bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase III trial of 68Ga-PSMA-11 PET/CT molecular imaging for prostate cancer salvage radiotherapy planning [PSMA-SRT].
Authors: Calais Jeremie , Czernin Johannes , Fendler Wolfgang P , Elashoff David , Nickols Nicholas George 
Published: March 2019

TPS136 Background: Salvage radiotherapy (SRT) for prostate cancer (PCa) biochemical recurrence (BCR) after radical prostatectomy (RP) is commonly initiated in patients with PSA < 1 ng/mL, a threshold at which standard-of-care imaging is insensitive for detecting recurrence. The purpose of this randomized phase 3 trial is to evaluate the success rate of SRT for PCa BCR after RP with and without planning based on 68Ga-PSMA-11 PET/CT (PSMA). Here we present the study protocol. Methods: This is an interventional phase 3 randomized prospective open label clinical trial with parallel assignment designed for superiority. Patients who are planned to undergo SRT for PCa BCR with PSA > 0.1 ng/ml are eligible. The choice of treating the prostate bed with/without pelvic lymph nodes, with/without androgen deprivation therapy, is left to the discretion of the treating radiation oncologist (RO). RO may or may not change the RT plan depending on the PSMA findings. Any other imaging is allowed for SRT planning if done per routine care. The primary endpoint is the success rate of SRT measured as biochemical progression-free survival (PFS) after initiation of SRT. Biochemical progression is defined by PSA≥0.2 ng/mL and rising. Based on literature data we hypothesized that 1) the incorporation of PSMA to SRT planning will improve 5-year PFS by 20%, 2) the 5-year PFS will be 60% in standard Arm 1 and 80% in interventional Arm 2, and 3) 13% of subjects randomized to Arm 2 will have extra-pelvic metastasis detected by PSMA and will not be included in analysis of the primary endpoint. We will randomize 193 patients (1:1.13 ratio) to proceed with standard SRT (n = 90) or undergo PSMA scan (free of charge for patients) prior SRT planning (n = 103). Patients will be followed for 5 years after the date of initiation of SRT. Discussion: Main pitfalls in study design include 1) drop-out of patients randomized to the control arm and 2) potential FDA approval of PSMA PET imaging probes in the near future (no randomization to standard arm would be then acceptable). This is the first prospective randomized phase 3 trial designed to determine whether PET/CT can improve outcome of SRT in patients with BCR. Clinical trial information: NCT03582774.
The “ProPSMA Study” clinical trial protocol: A prospective randomized multi-center study of the impact of Ga-68 PSMA PET/CT imaging for staging high-risk prostate cancer prior to curative-intent surgery or radiotherapy.
Authors: Hofman Michael , Murphy Declan G. , Williams Scott , Nzenza Tatenda , Herschtal Alan , Matera Anetta , Marusic Petra , De Abreu Lourenco Richard , Bailey Dale L , Iravani Amir , Hicks Rodney J , Francis Roslyn J , Lawrentschuk Nathan 
Published: March 2019

TPS138 Background: Disease persistence or relapse following curative-intent surgery or radiotherapy of high-risk prostate cancer is not uncommon. This is attributable, in part, to a failure of accurate staging with diagnostic imaging being insensitive for detection of small volume metastatic disease. Prostate-specific-membrane-antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is a new whole body scanning technique that enables visualisation of prostate cancer with high sensitivity. The hypotheses of this study are that PSMA-PET/CT (a) has improved diagnostic accuracy compared to conventional imaging, (b) should be used as a first-line diagnostic test for staging, (c) the improved diagnostic accuracy will result in significant management impact and (d) provides economic benefits when incorporated into the management algorithm. Methods: This is a 300 patient phase III multi-centre randomized study of patients with untreated high-risk prostate cancer defined by Gleason grade group 3-5, PSA ≥ 20ng/ml or clinical stage ≥ T3. Patients are randomized to Gallium-68-PSMA11 PET/CT or conventional imaging, consisting of computer tomography of the abdomen/pelvis and bone scintigraphy with SPECT/CT. Patients with negative, equivocal or oligometastatic disease cross-over to receive the other imaging arm. The primary objective is to compare the accuracy of PSMA-PET/CT to conventional imaging for detecting nodal or distant metastatic disease. Accuracy is defined by a pre-defined “ground truth” scoring system incorporating histopathologic, imaging and clinical follow-up at six months post randomisation. Secondary objectives include comparing management impact, the number of equivocal studies, the incremental value of second-line imaging in patients who cross-over, health economics, radiation exposure, inter-observer agreement and safety of PSMA-PET/CT. Longer term follow-up will also assess the prognostic value of a negative PSMA-PET/CT. 294 of 300 (98%) patients randomised at time of abstract submission. Clinical trial information: 12617000005358.
Design of phase Ib/II study of oral VERU-111, an α and β-tubulin inhibitor, for the treatment of metastatic castration- and androgen-blocking-agent-resistant prostate cancer.
Authors: Markowski Mark Christopher , Eisenberger Mario A. , Antonarakis Emmanuel S. , Yu Evan Y. , Barnette Gary , Rodriguez Domingo , Getzenberg Robert H. , Steiner Mitchell S. 
Published: March 2019

TPS330 Background: VERU-111 is a novel oral small molecule (NCE) that targets α and β-tubulin subunits of microtubules resulting in the inhibition of tubulin polymerization. Agents that target microtubules are among the most effective for the treatment of metastatic cancers. However, these currently available agents target only the β-tubulin subunit and are administered IV. VERU-111 has high oral bioavailability and does not interact with MDR proteins. In nonclinical models, VERU-111 has high activity against many tumor types as well as against prostate cancers that have become resistant to taxanes and novel androgen blocking agents (abiraterone and enzalutamide). In 28-day dog and rat toxicity studies, no neutropenia, myelosuppression, or liver function test changes were observed at oral daily doses in blood concentrations that resulted in antitumor activity in preclinical models. Based on these unique properties, VERU-111 has advanced into a Phase1b/2 clinical trial. Methods: V1011101 is a Phase 1b/2 study, being conducted in at least three sites in the US, evaluating the safety and preliminary efficacy of VERU-111 in men with metastatic castration and androgen blocking agent resistant prostate cancer (mCARPC). The Phase 1b portion of the study consists of 21-day cycles where VERU-111 is taken daily, orally for 7-days followed by a 14-day hiatus (dose cycle). Safety/tolerability of VERU-111 and MTD of VERU-111 will be determined. The Phase 2 will use the selected dose cycle from the Phase 1b and the primary endpoint will be the PSA50 response rate, defined as a decline in PSA to > 50% of baseline level, confirmed with a second measurement at least 3 weeks apart (PCWG3) and determine the pharmacokinetic profile of VERU-111. The secondary endpoints include determining the safety/tolerability of VERU-111 as defined as incidence of CTCAE v5.0 grade ≥3 toxicities; estimating the median PSA progression-free survival (PCWG3); estimating the median progression-free survival (PCWG3); and estimating the objective response rate. It is anticipated that based upon the Phase 1b/2 clinical findings VERU-111 will also be expanded into other cancer types.
Modulation of plasma lipidomic signature in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Mak Blossom , Mahon Kate Lynette , Stockler Martin R. , Joshua Anthony M. , Zhang Alison Yan , Parnis Francis , Meikle Peter , Horvath Lisa 
Published: March 2019

TPS331 Background: Altered lipid metabolism and its impact on prostate cancer (PC) is increasingly recognised, in light of the association between obesity and worse PC outcomes. Our exploratory study was the first to identify baseline plasma lipidomic profiles in men with mCRPC commencing docetaxel that were associated with survival. A prognostic three-lipid signature was derived, consisting of ceramide, sphingomyelin and phosphatidylcholine (HR 4.8, 95% CI 2.06-11.1, p = 0.0003). This signature was independently prognostic when modelled with clinicopathological factors and metabolic characteristics. A key question is whether therapeutic modulation of a patient’s lipid profile is possible. Statins significantly reduce the plasma levels of ceramides, sphingomyelin and cholesterol in cardiovascular disease, suggesting that this therapy could change the poor prognostic lipid profile of mCRPC patients. This trial assesses whether addition of simvastatin to docetaxel for mCRPC can reverse the poor prognostic lipid signature with the aim of developing a precision medicine strategy for metabolic targeting. Methods: This investigator-initiated, multi-centre, open-label, single arm, pilot study enrols patients with mCRPC commencing docetaxel for disease progression, not already receiving a lipid-lowering agent. Patients are treated with simvastatin 40mg orally once daily for 12 weeks, commencing on day 1 of the first cycle of docetaxel. Blood is taken at baseline and after 12 weeks of simvastatin and the plasma lipidomic profile is determined using liquid chromatography and electrospray ionisation-tandem mass spectrometry. The lipidomic profile is classified as either good or poor prognostic as per our three-lipid signature model derived by logistic regression. The primary objective is to assess the rates of conversion from a poor prognostic lipid signature to good prognostic after simvastatin. A sample size of 60 men provides over 90% power, with a 1-sided type 1 error of 10%, to detect conversion to the good prognostic signature in 50% of patients, assuming 25% of patients have the poor prognostic signature at baseline as previously detected. To date, 6 patients have been enrolled to the trial. Clinical trial information: ACTRN12617000965303.
Evaluating the clinical, environmental, genetic, and genomic profile of men with early-onset aggressive prostate cancer (PCa).
Authors: Zarzour Ahmad , Morgans Alicia K. , Palmbos Phillip Lee , Jovanovic Borko , Tomlins Scott A. , VanderWeele David James , Yang Ximing J , Schaeffer Edward M. , Sharifi Roohollah , Meeks Joshua J , Abdulkadir Sarki , Hussain Maha H. A. 
Published: March 2019

TPS333 Background: Although PCa incidence has stabilized or decreased in most age groups, the incidence of metastatic disease has increased among men 50-69 years old. The incidence of fatal PCa has decreased for most age groups, it has remained unchanged in men under 55 years old. These observations are supported by data from 3 randomized trials. In S9346 in newly diagnosed M1, 18% of men (all-comers N = 3040) were ≤ 60 years. A significant percentage of younger men enrolled in CHAARTED had de-novo metastases at diagnosis; among 575 patients without prior local therapy, the median age was 62 years, and among men < 60 years old (n = 274), 80.3% (n = 220) had de novo metastatic disease. Lastly, in S9921 (N = 983) 15% of men ≤ 60 years had pN1 disease at enrollment. A significant proportion of men with metastatic disease progress to castration -resistance within a short interval of initiating androgen-deprivation therapy (ADT) ± docetaxel or abiraterone for metastatic hormone sensitive PCa. Pivotal studies have described genetic abnormalities in aggressive localized or end stage prostate cancers, but early-onset cases and those with early progression on systemic therapy are not included or are under-represented in these studies. Methods: The primary objective of this multi-institutional trial is to characterize the clinical, environmental, genetic and genomic features of high-risk advanced PCa: Cohort 1: men ≤ 60 years old with N1 or M1 at diagnosis or who develop metastases shortly after local therapy; Cohort 2: men with early progression to castration-resistant PCa in ≤ 1 year on ADT ± docetaxel or ADT ± abiraterone. Clinical and environmental history, peripheral blood for cell free DNA and germline analysis will be collected. Primary/metastatic tumor tissue will be tested via the Tempus platform, which includes DNA sequencing, whole transcriptome expression profiling, copy number analysis, comprehensive fusion gene analysis and calculation of tumor mutational burden. We will also prospectively correlate clinical and molecular characteristics with outcomes. To date, 5 patients have been registered.
ODENZA: A study of patient preference between ODM-201 (darolutamide) and enzalutamide in men with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Martineau Geraldine , Foulon Stéphanie , Baciarello Giulia , Joly Florence , Delva Remy , Barthelemy Philippe , Neuzillet Yann , Priou Franck , Hue Anne Sophie , Fizazi Karim 
Published: March 2019

TPS334 Background: In recent years, the treatment of mCRPC has evolved and next-generation androgen receptor (AR)-axis targeting drugs (enzalutamide (ENZ), and abiraterone) have been approved and are routinely used. Darolutamide (DARO) is a new next-generation AR inhibitor which has shown strong activity and minimal toxicity in two phase I-II trials ARADES (Fizazi, Lancet Oncol 2014) and ARAFOR (Massard, Eur Urol 2016) and is currently evaluated in a study in men with non-metastatic CRPC (ARAMIS trial). In contrast to ENZ, DARO does not significantly penetrate the blood-brain barrier in vivo, and this may reduce the risk of fatigue, cognitive impairment, and seizure. Assessing patient preference between DARO and ENZ may contribute further differentiating between these two agents. Methods: ODENZA is a prospective, randomized, open-label, multicenter, cross-over phase II trial assessing patient preference between DARO and ENZ. It was initiated in November 2017. Eligibility criteria include: men with asymptomatic or mildly symptomatic mCRPC, performance status 0-1, no prior next generation AR axis-targeted agent. The randomization is stratified on performance status and prior treatment with a taxane for CSPC. 250 patients will be randomized 1:1 to: 12-week ENZ followed by 12-week DARO or 12-week DARO followed by 12-week ENZ. The primary endpoint is patient preference between DARO and ENZ, assessed after the second treatment period. A two-sided binomial test with a power of 80% and a bilateral α of 0.05 will be used. Secondary endpoints include: reasons for patient preference, dose modifications and time to dose modification, safety, fatigue (BFI), cognitive function as assessed by Cogstate computerized cognitive tests, depression screening (CES-D) test, frequency of falls, PSA declines using Waterfall plots after each treatment period, Progression-Free Survival (PFS), association between 4-weeks PSA value and PFS, incidence of cancer progression or death, and tumor response. The study is recruiting. By October 23, 2018, 75 patients have been screened and 66 have been randomized. Clinical trial information: NCT03314324.
ProSTAR: A phase Ib/II study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Taplin Mary-Ellen , Hussain Arif , Shah Satish , Shore Neal D. , Agrawal Manish , Clark William , Edenfield William Jeffery , Nordquist Luke T. , Sartor Oliver A , Butrynski James E. , Chatta Gurkamal S. , Fleming Mark T. , Oh William K. , Bradley Bill , Piel Jessica , Nash David , Colak Gozde , Li Jian , Lebedinsky Claudia , Antonarakis Emmanuel S. 
Published: March 2019

TPS335 Background: EZH2 is frequently mutated and/or overexpressed in numerous cancers. High EZH2 expression is correlated with poor outcomes in prostate cancer patients (Varambally, 2002). EZH2 inhibition combines synergistically with anti-androgen therapies in preclinical models of advanced prostate cancer, suggesting epigenetic reprogramming as a pathophysiologic mechanism to enhance the combination therapy (Ku, 2017; Xiao 2018; Constellation, unpublished). CPI-1205 is a potent, selective, and cofactor-competitive inhibitor of wild type and mutant EZH2 catalytic activity, which demonstrates anti-proliferative effects in prostate and other cancer cell models. Methods: We present a Phase 1b/2 multicenter study of CPI-1205 combined with either E or A/P in patients with mCRPC, which includes phase 1 dose escalation, an expansion cohort in heavily pretreated patients (HPEC), and a randomized phase 2 study. Key eligibility criteria include progressive mCRPC in patients previously treated with a second-generation androgen inhibitor, ECOG 0-1, and measurable or non-measurable disease. During the phase 1b, patients will receive CPI-1205 continuously in 28-day cycles combined with the standard dose of either E (160mg PO once daily) or A/P (1000mg PO once daily/5 mg BID). The primary objective in Phase 1b is to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of CPI-1205 combined with either E or A/P. Secondary objectives include safety, pharmacokinetic and pharmacodynamic profiles, and anti-tumor activity. The HPEC arm, with Simon’s 2-stage design, may begin with the regimen that is deemed safe by the study safety committee. The primary endpoint of the HPEC arm is objective response rate (ORR) per PCWG3, with a requirement ≥ 1 measurable lymph node at baseline. Once RP2D is established, we will start a randomized Phase 2 trial of E or A/P combined with CPI-1205 vs. E or A/P alone. The co-primary endpoint includes PSA50 and composite response rate (either CTC 30% reduction or ORR per PCWG3). Patient accrual in US sites began in December 2017. Clinical trial information: NCT03480646.
A phase II, multicenter, single-arm trial of CV301 plus atezolizumab (Atezo) in locally advanced (unresectable) or metastatic urothelial cancer (UC).
Authors: Sonpavde Guru , Maughan Benjamin Louis , Wei Xiao X. , McGregor Bradley Alexander , Kilbridge Kerry L. , Lee Richard J. , Yu Evan , Schweizer Michael Thomas , Montgomery Robert B. , Cheng Heather H. , Hsieh Andrew Caleb , Birhiray Ruemu E. , Gabrail Nashat Y. , Nemunaitis John J. , Rezazadeh Arash , Van Veldhuizen Peter J. , Vogelzang Nicholas J. , Heery Christopher Ryan , Grivas Petros 
Published: March 2019

TPS494 Background: Anti-PD1/PD-L1 can achieve durable responses in advanced UC but most patients (pts) do not respond. Combination strategies with agents that “prime” the immune system may improve outcomes. CV301 comprises two recombinant poxviruses, Modified Vaccinia Ankara (MVA) and Fowlpox (FPV), encoding the human transgenes for CEA, MUC-1, and a Triad of Co-stimulatory Molecules (TRICOM: ICAM-1, LFA-3, and B7-1). MVA-CV301 is used for priming doses and FPV-CV301 is used for booster doses to achieve a heterologous prime boost regimen. In preclinical studies, BN-platform vaccine plus PD1/PD-L1 inhibitors exhibited synergistic anti-tumor efficacy, T-cell infiltration, and PD-L1 upregulation in tumors. CEA and MUC-1 are expressed, in 41-90% and 55-91% of any stage UC, respectively, and in ~100% of metastatic UC. An ongoing Phase Ib trial of CV301 plus anti-PD-1 agent has demonstrated a similar safety profile to anti-PD-1 monotherapy with only mild vaccine-related adverse events (AEs). Methods: This is a Phase 2, single-arm, multi-institutional trial designed to study CV301 plus atezo as 1st-line treatment in pts with advanced UC ineligible for cisplatin-based chemotherapy regardless of PD-L1 (Cohort 1) and as salvage treatment in pts with UC progressing after platinum-based chemotherapy (Cohort 2). MVA-CV301 is given subcutaneously (SC) on Days 1 and 22 and FPV-CV301 SC every 21 days for 4 doses, then every 6 weeks until 6 months, then every 12 weeks until 2 years. Atezo 1200mg is given every 21 days. Primary endpoint is objective response rate (ORR; RECIST 1.1). Secondary endpoints: immune response, OS, PFS, response duration, AEs. Tumor and serial blood samples will be collected for biomarker analyses; 1-sided α is 0.025/cohort in this design. With a 2-stage design, success criteria are based on historic ORR (H0) and alternative ORR (H1) with ≥70% power. For Cohort 1, assuming H0 = 0.23, H1 = 0.43, then Cohort 1 sample size N1= 14, responders required at stage 1 to continue R1≥3, total accrual goal N = 33, total responders to reject H0, R≥13. For Cohort 2, assuming H0 = 0.15, H1 = 0.33, then N1= 13, R1≥2, N = 35, R≥10. Accrual has begun; completion is expected within 1 year. Clinical trial information: NCT03628716.
ATLAS: A phase II open-label study of rucaparib in patients with locally advanced or metastatic urothelial carcinoma (mUC).
Authors: Grivas Petros , Vogelzang Nicholas J. , Alva Ajjai Shivaram , Feyerabend Susan , Loriot Yohann , Necchi Andrea , Gupta Sumati , Josephs Debra Hannah , Rodriguez-Vida Alejo , Srinivas Sandy , Zakharia Yousef , Wride Kenton , Thomas Daleen , Dusek Rachel , Simmons Andrew , Nepert Dale L. , Chowdhury Simon 
Published: March 2019

TPS496 Background: There are currently no standard treatment options for patients with mUC that has progressed on or after platinum (cisplatin/carboplatin)–based chemotherapy (PBC) and/or immune checkpoint inhibitors (ICIs), emphasizing the need for new therapies. Analysis of The Cancer Genome Atlas bladder cancer dataset suggests that approximately 60% of bladder cancer tumors have homologous recombination deficiency (HRD), as defined by high genomic loss of heterozygosity (LOH) or a deleterious mutation in a homologous recombination pathway gene. The poly(ADP-ribose) polymerase inhibitor (PARPi) rucaparib has demonstrated activity in tumors with HRD and in homologous recombination proficient tumors in the recurrent ovarian cancer setting. The ATLAS (NCT03397394) trial will evaluate the efficacy and safety of rucaparib in patients with locally advanced/unresectable UC or mUC treated with 1–2 prior anticancer treatments. Methods: Eligible patients must have measurable disease per RECIST v1.1, adequate organ function, and radiographic progression after 1–2 prior regimens (eg, PBC and/or ICI). Confirmation of HRD status before enrollment is not required, but fresh tumor tissue or recently obtained archival tissue is mandatory for HRD profiling. Prior PARPi treatment is exclusionary. All patients will receive oral rucaparib 600 mg BID until disease progression or other reason for discontinuation. The coprimary endpoints are confirmed objective response rate (investigator-assessed per RECIST v1.1) in the intent-to-treat and HRD-positive (signature based on tumor genomic LOH) populations. Secondary endpoints include response duration, progression-free survival, overall survival, safety, and pharmacokinetics. Exploratory endpoints include evaluation of molecular biomarkers associated with response and resistance to rucaparib, including changes in plasma and tumor samples, and circulating tumor DNA. Patients are being enrolled in 6 countries (France, Germany, Italy, Spain, UK, and USA), with a target enrollment of 200 patients. The study has > 90% power to reject the null hypothesis (P = 0.10) at a 5% significance level if the true response rate for rucaparib is 20%. Clinical trial information: NCT03397394.