bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of treatment sequence on survival outcome in patients with a second treatment line for metastatic castration-resistant prostate cancer: A new user design in the French nationwide claims database.
Authors: Gross-Goupil Marine , Thurin Nicolas H. , Rouyer Magali , Haaser Thibaud , Rebillard Xavier , Soulie Michel , de Pouvourville Gérard , Messaoudi Fatiha , Capone Camille , Bignon Emmanuelle , Jové Jérémy , Lamarque Stéphanie , Droz-Perroteau Cécile , Moore Nicholas , Blin Patrick 
Published: March 2021

91 Background: Abiraterone acetate in association with prednisone/prednisolone and docetaxel can both be used as first or second line treatments for metastatic castration-resistant prostate cancer (mCRPC). As a result, one may wonder if it is better to start with an abiraterone acetate first line followed by a docetaxel second line (ABI–DOCE sequence) or to use the inverse sequence DOCE-ABI. Methods: A new user cohort study design with a 3-year follow-up: patients initiating a first-line treatment for mCRPC in 2014 followed by a second treatment line were identified from the French nationwide claims database (SNDS), which covers about 86% of the population at the time of the study. Patients with sequence ABI–DOCE and those with DOCE-ABI were 1:1 matched on prostate cancer stage before mCRPC status, duration from prostate cancer diagnosis, and a high-dimensional propensity score. The 36-month overall survival and the 36-month survival time until treatment switch or death (proxy of progression-free survival) were compared using Cox proportional hazards risk model. Results: Out of the 3 949 mCRPC patients that initiated a first-line treatment in 2014, 1 162 died during this first line, and 2 283 had a second-line treatment. Among them, 693 received the sequence ABI–DOCE and 354 DOCE–ABI. A total of 159 patients per group were 1:1 matched. The median duration of the first treatment line was 8.4 months in the ABI–DOCE sequence and 6.6 months in the DOCE–ABI sequence. The median duration of the second line was 6.3 months and 6.5 months in the ABI–DOCE and DOCE–ABI sequences, respectively. Results are presented in the table below. Median survivals were similar in both groups with no significant differences observed in the 36-month survival probabilities. Around 60% of the patients received a third-line treatment in both groups. Conclusions: In real life settings, treatment sequences (ABI–DOCE versus DOCE–ABI) seem to have no differential impact on survival outcome in mCRPC patients sharing same characteristics. [Table: see text]
A multicenter, randomized, controlled phase II study: Efficacy and safety of PSMA-targeted radioligand therapy I-131-1095 (1095) plus enzalutamide (enza) in 18F-DCFPyL PSMA scan avid, metastatic castration-resistant prostate cancer (mCRPC) patients post-abiraterone (abi) progression (ARROW).
Authors: Sartor A. Oliver , Laidley David , Pouliot Frederic , Probst Stephan , Sabbagh Robert , Esposito Giuseppe , Saad Fred , Stambler Nancy , Yu Evan Y. 
Published: March 2021

TPS187 Background: PSMA is a transmembrane glycoprotein overexpressed in prostate cancer (PC) and further upregulated in castrate resistant disease. 1095 is a novel PSMA-targeted small molecule radioligand therapeutic that binds to the extracellular domain of PSMA selectively with high affinity, internalized, and delivers a targeted lethal radiation dose to PC cells. 18F-DCFPyL is a novel PSMA-targeted PET imaging agent that has shown robust diagnostic performance for detecting recurrent and metastatic PC. In the ARROW study, pts must demonstrate 18F-DCFPyL avidity prior to 1095 treatment. Methods: ARROW is an open-label, randomized (2:1) trial of enza plus 1095 or enza alone in pts with progressive mCRPC who previously received abi. ~120 pts (80: 1095 + enza; 40: enza alone) will be treated at multiple sites in the US and Canada. Eligible male pts must have metastatic disease documented by bone scan or soft tissue lesions measurable per RECIST 1.1 on CT/MRI, be PSMA-avid as determined by 18F-DCFPyL PET/CT, have evidence of biochemical or radiographic progression on abi, and be ineligible for or refuse to receive chemotherapy. Pts will receive enza (prescribed per approved labeling) with or without 1095 (100 mCi dose, followed by up to 3 additional doses administered at least 8 weeks apart, as determined by dosimetry evaluation and occurrence of dose-limiting events). The primary objective is to determine the efficacy of 1095 plus enza compared to enza alone, based on PSA response (confirmed PSA decline ≥50%) rate according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Additional objectives include objective response rate based on PCWG3-modified RECIST 1.1, progression-free survival (PFS) defined as the first occurrence of radiographic progression (PCWG3-modified RECIST 1.1), unequivocal clinical progression, or death from any cause, duration of response, overall survival, and the safety and tolerability of 1095 radioligand therapy. Due to the COVID-19 pandemic, enrollment was halted in April 2020 but is reopening in October 2020. Clinical trial information: NCT03939689.
PLANETTE: A modular phase IIa multicenter open-label study evaluating the ATR inhibitor ceralasertib (AZD6738) in ATM mutant advanced solid tumors.
Authors: Abida Wassim , Sanay Elkhan , Lukashchuk Natalia , Pierce Andrew , de Graaf Wessel , Lau Alan , Rocher Ros Vidalba , Kurian Nisha , Parr Graeme , LoembE Bienvenu , Dean Emma , Aggarwal Rahul Raj 
Published: March 2021

TPS189 Background: Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) are kinases that orchestrate cellular responses to DNA damage. ATM is primarily activated by DNA double strand breaks, and ATR is recruited to regions of single stranded DNA that arise due to collapsed or stalled replication forks. Although ATM and ATR are activated by distinct pathways, their downstream targets and effects partially overlap to activate cell cycle checkpoints and DNA damage repair. Ceralasertib is a potent, oral, selective inhibitor of ATR. Pre-clinical studies have consistently demonstrated synthetic lethality of ATR inhibitors, including ceralasertib, in ATM-deficient models across multiple tumor types (Kwok et al 2017, Min et al 2017, Lloyd et al 2020, Hustedt et al 2019). Early clinical evidence of efficacy is from a phase I study of ceralasertib in combination with olaparib in relapsed, refractory cancer (NCT02576444). Amongst 5 participants with a range of solid tumors harboring deleterious ATM mutations, there was 1 complete response, 3 stable diseases (1 with minor response 20-30%) and 1 patient with disease progression. Two participants had clinical benefit ongoing for more than 12 months (Eder et al 2019). ATM deficiency may be detected through genomic testing for loss-of-function alterations in the gene, or through immunohistochemical methods to detect loss of protein expression. Genomic alterations in ATM occur across multiple solid tumor types, including approximately 4% of advanced prostate cancers. Methods: PLANETTE (clinicaltrials.gov identifier (NCT 04564027) is a modular phase 2a multicenter open-label study investigating DNA-damage response agents in patients with advanced cancers that harbor molecular alterations. Module 1 will study the ATR inhibitor ceralasertib in tumors with deleterious or suspected deleterious mutations in ATM. Patients will be identified at cancer centers which routinely perform molecular profiling to detect ATM mutations. Central confirmation of ATM mutation by NGS and ATM IHC testing will be conducted retrospectively. Cohort A will enroll ~25 patients with advanced solid tumors (except NSCLC and prostate cancer), cohort B will include ~27 patients with metastatic CRPC who have previously progressed on a novel hormonal agent. The primary endpoints are investigator assessed ORR in Cohort A and composite response that includes radiographic, PSA, and CTC response per PCWG criteria in Cohort B. Secondary endpoints include duration of response, and progression free survival. Pharmacodynamic and other biomarkers will be explored. Enrolment is planned to start in November 2020. Clinical trial information: 04564027.
A phase III, randomized, open-label, study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy (NHT) in patients (pts) with metastatic, castration-resistant prostate cancer (mCRPC).
Authors: Agarwal Neeraj , Azad Arun , Carles Joan , Chowdhury Simon , McGregor Bradley Alexander , Merseburger Axel Stuart , Oudard Stephane , Saad Fred , Soares Andrey , Panneerselvam Ashok , Wang Fong , Pal Sumanta K. 
Published: March 2021

TPS190 Background: Cabozantinib inhibits multiple tyrosine kinases, including MET, VEGFR, RET, and TAM kinases (Tyro3, AXL, MER), involved in tumor growth and angiogenesis, and whose mutations and expression are associated with prostate cancer aggressiveness and poor prognosis. Targeting these kinases with cabozantinib may promote an immune permissive tumor environment and may enhance response to immune checkpoint inhibitors. In the ongoing phase 1b COSMIC-021 study of pts with solid tumors, cabozantinib plus the PD-L1 inhibitor atezolizumab, showed preliminary meaningful clinical activity in soft tissue disease and a tolerable safety profile for 44 pts with mCRPC (Agarwal et al., ASCO 2020; abstract 5564). We present the study design of a phase 3 trial of cabozantinib plus atezolizumab versus second NHT in pts with mCRPC. Methods: This randomized, open-label, controlled phase 3 study (NCT04446117) evaluates the efficacy and safety of cabozantinib plus atezolizumab versus second NHT (abiraterone or enzalutamide) in pts with mCRPC who previously received one NHT to treat metastatic castration-sensitive PC (mCSPC), non-metastatic CRPC (M0 CRPC), or mCRPC. Additional eligibility criteria include histologically or cytologically confirmed adenocarcinoma of the prostate, measurable visceral disease or measurable extrapelvic adenopathy per RECIST 1.1 by investigator, prostate specific antigen progression and/or soft-tissue disease progression, ECOG 0 or 1, and age ≥18 years. Key exclusion criteria include prior nonhormonal therapy for mCRPC and uncontrolled significant illness. Eligible pts (N = 580) are randomized 1:1 to receive cabozantinib (40 mg PO QD) + atezolizumab (1200 mg IV Q3W) vs abiraterone (1000 mg PO QD) + prednisone (5 mg PO BID) or enzalutamide (160 mg PO QD). Designated NHT will differ from previous NHT taken. Randomization is stratified by: liver metastasis (yes, no), prior docetaxel treatment for mCSPC (yes, no), and disease stage for which the first NHT was given (mCSPC, M0 CRPC, mCRPC). Treatment will continue until there is no longer clinical benefit as determined by the treating investigator, unacceptable toxicity, or consent withdrawal. The multiple primary endpoints are progression-free survival per RECIST 1.1 by blinded independent radiology committee (BIRC) and overall survival. Additional endpoints include objective response rate per RECIST 1.1 by BIRC, safety, correlation of biomarkers with outcomes, quality of life and pharmacokinetics. Patient enrollment is ongoing. Clinical trial information: NCT04446117.
Phase II trial of opaganib in patients with metastatic castration-resistant prostate cancer progressing on abiraterone or enzalutamide (NCT04207255).
Authors: Kucuk Omer , Smith Charles , Plasse Terry , Ogretmen Besim , Mehrotra Shikhar , Gourdin Theodore Stewart , Bilen Mehmet Asim , Carthon Bradley Curtis , Nazha Bassel , Goldman Jamie , Lilly Michael B. 
Published: March 2021

TPS191 Background: Opaganib (Yeliva, ABC294640) is a first-in-class, sphingosine kinase-2 (SK2) selective inhibitor, with anticancer, anti-inflammatory and anti-viral activities. SK2, a lipid kinase catalyzes formation of the lipid signaling molecule sphingosine 1-phosphate (S1P). S1P promotes cancer growth, and proliferation and pathological inflammation, including inflammatory cytokine production. Specifically, by inhibiting the SK2 enzyme, opaganib blocks the synthesis of S1P which regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and are also involved in immune-modulation and suppression of innate immune responses from T cells. Opaganib is a sphingosine-competitive inhibitor of SK2 and also inhibits dihydroceramide desaturase. Opaganib has antitumor activity against human and murine prostate cancer cell lines, and in xenograft (LNCaP) and syngeneic (MycCAP, TRAMP-C1) murine tumor models. In addition to its target effect of reducing sphingosine-1-phosphate, opaganib reduces both MYC and AR proteins through its kinase-blocking and desaturase-inhibiting properties, respectively. Methods: The study is open to patients with mCRPC who have been treated with at least one newer androgen antagonist (abiraterone or enzalutamide) and no prior chemotherapy for castration-resistant disease. Patients who are failing either abiraterone or enzalutamide may enroll, with the addition of opaganib. The trial design includes brief safety lead-in cohort 1a (abiraterone + opaganib 250 mg Q 12hr, 3/3 enrolled) and 1b (enzalutamide + opaganib 250 mg Q 12hr, 3/3 enrolled). These cohorts have been completed without any DLTs. We are now enrolling cohort 2 (abiraterone + opaganib 500 mg Q 12hr, 0/27 enrolled) and cohort 3 (enzalutamide + opaganib 500 mg Q 12hr, 8/27 enrolled). A total of 60 patients will be enrolled and response will be evaluated after 4 cycles (28 days/cycle) using a composite metric based on PSA, bone scan and RECIST measurements per PCWG3 criteria. Safety and tolerability will be monitored, and dose modifications will be allowed. Primary endpoint is disease control (stable disease or better) after 4 cycles. Secondary endpoints include overall survival, radiographic progression-free survival and PSA progression-free survival. Correlative studies include assessment of quality of life (QOL), circulating MDSCs, immune cells and clones with amplified AR or MYC. Supported by NIH grant P01 CA203628. Clinical trial information: NCT04207255.
PDIGREE: An adaptive phase III trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704).
Authors: Zhang Tian , Ballman Karla V. , Choudhury Atish Dipankar , Chen Ronald C. , Watt Colleen , Wen Yujia , Shergill Ardaman , Zemla Tyler J. , Emamekhoo Hamid , Vaishampayan Ulka N. , Morris Michael J. , George Daniel J. , Choueiri Toni K. 
Published: March 2021

TPS366 Background: First-line treatment of mRCC has rapidly changed to include IPI-NIVO or CABO, with clinical benefit of each based on the Checkmate 214 and CABOSUN (A031203) trials. Combination immunotherapy with VEGF therapies has shown benefit over sunitinib in the JAVELIN 101 and KEYNOTE 426 trials. It is yet unclear which patients (pts) benefit most from combination immunotherapy-VEGF inhibitors, and the optimal sequence of drugs. Methods: In an adaptive, randomized, multicenter phase III trial (Alliance A031704, PDIGREE), pts start treatment with induction IPI 1 mg/kg and NIVO 3 mg/kg intravenously (IV) once every 3 weeks. Key inclusion criteria include clear cell mRCC, International Metastatic RCC Database Consortium (IMDC) intermediate or poor risk, Karnofsky performance status >70, and no prior treatments for mRCC. Based on 3-month radiographic assessment (after completing IPI-NIVO combination), pts with complete responses (CR) undergo maintenance NIVO 480 mg IV every 4 weeks; pts with progression of disease (PD) switch to CABO 60 mg oral daily; pts with non-CR/non-PD are randomized to NIVO 480 mg IV every 4 weeks versus NIVO 480 mg IV every 4 weeks with CABO 40 mg oral daily. Randomization is stratified by IMDC risk criteria and presence of bone metastases. The primary endpoint of the study is overall survival (OS). We hypothesize that 3-year OS will improve to 70% for NIVO-CABO compared to 60% for NIVO alone; to achieve 85% power with a two-sided alpha of 0.05 and exponential distribution, 696 patients will be randomized. Accounting for 30% patients with either CR or PD, and 5% dropout from toxicity, up to 1046 pts will be enrolled. Key secondary endpoints include progression-free survival, 12-month CR rate, overall response rate based on RECIST 1.1 and iRECIST criteria, and toxicity profiles. Quality of life will be assessed based on the FKSI-19, PROMIS-fatigue, and EQ5D-5L questionnaires. Biomarkers associated with CR, tissue-based and plasma-based biomarkers will be assessed. Updated enrollment through January 2021 will be presented. Clinical trial information: NCT03793166 .
Denosumab and pembrolizumab in clear cell renal carcinoma (KEYPAD): A phase II trial (ANZUP1601).
Authors: Gedye Craig , Joshi Abhishek Jagdish , Zhang Alison Yan , Martin Andrew James , Joshua Anthony M. , Harris Carole A. , Underhill Craig , Pook David William , Toner Guy C. , Kichenadasse Ganessan , So Jane Yeojeong , Goh Jeffrey C. , Morris Michelle Frances , Lawrence Nicola Jane , Ferguson Tom , Vasey Paul Austin , Prithviraj Prashanth , Subramaniam Shalini , Stockler Martin R. , Davis Ian D. ,   Austraila and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: March 2021

TPS367 Background: Inhibitors of the programmed death-1 pathway (PD-1) are effective in clear cell renal cell cancer (ccRCC). Preclinical data and case reports suggest that denosumab, an inhibitor of Receptor Activator of Nuclear Factor κ-B Ligand (RANKL) signaling, could potentiate the anti-tumour effects of anti-PD1 inhibitors without overlapping toxicities. We aim to determine the activity and safety of combining denosumab and pembrolizumab in advanced ccRCC. Methods: This single arm, multi-center, phase II trial will recruit 70 participants with metastatic or unresectable ccRCC, progressing during or after treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors, and with no prior treatment with immunotherapy or denosumab. Participants will receive pembrolizumab 200mg IV every 3 weeks plus denosumab 120mg SC on days 1, 8 and 22 and then every 3 weeks until disease progression, prohibitive toxicity or maximum treatment of 24 months. Response will be assessed at weeks 12, 18, 24, then every 12 weeks until disease progression. Bloods for translational studies are collected at baseline, week 6 and on disease progression. The primary endpoint is objective tumour response rate (OTRR) per RECIST 1.1. Secondary endpoints include OTRR per iRECIST, progression free survival (PFS), time to OTRR, time to first skeletal related event, adverse events, and frequency of treatment delays/discontinuations. Correlative studies will include identification of prognostic and/or predictive biomarkers relating to immune and RANKL signaling. A sample size of 70 provides 90% power with a 1-sided type 1 error rate of 10% to distinguish the observed OTRR (and PFS at 6 months) from an OTRR of 40% (worthy of pursuit) versus 25% (not worthy of pursuit). 15 sites are open across Australia. As of September 23, 2020, 40 patients have been recruited. Clinical trial information: NCT03280667 .
A phase III, randomized, open-label, multicenter, global study of efficacy and safety of durvalumab in combination with gemcitabine plus cisplatin for neoadjuvant treatment followed by durvalumab alone for adjuvant treatment in muscle-invasive bladder cancer (NIAGARA).
Authors: Powles Thomas , Meeks Joshua J , Galsky Matt D. , Van Der Heijden Michiel Simon , Nishiyama Hiroyuki , Al-Ahmadie Hikmat A , Goluboff Erik T. , Hois Stephan , Donegan Sarah E. , Williams Vanessa , Xiao Feng , Catto James WF 
Published: March 2021

TPS505 Background: Management of muscle-invasive bladder cancer (MIBC) includes both surgery and systemic therapy. Neoadjuvant cisplatin-based combination chemotherapy has demonstrated improved pathologic complete response (pCR), event-free survival (EFS), and overall survival (OS) compared with radical cystectomy alone. Yet at least half of patients will still experience recurrence and will progress to metastatic disease. Durvalumab (anti–PD-L1 antibody) combined with gemcitabine + cisplatin, administered as either neoadjuvant or adjuvant treatment, may increase the rate of pathologic response and prolong long-term survival. This approach will be evaluated in this study in patients with MIBC identified for curable intent, as reflected in the NCCN guidelines. Methods: NIAGARA (NCT03732677) is a phase III, randomized, open-label, multicenter, international trial that will enroll ~1050 patients with MIBC who, prior to radical cystectomy, will be randomized (1:1) to durvalumab and gemcitabine + cisplatin (Arm 1) or gemcitabine + cisplatin (Arm 2). Following radical cystectomy, patients in Arm 1 will receive durvalumab monotherapy for 8 cycles (8 months) while patients in Arm 2 will receive no adjuvant treatment. Eligible patients are aged ≥18 years with resectable MIBC (clinical stage T2-T4aN0/1M0) with urothelial histology eligible for a radical cystectomy. Patients with pure non-transitional cell variant histologies and any small cell histology are not eligible. A tumor tissue sample for biomarker analysis is mandatory as PD-L1 expression is a stratification factor. Primary endpoints are pCR and EFS in patients with adequate renal function. Secondary and exploratory endpoints include proportion of patients who achieve pathologic response < stage II (stages Ta, T1, and carcinoma in situ) at the time of cystectomy following neoadjuvant treatment, EFS at 24 months, metastasis-free survival, efficacy of Arm 1 vs Arm 2 at radical cystectomy and proportion of patients who undergo cystectomy, OS rate at 5 years, safety, patient-reported outcomes, and pharmacokinetics. Immunogenicity and biomarkers are exploratory endpoints. Enrollment opened in Dec 2018. Clinical trial information: NCT03732677.
Hepatic Igf1-Deficiency Protects Against Atherosclerosis in Female Mice
Authors: Sivasubramaniyam Tharini , Yang Jiaqi , Pollock Evan , Chon Joseph , Schroer Stephanie A , Li Yu Zhe , Metherel Adam H , Dodington David W , Bazinet Richard P , Woo Minna 
Published: March 2021

Abstract
Atherosclerosis is the leading cause of cardiovascular disease (CVD), with distinct sex-specific pathogenic mechanisms that are poorly understood. Aging, a major independent risk factor for atherosclerosis, correlates with a decline in circulating insulin-like growth factor-1 (IGF-1). However, the precise effects of Igf1 on atherosclerosis remain unclear. In the present study, we assessed the essential role of hepatic Igf1, the major source of circulating IGF-1, in atherogenesis. We generated hepatic Igf1-deficient atherosclerosis-prone apolipoprotein E (ApoE)-null mice (L-Igf1-/-ApoE-/-) using the Cre-loxP system driven by the Albumin promoter. Starting at 6 weeks of age, these mice and their littermate controls, separated into male and female groups, were placed on an atherogenic diet for 18 to 19 weeks. We show that hepatic Igf1-deficiency led to atheroprotection with reduced plaque macrophages in females, without significant effects in males. This protection from atherosclerosis in females was associated with increased subcutaneous adiposity and with impaired lipolysis. Moreover, this impaired lipid homeostasis was associated with disrupted adipokine secretion with reduced circulating interleukin-6 (IL-6) levels. Together, our data show that endogenous hepatic Igf1 plays a sex-specific regulatory role in atherogenesis, potentially through athero-promoting effects of adipose tissue–derived IL-6 secretion. These data provide potential novel sex-specific mechanisms in the pathogenesis of atherosclerosis.