bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of cabazitaxel on metastatic bone health in patients with castration resistant prostate cancer previously treated with docetaxel: CaBone Study.
Authors: Santini Daniele , Morelli Franco , Bertoldo Francesco , Facchini Gaetano , Rizzi Daniele , Gatti Davide , Maiello Evaristo 
Published: February 2018

TPS405 Background: The most significant morbidity of prostate cancer (PC) is bone metastasis (BM). More than 90% of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) have radiologic evidence of BM, which are a major cause of death, disability, decreased QoL, and increased treatment cost. Unlike deaths from many other types of cancer, deaths from PC are often due to bone disease and its complications. In vitro data demonstrate a role for taxanes in the regulation of osteoclast formation and function, with a decreased resorption activity. ÊSTAMPEDE study has shown a strong clinical benefit, in term of OS, PFS and skeletal related events (SREs) delay compared with ADT alone, in metastatic hormone-sensitive pts treated with docetaxel (DOC) and ADT. TROPIC Study has shown that cabazitaxel (CBZ) prolongs OS regardless of DOC response in responder, resistant and refractory pts. Some data are available on pain progression, pain response and ECOG PS deterioration but in a unselected ITT population with a low prevalence of only BM disease at baseline, 25% of men had visceral metastasis. No data are available on effects of CBZ on BM and his direct impact on quality of life, bone turnover markers and time to the first SRE events. The aim of CaBone phase II study is to investigate, specifically, the effects on bone disease, bone turnover and on the bone related quality of life of CBZ in mCRPC pts with skeletal involvement without visceral disease. Methods: CaBone is a single arm, prospective, open label, multi center, phase II - GOIM - cooperative study of CBZ 25 mg/m2 q21 plus daily PDN (10 mg) in mCRPC pts with bone mets without visceral disease progressed during or after DOC treatment. Primary endpoint is Bone PFS according to PCWG2 while the Secondary are related on Evaluation of bone disease: Time to SRE, Time to Bone Pain Progression, Bone Pain Response, Time to opiate use for cancer-related pain, Time to deterioration in ECOG PS, Evaluation of Quality of Life and Functional status, Safety and centralized bone turnover markers: ALP, Bone ALP , LDHÊ, Serum CTx, iPTH, 1.25 (OH)2ÊD3. 107 subjects will be enrolled in CaBone study. CaBone is partially supported by Sanofi Genzyme. Clinical trial information: 2016-001253-41.
Randomized phase III study of gemcitabine and cisplatin (GC) versus dose dense methotrexate, vinblastine, doxorubicin and cisplatin (DD-MVAC) in the perioperative setting for patients with locally advanced transitional cell cancer of the bladder: The French GETUG/AFU V05 VESPER trial.
Authors: Pfister Christian , Gravis Gwenaelle , Pignot Geraldine , Flechon Aude , Soulie Michel , Chevreau Christine , Guy Laurent , Laguerre Brigitte , Mottet Nicolas , Joly Florence , Henry-Amar Michel , Radvanyi Francois , Allory Yves , Culine Stephane 
Published: February 2018

TPS530 Background: Radical cystectomy remains the gold standard treatment for invasive non metastatic transitional cell cancer of the bladder. Perioperative chemotherapy (adjuvant ou neoadjuvant) has been developed to increase overall survival. However, the chemotherapy administration time and optimal chemotherapy regimen are not yet determined. As DD-MVAC has been shown to be associated with higher response rates in bladder metastatic disease, also a better efficacy can be suspected in the perioperative setting. Methods: We designed a randomized phase III study to compare the efficacy of GC and DD-MVAC in term of progression-free survival in patients for whom chemotherapy has been decided, before or after radical cystectomy (disease defined by a T2, T3 or T4a N0 M0 stadification for patients receiving neoadjuvant chemotherapy or pT3 or pT4 or pN+ and M0 for patients receiving adjuvant chemotherapy). Secondary endpoints include overall survival, side effects, response rate in the neoadjuvant setting. Main exclusion criteria were histological variants (pure adenocarcinoma or pure epidermoid carcinoma or pure or mixed small-cell neuro-endocrine carcinoma) and ventricular ejection fraction under 50%. The total number of patients projected was 500 based on the median progression-free survival rate of 50% at 3 years observed in patients treated with GC (standard arm A) in the perioperative setting. An absolute improvement of 10% (HR = 0.74) was expected with DD-MVAC (experimental arm B) with a = 0.05 and b = 0.20. In October 2017, 460 patients have been included. An interim analysis is planned after the occurrence of 174 events. With an estimated uniform accrual rate of 140 patients per year for 3.5 years and exponential survival, the final analysis is expected to occur 8 years after the start of the trial. Concomitant ancillary study has also started, focusing on the identification of subgroups for muscle invasive bladder tumors sensitivity to neoadjuvant chemotherapy, as suggested by the recent MDA classification. Clinical trial information: NCT 018 12369.
Interim results from PURE-01: A phase 2, open-label study of neoadjuvant pembrolizumab (pembro) before radical cystectomy for muscle-invasive urothelial bladder carcinoma (MIUC).
Authors: Necchi Andrea , Briganti Alberto , Raggi Daniele , Giannatempo Patrizia , Mariani Luigi , Messina Antonella , Anichini Andrea , Calareso Giuseppina , Crippa Flavio , Catanzaro Mario , Fossati Nicola , Gandaglia Giorgio , Salonia Andrea , Salvioni Roberto , Montorsi Francesco 
Published: February 2018

TPS533 Background: MIUC is an aggressive disease and > 40% of patients (pts) will develop recurrence after radical cystectomy (RC). Despite cisplatin-based neoadjuvant chemotherapy yields Level 1 evidence, it is administered in a minority of pts worldwide. Pembro is an EMA and FDA-approved standard therapy for metastatic UC after platinum failure or for cisplatin-ineligible pts. Our hypothesis was that pembro, given neoadjuvantly, could downstage MIUC and reduce recurrence. Methods: PURE-01 (NCT02736266) is an open-label, single-arm, phase 2 study to evaluate the activity, medical and surgical safety, and immune modulatory effects of pembro administered as a short window-of-opportunity course of therapy preceding RC. Eligibility criteria included: T2-T4aN0 stage, and residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence). The study includes cisplatin eligible- and ineligible pts. Pts receive 3 cycles of pembro 200mg 3 weekly before RC (planned < 3 weeks of the last dose). Computed tomography (CT) scan, FDG-PET/CT scan, and bladder multiparametric magnetic resonance imaging (mpMRI) are done during screening and before RC. Radiologically non responders to pembro (per investigator decision; i.e., study failures) are given 3 additional courses of dose-dense MVAC chemotherapy. After RC, pts are managed according to local guidelines (adjuvant chemotherapy vs observation). Further anti PD-1/PD-L1 therapy will not be given post-operatively. Pathologic complete response (pT0) is the primary endpoint. All pts enrolled who receive at least 1 cycle of study drug will be included in the ITT analysis. The H1 is pT0 ≥20% and H0 pT0≤10%. In a 2-stage design, 90 pts overall will be accrued (80% power and a 2-sided test of significance at the 10% level). A first interim analysis for safety is planned after 18 patients enrolled and treated (by December 1st, 2017). Activity results and early translational findings (immune-cell profiling) will be added, and may be regarded to as first data of preoperative immunotherapy before major surgery. Clinical trial information: NCT02736266.
PECULIAR: An open label, multicenter, single-arm, phase 2 study of neoadjuvant pembrolizumab (PEM) and epacadostat (EPA), preceding radical cystectomy (Cy), for patients (pts) with muscle-invasive urothelial bladder cancer (MIUBC).
Authors: Necchi Andrea , Mariani Luigi , Anichini Andrea , Messina Antonella , Giannatempo Patrizia , Raggi Daniele , Briganti Alberto , Montorsi Francesco 
Published: February 2018

TPS534 Background: MIUBC is a systemic disease and > 40% of pts develop recurrence after Cy. Despite neoadjuvant chemotherapy yields Level 1 evidence, it is underutilized worldwide and a small survival improvement is deemed over Cy alone. PEM (MK-3475) is the standard-of-care for second-line metastatic UC and is being evaluated as single-agent neoadjuvant therapy for MIUBC (NCT02736266). EPA, an anti-IDO1 agent, combined with PEM, safely improved the response-rate in metastatic UC. Our hypothesis is that PEM+EPA, given neoadjuvantly, could further improve downstaging MIUBC. Methods: Pts with T2-T4a N0 UC with residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence), regardless of cisplatin eligibility, will receive 3 cycles of PEM 200mg intravenously, q3 weekly. EPA will be orally taken at the dose of 100 mg BID, from d1 until 10 days before Cy. Cy should be performed within 3 weeks of the last PEM dose. Computed tomography (CT) scan, 18FDG-PET/CT scan, and multiparametric bladder MRI (mpMRI) will be done during screening and before Cy to stage and evaluate response. After Cy, pts will be managed according to EAU guidelines. Adjuvant anti PD-1 therapy is not allowed. PD-L1 status will be assessed on TURB specimen (Dako, clone 22C3), relying on the combined positivity score (CPS, 10% cutoff). Pathologic complete response (pT0) is the primary endpoint. All pts enrolled who receive at least 1 cycle of study drug will be includes in the ITT analysis. The H1 is pT0≥20% and H0 pT0≤10%. A 2-stage design will be used to estimate the number of pts required. Out of 90 pts overall, with the first stage of 49 pts, ≥6 pT0 will be required in the first stage, and ≥13 pT0 in the whole study population (80% power and a 2-sided test of significance at the 10% level). Correlative research on tissue/blood samples will include immune-cell profiling, cytokine assessment, gene expression analyses and next-generation sequencing (FoundationOne). Radiologic findings from mpMRI will be associated with pathologic response (EudraCT number 2017-002379-24). Clinical trial information: 2017-002379-24.
A phase II trial of risk-adapted treatment for muscle invasive bladder cancer after neoadjuvant accelerated MVAC.
Authors: Geynisman Daniel M. , Abbosh Philip , Zibelman Matthew R. , Feldman Rebecca , McConkey David James , Hahn Noah M. , Bivalacqua Trinity , Trabulsi Edouard John , Lallas Costas D. , Hoffman-Censits Jean H. , Viterbo Rosalia , Horwitz Eric M. , Churilla Thomas M. , Alpaugh R. Katherine , Greenberg Richard E. , Smaldone Marc C. , Uzzo Robert , Chen David , Kutikov Alexander , Plimack Elizabeth R. 
Published: February 2018

TPS537 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy (Cx) or chemoradiation (CRT) is the standard of care for urothelial carcinoma (UC) pts with muscle invasive bladder cancer (MIBC). Both Cx and CRT carry potential short and long-term toxicity and quality of life implications. Recent work has shown that mutations in DNA damage repair/response genes are predictive of pathologic downstaging after NAC at the time of Cx, with those pts achieving pT0 disease demonstrating excellent long-term survival (Van Allen et al. Cancer Discov. 2014; Plimack et al. Eur Urol. 2015; Liu et al. JAMA Oncol. 2016; Teo et al. CCR. 2017). Sparing pts Cx or CRT after NAC without compromising oncologic outcomes would improve quality of life and decrease morbidity. Methods: A phase II, parallel arm, multi-institutional clinical trial (NCT02710734) is being conducted to evaluate a risk-adapted approach to treatment of MIBC. Pts with cT2-T3N0M0 UC of the bladder, ECOG PS 0-1 and CrCl≥50 mL/min, undergo NAC with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin. Simultaneously, the pre-NAC TURBT specimen is submitted for deep sequencing to identify variants in a panel of cancer-relevant genes (Caris Life Sciences, Phoenix, AZ). Those with an alteration in ATM, RB1, FANCC or ERCC2 and no clinical evidence of disease by restaging TUR and imaging post-NAC will begin a pre-defined active surveillance regimen that includes urinary cytological, cystoscopic, and radiographic evaluations. The remaining pts will undergo bladder-directed therapy at the discretion of the pt and clinician applying either intravesical therapy ( < cT2 post-NAC), CRT or Cx (≤cT2 post-NAC) or Cx (≥cT3 post-NAC). The primary objective is metastasis-free survival (MFS) at 2 years for all enrolled and evaluable pts. The trial has a non-inferiority design with a 14% margin between risk-adapted treatment (MFS = 78%) and standard-of-care (MFS = 64%) with a sample size of 70 pts, 82% power and a type I error of 0.045. Key secondary and translational objectives: assess the rate of UC recurrence in active surveillance pts; validate biomarkers of response to NAC; evaluate urinary biomarkers consistent with persistent UC. Clinical trial information: NCT02710734.
A phase 3b safety study of fixed-dose durvalumab + tremelimumab or durvalumab monotherapy in advanced solid malignancies (STRONG): Urothelial and non-urothelial urinary tract carcinoma module A.
Authors: Sonpavde Guru , Peters Solange , Nordquist Luke T. , Kato Terufumi , Miranda Paulo Andre , Wang Qin , Socinski Mark A. 
Published: February 2018

TPS538 Background: Despite initial high response rates to current SoC first-line chemotherapy, most patients with locally advanced or metastatic urothelial carcinoma (UC) eventually experience disease progression. With no defined SoC second-line therapies, prognosis remains poor. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks programmed cell death ligand-1 binding to programmed cell death-1 and CD80. Most current Phase 3 trials of durvalumab were initiated using weight-based dosing (mg/kg) regimens. STRONG (NCT03084471), a Phase 3b safety study of durvalumab alone or in combination with the anti-CTLA-4 agent tremelimumab is being conducted to expand understanding of the safety of fixed dosing in patients with advanced solid tumors. Module A of the study is enrolling patients with UC and non-urothelial carcinoma of the urinary tract (any histology) for treatment with durvalumab in the second-line setting post-chemotherapy. Other study modules will include durvalumab + tremelimumab combination arms. Methods: This is an open-label, multicenter study. Module A will enroll approximately 1200 patients to receive durvalumab monotherapy 1,500 mg i.v. q4w until disease progression or unacceptable toxicity. The study opened for enrolment on 17 April 2017 and is expected to be completed within 5 years. Patients must have histologically or cytologically confirmed disease that has progressed during or after nonplatinum or platinum-based chemotherapy either for metastatic disease or progressive disease less than 12 months after adjuvant or neo-adjuvant chemotherapy, and ECOG performance status 0–2. The primary objective is to assess the safety of durvalumab in terms of incidence, severity, nature, seriousness, intervention, outcome and causality (including immune-relatedness) of adverse events of special interest (AESIs). Secondary objectives include additional assessment of safety and tolerability, the frequency of treatment interruption and discontinuation, and overall survival. Clinical trial information: NCT03084471.
A study of intravesical bacillus Calmette-Guerin (BCG) in combination with ALT-803 in patients with non-muscle invasive bladder cancer.
Authors: Rosser Charles Joel , Chamie Karim , Rock Amy , Ferguson Lydia , Wong Hing C. 
Published: February 2018

TPS545 Background: The current standard of care for patients with high risk NMIBC is a transurethral resection of the bladder tumor (TURBT) or biopsy followed by a 6-week induction course of intravesical BCG treatment and supplementary maintenance instillations every 3 months thereafter (Lamm 2000). While clinical response is significantly improved with BCG treatment, 50% of patients are still expected to recur within the first 12 months (Sfakianos 2014). Thus, the pursuit of novel agents to prevent progression and recurrence of NMIBC remains critical. This clinical trial evaluates the safety and efficacy of ALT-803, an IL-15 superagonist, plus BCG in BCG-naïve NMIBC patients. Methods: Patients with high-risk NMIBC (any high-grade disease, T1, or CIS) who are BCG naïve, will be randomized and enrolled into one of two study arms to be treated with either ALT-803 plus BCG or BCG alone. Patients will receive treatment via a urinary catheter in the bladder, weekly for 6 consecutive weeks during induction. A response assessment will be performed at Week 12: Patients with no disease or low-grade Ta disease will receive a maintenance course of therapy (3 weekly instillations of either ALT-803 plus BCG or BCG alone). Presence of Ta will require a TURBT procedure. Patients with presence of high-grade Ta, CIS or low-grade T1 disease will receive a re-induction course of therapy (6 weekly instillations of either ALT-803 plus BCG or BCG alone). Presence of Ta/T1 will require a TURBT procedure. Patients with high-grade T1 or greater disease (including disease progression) will be considered a treatment failure. Patients with no disease or low-grade Ta disease at months 6, 12, and 18 are eligible for maintenance treatment according to their assigned randomization. Patients with presence of disease greater than low-grade Ta will be considered a treatment failure. The primary endpoint of the study is the proportion of patients receiving ALT-803 plus BCG who are responders by Month 12 or earlier. Responders are defined as patients who experience a complete response (CIS patients) or no disease recurrence (defined as reappearance of high-risk disease). Enrollment is underway. Clinical trial information: NCT02138734.
A phase I/II study of sitravatinib (MGCD-516) plus nivolumab in patients (pts) with metastatic clear-cell renal cell carcinoma (ccRCC) that progressed on prior VEGF-targeted therapy.
Authors: Msaouel Pavlos , Thall Peter F. , Yuan Ying , Chen Isan , Tannir Nizar M. 
Published: February 2018

TPS708 Background: Sitravatinib is a potent oral tyrosine kinase inhibitor that targets multiple receptor tyrosine kinase pathways including the vascular endothelial growth factor (VEGF), c-MET, and the Tyro3, Axl, and MER family. These pathways can allow tumor cells to escape immune surveillance despite immune checkpoint therapy. We therefore hypothesized that combining sitravatinib with the anti-PD1 antibody nivolumab will enhance antitumor immune responses in pts with ccRCC. The present study is designed to determine the optimal dose for this combination using efficacy and toxicity as co-primary outcomes. Methods: This phase I/II trial uses the sequentially adaptive late-onset EffTox design (Jin et al. J Am Stat Assoc 2014), which accounts for potential late-onset toxicities induced by immunotherapy, and allows dose-finding based on both the efficacy and toxicity of each successive dose. Eligible pts have metastatic ccRCC that progressed on prior VEGF-targeted therapy. Each pt receives initially a pre-specified daily oral dose, among 4 dose levels (60mg, 80 mg, 120 mg, 150 mg), of sitravatinib monotherapy for 2 weeks to allow the drug to reach a pharmacokinetic steady state. Nivolumab is then added at the dose of 240 mg intravenously every 2 weeks. A maximum of 60 pts will be treated in up to 20 cohorts of 3 pts each. Tumor biopsies and peripheral blood are collected to assess changes in tumor microenvironment and immune markers at 4 different time points: 1) at baseline, up to 14 days prior to initiation of sitravatinib, 2) following 2 weeks of sitravatinib monotherapy, 3) after 2 infusions of nivolumab in combination with sitravatinib, and 4) at disease progression. The primary endpoint is optimal dose of sitravatinib based on toxicity (by week 12) and disease control rate (at week 6). Secondary endpoints include objective response rate, progression-free survival, and overall survival. At deadline for abstract submission, 4 pts have been treated on this study. Clinical trial information: NCT03015740.
Single-arm phase ib/II study of durvalumab and guadecitabine in advanced kidney cancer (NCT03308396).
Authors: Yentz Sarah Elizabeth , Reimers Melissa Andrea , Joshi Monika , Zakharia Yousef , Gupta Shilpa , Singer Eric A. , Daignault Stephanie , Zou Weiping , Musapatika Dana , Alva Ajjai Shivaram 
Published: February 2018

TPS711 Background: Checkpoint inhibitor immunotherapy directed at PD1/PDL1 has shown clinical efficacy in advanced clear cell Renal Cell Cancer (ccRCC). However, only a minority of patients respond to anti-PD1 monotherapy. There is an urgent unmet need to improve response rates including through rational combinations to reverse immune evasion by tumors. The chemokines CXCL9 and CXCL10 in the tumor micro-environment are chemo-attractants for activated NK and Th1 cells and are critical for anti-tumor immunity. Preclinical data from our group showed hypermethylation induced silencing of CXCL9/10 signaling is an important tumor immune evasion mechanism. In RCC cell lines (A-498, HTB-46 and CRL-1611), hypomethylating agents increased CXCL9/10. In mouse xenograft models, combination therapy with a hypomethylating agent and checkpoint inhibitors led to higher levels of CXCL 9/10, reversal of immune evasion and potent tumor regression. We hypothesized that the combination of guadecitabine (hypomethylating agent) with durvalumab (anti-PDL1 antibody) would increase T lymphocyte infiltration into RCC tumors including those that are immunologically ‘cold’ and result be effective in 1st and 2nd line RCC. Methods: The study is a single arm, multi-site, phase 1b/2 trial through the Big Ten Cancer Research Consortium of Guadecitabine (starting dose of 60 mg/m2/dose subcutaneously on days 1-5) with Durvalumab (1500 mg IV on day 8) in 28-day cycles in pts with metastatic ccRCC. Cohort 1 (N = 36) will consist of pts naïve to checkpoint inhibitor immunotherapy and 0-1 prior therapies. Cohort 2 (N = 16) will include pts who did not respond to prior anti-PD-1/PD-L1 therapy. The primary endpoint is objective response rate by RECIST 1.1 in cohort 1. Statistical analysis will use a binomial exact test to compare the ORR proportion in patients treated in Cohort 1 with the combination compared to an expected proportion of 25% with anti-PDL1 alone. The extensive correlative objectives include serial evaluation of serum CXCL9/10 levels and LINE-1 methylation status as well as tumor infiltrating lymphocytes profiling, PD-L1 expression, tumor mutational burden and NGS on mandatory baseline and optional biopsies at progression. Clinical trial information: NCT03308396.