkpoint inhibitor (CPI) therapy.
Authors: Vulsteke Christof , Grivas Petros , Tagawa Scott T. , Bellmunt Joaquim , De Santis Maria , Duran Ignacio , Goebell Peter-Juergen , Necchi Andrea , Sridhar Srikala S. , Sternberg Cora N. , Sierecki Mitchell Robert , Aziz Usman , Goswami Trishna , Loriot Yohann 
Published: February 2022

TPS582 Background: Treatment options are limited for pts with LA unresectable or mUC who progress after prior PLT-based and CPI therapies. SG is an antibody-drug conjugate (ADC) composed of an anti-trophopblast cell surface antigen 2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) via a proprietary hydrolyzable linker. In the phase 2 registrational study TROPHY-U-01 (NCT03547973), SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.9 months in pts with mUC who progressed after prior PLT-based and CPI therapies (n = 113; median, 3 prior lines of therapy; 84% with ≥1 Bellmunt risk factors; Tagawa et al, J Clin Oncol. 2021). These results compared favorably with historic data for single-agent chemotherapy (ORR, ̃18%; OS, 9 months; Powles et al. J Clin Oncol. 2021) and led to accelerated approval of SG by the US Food and Drug Administration for pts with LA or mUC who previously received a PLT-containing chemotherapy and CPI. The phase 3 TROPiCS-04 trial has been initiated to confirm these findings. Methods: TROPiCS-04 (NCT04527991) is a global, multicenter, open-label, randomized, controlled trial in pts with LA unresectable or mUC who progressed after prior PLT-based and CPI therapies. Key eligibility requirements include Eastern Cooperative Oncology Group performance status 0-1; no prior CPI or ADC therapy within 4 weeks of study drug initiation; no history of active interstitial lung disease or noninfectious pneumonitis; and adequate hematologic, hepatic, and renal function. Pts will be randomly assigned 1:1 to receive SG 10 mg/kg intravenously (IV) on days 1 and 8 of 21-day cycles or single-agent treatment of physician’s choice (paclitaxel 175 mg/m2, docetaxel 75 mg/m2, or vinflunine 320 mg/m2 IV on day 1 of 21-day cycles) until progressive disease, unacceptable toxicity, or withdrawal of consent. Treatment beyond progressive disease may be permitted in pts deemed to be receiving clinical benefit per investigator assessment. Approximately 600 pts will be enrolled across ̃280 sites in 3 regions (North America, Europe, and Asia-Pacific) to provide 90% power on the primary endpoint of OS. Secondary endpoints include progression-free survival, ORR, clinical benefit rate, duration of response (all per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review and investigator assessment), safety, and quality of life. Study enrollment started in January 2021 and is ongoing with pts currently enrolled at 30 sites across all 3 regions. Clinical trial information: NCT04527991.
SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations—Urothelial cancer cohort (trial in progress).
Authors: Galsky Matt D. , Ramos Jorge , Tan Qianwen , Yu Evan Y. 
Published: February 2022

TPS586 Background: Tucatinib, a highly selective HER2-directed tyrosine kinase inhibitor approved in multiple regions for HER2+ metastatic breast cancer, is being investigated as a novel therapy for metastatic colorectal cancer, gastric cancer, and other GI tumors. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with tucatinib and trastuzumab showed superior activity to either alone (Kulukian 2020; Peterson 2020 ). Despite development of several new therapies for metastatic urothelial cancer, most patients do not respond to subsequent therapies, and majority of patients succumb to the disease, highlighting the need for additional therapeutic approaches. Given 20%-30% of metastatic urothelial cancers have molecular alterations of the ErbB family, tucatinib + trastuzumab warrants further evaluation. SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, international Phase 2 study evaluating tucatinib + trastuzumab in patients with previously treated solid tumors displaying HER2+ or HER2-mutated solid tumors, including a cohort with locally advanced or metastatic urothelial cancer (UC). Methods: Eligible patients must have HER2+ or HER2-mutated locally advanced or metastatic solid tumors, with progression on or after the last systemic therapy for advanced disease. Additionally, patients must have an ECOG PS ≤1, adequate hepatic, hematologic, renal, and cardiac function, and no prior exposure to HER2-directed therapy in the UC cohort. For eligibility, HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH, or by HER2 amplification/mutation in prior or pre-screening NGS assay of ctDNA or prior tissue NGS assay. The HER2 overexpression/amplification UC cohort will enroll 12 response-evaluable patients per RECIST 1.1. If ≥2 responses are observed, the cohort will be expanded to 30. Patients with HER2-mutated UC will be enrolled into a cohort of 30 patients with HER2-mutated solid tumors (except breast and non-squamous non-small cell lung cancers). The primary objective is antitumor activity, with confirmed ORR as the primary endpoint, and disease control rate, duration of response, PFS, and OS as secondary efficacy endpoints. Patients will receive tucatinib 300 mg orally twice daily and trastuzumab 8 mg/kg intravenous on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. Trough concentrations of tucatinib will be evaluated in Cycles 2-6, with a peak concentration sampled in Cycle 3. Quality of life will be evaluated q2 cycle using EQ-5D-5L. Sites are currently enrolling within the US, EU, and Asia Pacific. Clinical trial information: NCT04579380.
Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR2/3 genetic alterations (GAs).
Authors: Jain Rohit K. , Kim Youngchul , Rembisz Jennifer , Piekarz Richard , Synold Timothy W. , Zhang Jingsong , Sonpavde Guru P. 
Published: February 2022

TPS595 Background: Erdafitinib and enfortumab vedotin are available treatment options in mUC patients with somatic FGFR2/3 GAs after progression on platinum-based chemotherapy and PD-1/L1 inhibitors. However, due to decline in their clinical condition, the sequential delivery of these agents is challenging. Tubulin antagonists induce a G2-M cell-cycle block, while FGFR inhibitors cause a G1 block, with studies suggesting that their combination may be additive or synergistic. Retrospective studies suggest that the activity of EV is not compromised by somatic FGFR2/3 GAs. Hence, there is rationale to evaluate the feasibility of the combination of EV and E, to overcome the difficulties of resistance and sequencing these agents in mUC patients with FGFR2/3 GAs. Methods: This is a phase Ib, single arm, multicenter study in patients with mUC harboring somatic FGFR2/3 GAs who have progressed after platinum and PD-1/L1 inhibitor therapies with enrollment of up to 30 patients. Pts are required to have predominant urothelial component, ECOG-PS 0-2, neuropathy ≤ grade 1 and no ophthalmologic conditions precluding treatment with E. FGFR2/3 GAs may be identified by tumor tissue or circulating tumor (ct)-DNA profiling. The primary objective is feasibility and establishing a recommended phase-2 dose (RP2D). Secondary objectives include objective response rate, duration of response, progression-free survival and overall survival. The dose-escalation component will enroll up to 18 pts with 3+3 design (dosing cohorts in table), followed by dose-expansion component of 12 pts. The dose limiting toxicities (DLTs) will be evaluated using a sequential Bayesian toxicity monitoring that allows a maximum DLT rate of 0.33 during the dose-expansion phase. Exploratory biomarker analyses will be performed including 1) tumor PD-L1, Nectin-4 assessment by immunohistochemistry and association with response 2) ct-DNA evaluation at baseline and progression to evaluate resistance pathways 3) pharmacokinetic studies will assess plasma levels of E and free monomethyl auristatin-E (MMAE). This is led by North American Star Consortium as part of Experimental Therapeutics. Clinical trial information: NCT04963153. [Table: see text]