bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRITON3: An international, randomized, open-label, phase III study of the PARP inhibitor rucaparib vs. physician’s choice of therapy for patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD).
Authors: Ryan Charles J. , Abida Wassim , Bryce Alan Haruo , Balar Arjun Vasant , Dumbadze Igor , Given Robert W. , Morris David , Petrylak Daniel Peter , Redfern Charles H. , Scher Howard I. , Watkins Simon Paul , Simmons Andrew , Passler Luke , Golsorkhi Tony , Chowdhury Simon 
Published: February 2018

TPS389 Background: Recent data have shown that up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or another homologous recombination DNA repair gene. Such mutations can be used as a molecular marker to select patients for targeted treatment with poly(ADP-ribose) polymerase inhibitors (PARPis), which are lethal to cells with HRD. Treatment with PARPis has shown preliminary evidence of antitumor activity in patients with mCRPC and a mutation in a homologous recombination DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent inhibitor of PARP1, PARP2, and PARP3, in patients with mCRPC associated with HRD. Methods: TRITON3 (NCT02975934) is a randomized, phase 3 study evaluating rucaparib 600 mg BID vs physician’s choice of abiraterone, enzalutamide, or docetaxel in patients with mCRPC and a deleterious germline or somatic BRCA1, BRCA2, or ATM mutation (identified by prior local testing or central testing during screening). Patients must have progressed on androgen receptor signaling–directed therapy in the mCRPC setting; prior PARPi treatment or chemotherapy for mCRPC are exclusion criteria. Patients will be randomly assigned in a 2:1 ratio to either rucaparib or physician’s choice, with the possibility for cross over from the comparator treatment to rucaparib upon radiographic progression confirmed by independent radiology review. The primary endpoint is radiographic progression-free survival (modified RECIST v1.1/PCWG3 criteria) assessed by independent radiology review. Secondary endpoints include objective response rate, duration of response, patient-reported outcomes, overall survival, and safety. Pretreatment blood samples collected from all patients will enable development of a noninvasive plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈400) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02975934.
A phase Ib open-label, dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer.
Authors: Vaishampayan Ulka N. , Narayan Vivek , Wise David , Lang Joshua Michael , Lowentritt Benjamin H , Mellado Begona , Carles Joan , Sáez M Isabel , Abida Wassim , Taplin Mary-Ellen , Azad Arun , Wang Karrie , Barbash Olena , Ferron-Brady Geraldine , Fecteau Doug , Khaled Ahmed Hussein , Dhar Arindam , De Bono Johann S. 
Published: February 2018

TPS391 Background: Metastatic castrate-resistant prostate cancer (mCRPC) remains an incurable illness as resistance develops after androgen deprivation therapy (ADT) and/or androgen receptor (AR) axis targeted therapies. The bromodomain (BRD) and extraterminal (BET) proteins are critical for transcription. Preclinically, one of these proteins, BRD4, acts in complex with AR to mediate androgen signaling that leads to prostate cell growth and proliferation. GSK525762 is an oral pan-BET inhibitor that suppresses BET dependent activated AR-driven transcription. Combined with androgen production or receptor targeted agents like abiraterone or enzalutamide, GSK525762 may enhance efficacy of or overcome resistance to either agent. Methods: This is a Phase Ib open-label, dose-escalation study to evaluate the safety and efficacy of oral administration of GSK525762 in combination with either abiraterone plus prednisone (Arm A) or enzalutamide (Arm B) in mCRPC patients whose disease has progressed on prior abiraterone or enzalutamide. Patients must have documented prostate cancer progression as assessed by rising PSA or radiographic progression of soft tissue by PCWG3-modified RECIST 1.1 criteria or bone metastasis. Dose escalation is designed to identify safe doses to move into dose expansion. Dose expansion will explore safety and efficacy in patients who failed in first line (L2 population) or after multiple lines of prior therapy (LX population). Primary objectives include defining the safety, tolerability and clinical activity of GSK525762 when combined with products in Arm A or Arm B. Primary clinical activity endpoint is defined as the response rate of subjects achieving a 50% or more reduction from baseline of PSA at 12 weeks or thereafter. Dose escalation will employ a modified Toxicity Probability Interval (mTPI) design. Dose expansion will use a Bayesian adaptive design, which will calculate posterior probability that utility of the dose is clinically significant at interim futility analysis for each dose level. Funding: GSK Clinical trial information: NCT03150056.
A phase 2 trial of ODM-201 maintenance therapy in patients with metastatic castration resistant prostate cancer (mCRPC) previously treated with a AR targeting agent and non-progressive on a second line taxane (SAKK 08/16).
Authors: Gillessen Silke , Hayoz Stefanie , Fuhrer Andrea Corinne , Biaggi Christine , Pedrazzini Augusto , Procopio Giuseppe , Cathomas Richard 
Published: February 2018

TPS393 Background: Treatment with the AR targeting agents abiraterone or enzalutamide followed by a taxane is currently the most used treatment for men with mCRPC. Further treatment after response to chemotherapy is only indicated in case of disease progression, with limited treatment options available. ODM-201 (Darolutamide) is a second-generation oral androgen receptor antagonist which has demonstrated a good safety profile and antitumor activity in mCRPC. This trial evaluates whether the immediate use of darolutamide after successful chemotherapy can prolong radiographic progression-free survival (rPFS) compared with watchful waiting in patients with mCRPC. Methods: This is a multicenter, randomized, double-blind, placebo-controlled phase 2 trial (NCT02933801) conducted in approximately 19 sites in Switzerland and Italy. Patients with mCRPC are required to have been previously treated with abiraterone or enzalutamide and have no evidence of disease progression on docetaxel or cabazitaxel. Patients (N = 88) will be randomized 1:1 to receive 600 mg darolutamide BID or placebo BID, both with best supportive care, until disease progression. Patients will be stratified by country, WHO performance status (0, 1 vs 2), presence/absence of visceral metastases, enzalutamide vs abiraterone prior to chemotherapy, and planned start of trial treatment after last taxane dose ( < 35 days vs ≥35 days). The primary endpoint is rPFS at 12 weeks after treatment initiation. The secondary endpoints are rPFS, time to PSA progression, time to symptomatic/clinical progression, event-free survival, overall survival, PSA response (30%, 50%, 90%, and best), duration of PSA response (50%), adverse events, and fatigue. The rPFS rate at 12 weeks after treatment initiation will be compared between the two treatment arms using a one-sided test statistic using the Kaplan–Meier method. Recruitment is ongoing, with the first patient randomized on 20.04.2017. Clinical trial information: NCT02933801.
A multicenter, randomized, controlled trial comparing the occurrence of major adverse cardiovascular events (MACEs) in patients (pts) with prostate cancer (pc) and cardiovascular disease (CVD) receiving degarelix (GnRH receptor antagonist) or leuprolide (GnRH receptor agonist).
Authors: Slovin Susan F. , Melloni Chiara , Mansor-Lefebvre Samreen , Neijber Anders , Roe Matthew 
Published: February 2018

TPS395 Background: Epidemiological studies showed an association between GnRH agonists and a long-term increased risk of CVD, early after treatment initiation and with a higher risk seen in pts with pre-existing CVD. Retrospective pooled safety analyses of 6 randomized trials showed that significantly fewer pts treated with the GnRH receptor antagonists, degarelix, had a CV event or death compared with pts receiving a GnRH receptor agonist. In those studies showing an increased CV risk, Androgen-Deprivation Therapy (ADT) was primarily with GnRH receptor agonists. The mechanistic differences between GnRH antagonists and agonists, including testosterone surge and time to suppression at initiation, effect on follicle-stimulating hormone and on GnRH receptors e.g. T-lymphocytes in atherosclerotic plaque, raises the possibility of different CV risk profiles. The PRONOUNCE trial is the first to prospectively assess whether a GnRH agonist/antagonist can worsen pre-existing CVD; assess the impact of GnRH agonist/antagonist on CV risk biomarkers; and effects of hormonal therapy on immune system. Methods: PRONOUNCE is a multi-center, randomized, controlled trial of 900 men with pc and concomitant CVD, assessing adjudicated MACEs, i.e. myocardial infarction (fatal, non-fatal), stroke (fatal, non-fatal), or death in pts randomized 1:1 to either degarelix or leuprolide according to label recommendations for up to one year. Eligibility include pre-defined CVD, metastatic or locally advanced pc; high-risk disease with plan for definitive radiation therapy (RT); recurrence after local therapy with PSA doubling time <12 months; or salvage RT with neoadjuvant/adjuvant ADT for at least 12 months. Serum samples are collected for the analysis of various CV, inflammatory, and immune biomarkers. The primary endpoint will be based on Kaplan-Meier estimator of survival function and stratified for age group and region. Interim analysis is scheduled when 50% of MACE events have occurred allowing the DSMB to recommend for sample size correction. Clinical trial information: NCT02663908.
AR-V7 in Asian patients with metastatic CRPC: A multinational, multicentre study.
Authors: Tan Hui Shan , Wong Alvin Seng Cheong , Chong Kian Tai , Wong Siew Wei , Saad Marniza Bte , Ng Chi-Fai , Horie Shigeo , Chansriwong Phichai , Tan Min-Han , Toh Chee-Keong , Ng Quan Sing , Lim Kiat Hon , Tay Liang Seah , Ong Whee Sze , Kanesvaran Ravindran 
Published: February 2018

TPS401 Background: The detection of androgen-receptor splice variant 7 (AR-V7) mRNA transcript in circulating tumor cells (CTCs) of progressive metastatic castration-resistant prostate cancer (mCRPC) patients is associated with resistance to abiraterone and enzalutamide. This finding was validated by other studies that found no association between the presence of AR-V7 transcripts and response to both docetaxel and cabazitaxel. The results suggest that AR-V7 could represent a biomarker to guide treatment selection in mCRPC. However, data in Asian population is limited. This multinational study aims to prospectively investigate the incidence and prevalence of ARV7 in Asian mCRPC patients. This is also the first study to evaluate 3 different detection platforms and help provide guidance on which will be the best platform to carry forward in terms of clinical utility. Methods: 101 Asian subjects with histologically confirmed mCRPC whom are going to be treated with AR-directed therapies (abiraterone, enzalutamide) or taxane chemotherapy (docetaxel) will be enrolled from Singapore, Malaysia, Thailand, Hong Kong and Japan. Subjects will be excluded if they plan to receive additional concurrent anticancer therapies. Peripheral-blood samples will be obtained at baseline and at the time of progression. We will use 3 methods to analyse the samples: (i) CTC enrichment platform followed by automated immunofluorescent staining for DNA, cytokeratins, CD45 (lymphocyte common antigen), and AR-V7; (ii) CTC enrichment platform followed by reverse-transcription polymerase chain reaction analysis; and (iii) the AdnaTest platform for molecular characterization of CTCs. Subjects will be followed up to 2 years. The clinical outcomes of AR-V7-positive and AR-V7-negative patients will be compared. PSA response rates will be compared using the Fisher exact test. Time-to-event outcomes (PFS, OS) will be evaluated using Kaplan-Meier analysis, and survival time differences will be compared using log-rank test. Cox regression analyses will be used to assess the effect of AR-V7 status in predicting clinical outcomes. The study is in progress; 32 of 101 planned patients have been enrolled at the end of September 2017.
Radium-223 and atezolizumab in platinum refractory urothelial carcinoma with bone metastases: NCT03208712.
Authors: Yentz Sarah Elizabeth , Reimers Melissa Andrea , Daignault Stephanie , Piert Morand , Alva Ajjai Shivaram 
Published: February 2018

TPS543 Background: Immunologically, radiation increases tumor antigen release, cytotoxic CD8+ T cell infiltration while reducing myeloid derived suppressor cells (MDSCs), with distant abscopal responses occasionally reported. Radium-223 is a systemically administered bone-targeted alpha emitter that causes double-stranded DNA breaks and may induce similar immune effects. Anti-PD(L1) immune checkpoint inhibitor monotherapy with Atezolizumab demonstrates objective responses in metastatic urothelial cancer. In mouse models, radiotherapy and checkpoint immune inhibitor in combination synergistically reduce tumor growth. We hypothesized that the combination of Atezolizumab and Radium-223 in metastatic urothelial cancer pts with bone metastases would target bone metastases more effectively and yield higher response rates. Methods: Eligibility criteria for this single-site, phase 2 trial of Radium-223 in combination with Atezolizumab include diagnosis of advanced urothelial carcinoma with ≥1 bone metastasis, RECIST 1.1 measurable disease, progression of disease after/on platinum-containing chemotherapy in the metastatic or perioperative setting, ECOG PS of 0-2 and adequate organ function. Twenty-two pts will be treated with Radium-223 at a dose of 55 kBq/kg IV and Atezolizumab 1200mg IV both on day 1 of 21 day cycles. Up to 6 doses of Radium-223 will be administered. Atezolizumab will be continued until lack of clinical benefit or intolerable toxicity for up to 17 cycles. Routine response assessment will be performed every 12 weeks. Primary endpoint is best overall response per RECIST 1.1. Secondary objectives are to determine the safety and tolerability; determine the overall survival, progression free survival, clinical benefit rate, complete response rate and duration of response; and changes in quality of life as assessed by the EORTC QLQ-C30 score. Exploratory objectives are PD-L1 status by IHC, changes in bone scan per EXINI bone scan index and efficacy measures by irRC. If ≥6 pts respond, corresponding to an ORR of 27% with 80% confidence limits of 15%-43%, further study of the combination would be warranted. Blood and archival tissue will be collected for correlative studies. Clinical trial information: NCT03208712.
A multicenter clinical trial of intravesical BCG in combination with ALT-803 in patients with BCG-unresponsive non-muscle invasive bladder cancer.
Authors: Chamie Karim , Salmasi Amirali , Rosser Charles Joel , Rock Amy , Ferguson Lydia , Wong Hing C. 
Published: February 2018

TPS544 Background: BCG unresponsive NMIBC includes patients with persistent high-grade disease or recurrence within 6 months of receiving at least two courses of BCG; or T1 high-grade disease at the first evaluation following BCG induction alone. The recommendation after failing BCG in patients suitable for surgery is cystectomy or for unwilling/unfit patients, salvage chemotherapy or immunotherapy (administered with limited success). This highlights a critical need for novel preservation therapies to facilitate a better quality of life and reduce health-care costs for patients who are unresponsive to BCG (Correa 2015, Dalbagni 2006, Dinney 2013, Kamat 2017). Altor BioScience has initiated a phase II clinical study in BCG unresponsive patients to expand on promising data collected from a compassionate use patient who remains disease free more than 2.5 years after ALT-803 plus BCG treatment for refractory NMIBC (Huang 2017). Methods: This is a Phase II, open-label, single-arm, multicenter study of intravesical BCG plus ALT-803 in patients with BCG unresponsive high grade NMIBC. Group A will enroll patients who have histologically confirmed presence of CIS [with or without Ta or T1 disease]. Group B will enroll patients who have histologically confirmed high-grade Ta or T1 disease (in the absence of CIS). All patients will receive BCG plus ALT-803 weekly for 6 consecutive weeks. A cystoscopy will be performed at Week 12. Patients with no disease or low-grade Ta will receive a maintenance course of therapy (3 weekly instillations of BCG plus ALT-803). Patients with residual CIS and/or high-grade Ta will receive a re-induction course of therapy. Presence of Ta will require a TURBT. Patients with greater than or equal to T1 disease or new CIS will be deemed treatment failures. Patients with a Complete Response (CR) or low-risk disease at Months 6, 9 and 12 are eligible for continued BCG plus ALT-803 maintenance. Patients will be followed for recurrence, progression, and survival. The primary endpoint is to assess complete response (CR; absence of lesions on cystoscopy or negative, for cause, biopsies along with negative urine cytology) of CIS at six months. Enrollment is underway. Clinical trial information: NCT03022825.
P3BEP (ANZUP 1302): An international randomized phase 3 trial of accelerated versus standard BEP chemotherapy for adult and paediatric male and female patients with intermediate and poor-risk metastatic germ cell tumors (GCTs).
Authors: Nayar Namrata , Lawrence Nicola Jane , Stockler Martin R. , Martin Andrew James , Yip Sonia , Wong Nicole , Yeung Annie , Friedlander Michael , Mazhar Danish , Pashankar Farzana , Quinn David I. , McDermott Ray , Walker Rick , Winstanley Mark , Hanning Fritha J. , Weickhardt Andrew James , Stevanovic Amanda Gwendolyn , Davis Ian D. , Toner Guy C. , Grimison Peter S. ,   Australia and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: February 2018

TPS574 Background: Bleomycin, etoposide, cisplatin (BEP) given 3-weekly x 4 remains standard 1st line chemotherapy for metastatic GCTs. Acceleration of standard regimen with shorter cycle lengths has improved cure rates in other cancers. This is the first international randomised clinical trial for intermediate and poor-risk metastatic extracranial GCTs involving both adult and paediatric age group males and females. We aim to determine if accelerated BEP is superior to standard BEP. Methods: DESIGN: Open label, randomised, stratified multicentre, 2 stage, phase 3 trial. Primary endpoint for stage I (n = 150) is complete response rate (RR), and for entire trial (n = 500) is progression free survival (PFS). SAMPLE SIZE: 150 and 500 patients gives > 80% power to detect a 20% improvement in RR and 7% absolute improvement in 2yr PFS, respectively. POPULATION: Males and females aged 11-45 years with intermediate or poor-risk metastatic GCTs of the testis, ovary, retroperitoneum or mediastinum for 1st line chemotherapy. TREATMENT: Randomisation 1:1 to 4 cycles of “standard BEP” or “accelerated BEP”: cisplatin 20mg/m2 IV days (D) 1-5; etoposide 100mg/m2 IV D1-5; bleomycin 30000 IU IV (D 1, 8, 15 or D 2, 9, 16 of a 21 day cycle; D 1, 8 or D 2, 9 of a 14 day cycle); and peg G-CSF or Filgrastim; given every 3 weeks or every 2 weeks respectively. Accelerated BEP arm receives 4 additional weekly doses of bleomycin. ASSESSMENTS: Response assessments at 30 day safety assessment, and 6 months from randomisation or after all post-chemotherapy intervention is completed. Regular follow-up up to 5 years, then annually. Archival tumour tissue and baseline blood collected for translational substudies. STATUS: 25 sites open in ANZ, 1/19 sites open in UK (led by Cambridge Clinical Trials Unit), 41 patients recruited by September 2017. International collaborations with USA (led by Children’s Oncology Group) and Ireland (led by Cancer Trials Ireland) confirmed with sites expected to open by late 2017 and more sites sought for stage 2. Clinical trial information: NCT02582697.
A phase 2 study of cabozantinib as first-line treatment in collecting ducts renal cell carcinoma: The BONSAI trial.
Authors: Procopio Giuseppe , Ratta Raffaele , Fucà Giovanni , Grassi Paolo , Porcu Luca , Prisciandaro Michele , Calareso Giuseppina , Montone Rosanna , Sorrentino Margherita , Verzoni Elena 
Published: February 2018

TPS709 Background: Collecting ducts carcinoma (CDC) is a rare and aggressive form of renal cell carcinoma, characterized by extremely poor prognosis and resistance to agents effective in other forms of RCC. We hypothesized that cabozantinib, an inhibitor of multiple kinases including VEGFR 2, MET and AXL, may be superior in terms of efficacy to other angiogenesis inhibitors in the treatment of CDC due to its high-spectrum of activity against multiple and non-redundant oncogenic pathways. Methods: The BONSAI study is a prospective, single-centre, single-arm phase II trial evaluating cabozantinib in patients with untreated locally advanced or metastatic CDC. Cabozantinib will be administered at the dose of 60 mg orally once daily until the evidence of disease progression (PD) evaluated by RECIST 1.1 or unacceptable toxicity. Primary objective is the evaluation of objective response rate (ORR). Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety profile of cabozantinib. Exploratory objectives include the evaluation of genetic and immunological landscape of CDC and its correlation with response to treatment. Overall, 23 patients will be enrolled into the study based on a Simon’s two-stage optimal design. In order to reject an ORR equal to 15% with a one-sided alpha error of 10% and to detect an ORR equal to 35% with a power of 80%, 9 patients will be enrolled in the first stage. If at least 2 responses will be observed in the first stage, 14 additional patients will be included in the second stage. If at least 6 responses will be observed at the second stage the activity of cabozantinib will be proved. First patient enrollment is scheduled in November 2017.