bluuebunny/crossref_metadata_2025_split huggingface dataset:
c15-153: Randomized phase IB/II study of enzalutamide with and without ribociclib in patients with metastatic castrate resistant, chemotherapy naïve prostate cancer that retains RB expression.
Authors: Kelly William Kevin , Godwin James Luke , Hoffman-Censits Jean H. , Knudsen Karen E. , De Leeuw Renee , Leiby Benjamin E. , Southwell Traci , Hubert Christine , Smith David C. , Chatta Gurkamal S. , Aghalar Jahan , Scher Howard I. , Bose Rohit , Autio Karen A. , Abida Wassim , Slovin Susan F. ,   The Prostate Cancer Clinical Trials Consortium
Published: February 2018

TPS384 Background: Current data suggests RB function is often attenuated in tumors through hyperphosphorylation; thus, RB activity can be “re-awakened” in RB+ tumors by suppressing key kinases that phosphorylate RB (CDK4/6). Recent findings identified perturbations of the RB tumor suppressor as a major mechanism of androgen receptor (AR) deregulation and castration-resistant prostate cancer (CRPC) formation. Our preclinical studies indicate RB+ tumors are exquisitely responsive to CDK4/6 inhibitors, revealing tumor-specific cytostatic and cytotoxic effects. These analyses strongly support the use of CDK4/6 inhibitors to activate the RB pathway, and impede the transition to CRPC. We hypothesize the CDK4/6 inhibitor ribociclib (ribo) in combination with enzalutamide (enz) in patients (pts) with progressive metastatic CRPC (mCRPC) that retains RB expression will significantly increase the efficacy of enz. Methods: This is a phase IB/II study of pts with mCRPC with RB+ tumors who have not received chemotherapy. Since ribo and enz have not been combined together in pts, the standard doses of enz and a traditional 3x3 dose escalation schema will be used in phase I to establish the safe dose of the combination; this dose will be used in phase II. Since both drugs are metabolized via the liver, plasma concentrations of ribo and enz will be monitored. To determine if ribo will improve the clinical activity in pts treated with enz, a randomized (1:1) phase II study using enz as the control arm vs. the combination will follow. This study will evaluate an early clinical activity readout, thus the primary phase II endpoint will be a proportion of pts with ≥ 50% PSA decline at 12 weeks. Secondary endpoints are rPFS, PSA PFS, OS and safety. If there is clinical activity noted, further randomized testing will be required to establish ribo clinical benefit in combination with enz. 5 sites are participating, managed by the Prostate Cancer Clinical Trials Consortium. Dose Levels 1 and 2 have been completed without any DLTs in the phase I portion of the study. A review of Dose Level 3 is planned for October 2017. Clinical trial information: NCT02555189.
A randomized phase II study comparing cabazitaxel/prednisone to cabazitaxel alone for second-line chemotherapy in men with metastatic castrate resistant prostate cancer (mCRPC): CABACARE.
Authors: Buonerba Carlo , Bosso Davide , De Placido Sabino , di Lorenzo Giuseppe 
Published: February 2018

TPS387 Background: In the TROPIC trial, cabazitaxel (CAB) plus daily prednisone (PDN) was associated with a significant advantage in OS and PFS in docetaxel (DOC)-pretreated patients. Whether daily prednisone may significantly contribute to cabazitaxel efficacy or improve its safety profile is unknown. In the CHARTEED trial, DOC was administered without daily PDN with no concerns about the lack of efficacy or greater toxicity. Safety data about CAB without PDN are missing. Corticosteroids present multiple biological effects, which may potentially be either positive, such as those mediated by adrenal androgen and cytokine suppression, or detrimental, such as those associated with the activation of the glucocorticoid receptor (GR) and of the androgen receptor (AR). Furthermore, PDN is a CYP3A4 inducer and can potentially negatively affect cabazitaxel clearance. Finally, AR-V7 positivity in circulating tumor cells and retinoblastoma (RB) loss/inactivation have been identified as potential mechanisms of resistance to hormonal and chemotherapy treatments in prostate cancer. For this reason, we also aim to evaluate if CAB activity is related to such biomarkers. Methods: CABACARE is a randomized, phase II, open label, multi center study comparing CAB at 25 mg/m2 q21 plus daily PDN (10 mg) vs CAB at 25 mg/m2 q21 alone in mCRPC pts progressed during or after DOC treatment. The study is designed to test non inferiority in terms of PFS, according PCWG-2, of CAB alone vs CAB plus PDN assuming that the two arms are equally effective. Each arm will enroll 110 pts. Main secondary objectives are: safety, QoL, pain assessment, overall response rate (ORR), PSA response, time to PSA progression, Time to radiological progression; OS; time to skeletal related events (SRE). The influence of Arv7 and RB status on CAB activity will also be evaluated. Clinical trial information: 2016-005251-25.
TRITON2: An international, multicenter, open-label, phase II study of the PARP inhibitor rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD).
Authors: Abida Wassim , Bryce Alan Haruo , Balar Arjun Vasant , Chatta Gurkamal S. , Dawson Nancy Ann , Guancial Elizabeth A. , Hussain Arif , Jha Gautam Gopalji , Lipsitz David Uri , Patnaik Akash , Petrylak Daniel Peter , Ryan Charles J. , Stanton Thomas S. , Vogelzang Nicholas J. , Zhang Jingsong , Simmons Andrew , Go Jowell , Golsorkhi Tony , Chowdhury Simon , Scher Howard I. 
Published: February 2018

TPS388 Background: 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 (HR) DNA repair gene that can serve as a molecular marker to select those who may respond to poly(ADP-ribose) polymerase inhibitors (PARPis). PARPis are lethal to cells with HRD, and PARPi treatment has shown preliminary evidence of an antitumor effect in patients with mCRPC who harbor a mutation in an HR 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 PARP1, PARP2 and PARP3 inhibitor, in patients with mCRPC associated with HRD. Methods: TRITON2 (NCT02952534) is a phase 2 study evaluating rucaparib 600 mg BID in patients with mCRPC. Patients with a deleterious germline or somatic BRCA1, BRCA2 or ATM mutation (per prior local test or central test during screening) will be enrolled into 1 of 2 cohorts based on the presence or absence of measurable visceral and/or nodal disease. An exploratory cohort will enroll patients with an alteration in any of 12 other prespecified HR genes (eg, RAD51C, RAD51D and PALB2), with or without measurable visceral and/or nodal disease. Patients must have progressed on androgen receptor signaling–directed therapy and 1 prior taxane-based chemotherapy for mCRPC. Patients who received prior treatment with a PARPi, mitoxantrone, cyclophosphamide or platinum-based chemotherapy are excluded. The primary endpoint is objective response rate measured using modified RECIST v1.1/PCWG3 for patients with soft-tissue disease and prostate-specific antigen response for patients with nonmeasurable disease. Secondary endpoints include duration of response, radiographic progression-free survival, overall survival, clinical benefit rate and safety. Pretreatment blood samples collected from all patients will enable development of a plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈160) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02952534.
A phase Ib/II trial of indomethacin and enzalutamide to treat castration-resistant prostate cancer (CRPC).
Authors: Pan Chong-xian , Lara Primo , Evans Christopher P. , Parikh Mamta , de Vere White Ralph , Dall'era Marc , Liu Chengfei , Robles Daniel , Gao Allen 
Published: February 2018

TPS394 Background: Enzalutamide (Enza) and abiraterone (Abi) are commonly used to treat CRPC. Resistance is the most common cause of treatment failure. We discovered that a critical steroidogenic enzyme AKR1C3 was significantly elevated and contributed to intratumoral androgen synthesis in Enza-resistant prostate cancer cells and tumors. Overexpression of AKR1C3 induced androgen receptor variant 7 (AR-V7) expression, while inhibition of AKR1C3 downregulated AR-V7. We then discovered that indomethacin (Indo) inhibited AKR1C3 activation and sensitized resistant CRPC cells to Enza and Abi. One patient accidentally took Indo and achieved biochemical as well as radiological response of his prostate cancer. These findings prompted us to design a clinical trial to test the combination of Indo with Enza for the treatment of CRPC and to study the underlying mechanisms of action and resistance. Methods: This investigator-initiated single-arm Phase Ib/II trial enrolls patients with progressive CRPC after Abi, adequate vital organ function, ECOG performance status 0-2, and serum testosterone < 50 ng/dl. Major exclusion criteria include prior Enza treatment, brain metastasis and history of seizure. In the Phase Ib cohort, patients receive Enza 160 mg po qd and Indo 50 mg po tid to determine toxicity. The Phase II expansion will enroll 26 patients with 21 evaluable patients. This sample size provides 90% power to detect, at the 0.05 level (1-sided), the difference between a PSA response rate of 50% expected with the study treatment and a historical control of 20% with Enza alone. Co-primary endpoints are safety and PSA response of ≥50% decrease. Secondary endpoints include overall response rate as determined by the Prostate Cancer Working Group 2 criteria (PCWG2), progression-free survival and overall survival. Molecular correlative studies are exploratory endpoints. Serum and intratumoral androgen levels, full-length AR, AR-V7 and AKR1C3 will be measured to assess the effect of the combination therapy. To date, 4 patients have been enrolled to the trial (clinicaltrials.gov Identifier No: NCT02935205; this trial is funded by DoD Prostate Cancer Research Program IMPACT award). Clinical trial information: NCT02935205.
Oligometastatic prostate cancer patients stratification: A molecular signature identified by liquid biopsy.
Authors: Triggiani Luca , Bardoscia Lilia , Colosini Antonella , Bernardi Simona , Bresciani Roberto , Foroni Chiara , Pasinetti Nadia , Borghetti Paolo , Caraffini Bruno , Orizio Flavia , Buglione Michela , Magrini Stefano M. 
Published: February 2018

TPS400 Background: Oligometastatic prostate cancer (OPC) may represent the initial step of an unavoidable, rapid progression to a polymetastatic state, or the expression of a real oligometastatic phenotype related to a condition of stable disease for a long time. In the last scenario, stereotactic body radiation therapy (SBRT) can be considered as a potentially curative treatment option for hormone-naïve OPC. We propose a prospective, explorative trail with the aim of identifying by liquid biopsy a molecular signature (genes or differential expression of miRNA), and related clonal evolution, underlying metastatic prostate cancer progression after a course of SBRT. Methods: Study population will be 30 adult, hormone-naïve OPC undergoing SBRT. Table 1 summarizes gene and miRNA panel for molecular analysis. For each patient, 15 ml of peripheral blood will be collected before and at the end of SBRT, every 3 months for the first year, then every 6 months until disease progression, when another blood sample will be collected in case of instrumental evidence of failure (using PET-Choline or CT-scan plus bone scintigraphy). 7.5 ml of peripheral blood will be centrifuged to separate sera and 7.5 ml of peripheral blood will be centrifuged to separate plasma from the other blood components, respectively. Sera and plasma will be stored at -20°C and centralized to CREA Laboratory at our Institution, then immediately processed for cell free DNA (cfDNA) and miRNA extraction for NGS of target genes (by Illumina platforms MiSeq and MiniSeq) and dPCR analysis. Study duration will be 36 months. This protocol has been written and will be conducted in agreement with either the Declaration of Helsinki and subsequent amendments and ICH Harmonized Tripartite Guideline for Good Clinical Practice, and has received approval of local Ethics Committee. Panel for analysis. [Table: see text]
Phase II randomized study of abiraterone acetate plus ADT versus apalutamide versus abiraterone and apalutamide in patients with advanced prostate cancer with non-castrate testosterone levels. (LACOG 0415).
Authors: Maluf Fernando C. , Smaletz Oren , Schutz Fabio A. B. , Souza Vinicius Carrera , Fay Andre Poisl , Herchenhorn Daniel , Werutsky Gustavo , Santos Telma Murias 
Published: February 2018

TPS404 Background: Androgen deprivation therapy (ADT) combined with abiraterone (AA) or docetaxel are considered the standard of care (SOC) for patients with hormone sensitive (HS) advanced/ metastatic prostate cancer (PC) (STAMPEDE, LATITUDE, CHAARTED). Treatment that could delay disease progression with less toxicities and better quality of life is warrant. Recently, enzalutamide monotherapy showed a 92% PSA response in patients with advanced/ mestatatic prostate cancer without previous hormone therapy. Our study aims to evaluate the efficacy of apalutamide, a second-generation AR inhibitor, monotherapy or in combination with AA vs. SOC in advanced/metastatic HSPC. Methods: This is a phase II, open label, randomized trial evaluating the efficacy of AA 1000mg po qd plus prednisone 5mg po bid and ADT vs. Apalutamide 240mg po alone vs. AA and Apalutamide in patients with advanced or metastatic PC with non-castrate testosterone levels. Main eligible criteria are: 1. Histologically confirmed prostate adenocarcinoma; 2. Hormone naïve patients with indication to ADT in the following settings: Advanced loco-regional disease not amenable to curative local therapy (T3/4 or node positive); Biochemical relapse after primary treatment (surgery or radiotherapy) with PSA >= 4 ng/ml and rising with doubling time less than 10 months or PSA >= 20 ng/ml or N+ or M+; 3. Newly diagnosed metastatic disease; 4. Patient is symptomatic or moderately symptomatic; 5. Non-castration level of testosterone >= 230 ng/dL. The primary endpoint is undetectable PSA levels (below 0.2ng/mL) at week 25. The study aims for 65% of undetectable PSA at week 25 (power of 80% and alfa of 5%) and a total sample size of 126 patients. Secondary endpoints are PSA progression and PSA response (50% and 80%) at week 25, radiographic progression-free survival, safety, health quality of life (FACT-P) and correlation of serum androgen levels with response. As of October 17th, 2017 the study enrolled 1 patient and the recruitment is planned for 12 months in a total of 10 sites in Brazil. This trial is registered at Clinical trial information: NCT02867020.
S1605: Phase II trial of atezolizumab in BCG-unresponsive nonmuscle invasive bladder cancer.
Authors: Black Peter C. , Catherine Tangen , Lerner Seth P. , McConkey David James , Lucia M. Scott , Woods Michael , Bivalacqua Trinity , Kassouf Wassim , Bangs Richard Carlton , Plets Melissa , Thompson Ian Murchie , Singh Parminder 
Published: February 2018

TPS527 Background: Radical cystectomy is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC). Based on the reported efficacy of atezolizumab in metastatic urothelial carcinoma and the known expression of PD-L1 expression in NMIBC after BCG therapy, this trial will evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This is a single arm phase II trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year in 135 patients with BCG-unresponsive high risk NMIBC. The study will enroll 70 patients with CIS (with or without concomitant Ta/T1) and 65 with Ta/T1 only. Patients with CIS at baseline will undergo mandatory repeat biopsy at 6 months, and all other patients only for suspected recurrence. Patients with persistent CIS, high grade Ta/T1 recurrence or progression to muscle invasive or metastatic disease will be taken off treatment. The co-primary endpoints are: (1) complete response (CR) at 6 months in the CIS subgroup, and (2) event-free survival (EFS) at 18 months in the overall population. A hierarchical approach will be used to test the two co-primary endpoints. Secondary endpoints include duration of CR as well as progression-free, cystectomy-free, bladder cancer-specific, and overall survival in all patients. Response will be correlated to expression of PD-L1 and CD8 by IHC, and to molecular subtypes and immune signatures by RNA-sequencing. If ≥28 (40%) CIS patients respond, the agent will be considered promising. This design has a significance level of 4.6%, and a power of 96%. If the lower bound of the 90% confidence interval of the 18-month EFS excludes 20%, the investigators will conclude the regimen significantly improves EFS relative to historical data (type I error rate 0.05 and statistical power 0.93). Successful completion of this trial could lead to a new treatment paradigm for patients with BCG-unresponsive high risk NMIBC. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, and CA180863. Clinical trial registry: NCT02844816 Clinical trial information: NCT02844816.
A randomized phase III double-blind clinical trial (S1600) evaluating the effect of immune-enhancing nutrition on radical cystectomy outcomes.
Authors: Hamilton-Reeves Jill , Holzbeierlein Jeffrey M. , Unger Joseph M. , Lew Danika L , Fisch Michael Jordan , Henry Norah Lynn 
Published: February 2018

TPS529 Background: This phase III trial will compare the impact of consuming Specialized IMmunonutrition (SIM) to oral nutritional support on postoperative complications after radical cystectomy. Specialized IMmunonutrition is fortified with nutrients (L-arginine, omega-3 fatty acids, dietary nucleotides, and vitamin A) that have immediate effects on immune and inflammatory responses, muscle sparing, and wound healing after surgery. Methods: Two hundred patients will be randomized in a 1:1 fashion to one of two arms. Subjects will be stratified by diversion type (neobladder vs. ileal conduit) and whether the patient had neoadjuvant chemotherapy (any vs. none) to balance the intervention assignment according to important prognostic factors. Nutrition drinks are given three times a day for 5 days before and 5 days after surgery. The primary endpoint is 30 day overall complication rate. Two hundred patients gives 80% power to detect an absolute reduction of 23% in the 30 day overall complication rate (from 65% down to 42%). Secondary endpoints will assess infections, muscle mass, readmissions, quality of life, recurrence, DFS, OS, immune response, cytokines, amino acids, and fatty acids. The trial is testing a high yield, low-risk, low-cost strategy to improve the outcome of patients with bladder cancer who undergo cystectomy. Funding: NIH/NCI/DCP grant award UG1CA189974. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Pembrolizumab and chemoradiotherapy for muscle invasive bladder cancer: The ANZUP 1502 PCR-MIB trial.
Authors: Weickhardt Andrew James , Foroudi Farshad , Sengupta Shomik , Galletta Laura , Herschtal Alan , Grimison Peter S. , Patanjali Nitya , Ng Siobhan , Tang Colin , Goodwin Robert , Hovey Elizabeth J. , Jarvis Tom , Chen Colin , Sandhu Shahneen Kaur , Tai Keen Hun , Lawrentschuk Nathan , Davis Ian D. ,   Australia and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Published: February 2018

TPS531 Background: Pembrolizumab leads to responses in ~20% of metastatic bladder cancer patients. Irradiation of bladder cancer cells in-vitro and in-vivo leads to upregulation of PD-L1, and in immunocompetent mouse models blockade of PD-L1 leads to delayed tumour growth following irradiation. Randomised data from PACIFIC trial in NSCLC shows the addition of PD-L1 inhibition to chemoradiation significantly prolongs PFS. A trial of chemoradiotherapy with pembrolizumab will assess safety and synergy of the combination in localised bladder cancer. Methods: This pilot study enrols patients with maximally resected non-metastatic muscle invasive bladder cancer, who either wish for bladder preservation or are ineligible for cystectomy. This study will assess the safety and feasibility of combining pembrolizumab with chemoradiotherapy in ECOG 0-1 patients without contraindications to pembrolizumab. The study has enrolled 4 of a planned 30 patients. All patients treated with 64Gy of radiation therapy in 32 fractions over 6 weeks, 2 days. Cisplatin 35mg/m2 IV concurrently weekly for 6 doses with radiation. Pembrolizumab commences concurrently with radiation and is given 200mg IV q21 days for 7 doses. Surveillance cystoscopy is performed 12 & 24 weeks after the commencement of chemoradiotherapy to assess response to therapy. Patients will enter follow up with clinical assessment, cystoscopy and CT staging performed at intervals until close of study. The primary endpoint assessed will be safety, as defined by a satisfactorily low rate of unacceptable toxicity (G3-4 adverse events or failure of completion of planned chemotherapy and radiotherapy according to defined parameters). The secondary endpoint will be efficacy, as assessed by the proportion of patients achieving a best response of complete response based on the first two 12 and 24 week post chemoradiotherapy cystoscopic assessments. Exploratory analysis will include assessment of tumour histopathological, molecular, genetic and immunological parameters. It is expected that it will take two years to accrue the 30 patients across 5 Australian centres. NCT02662062. Clinical trial information: NCT02662062.
Avelumab as neoadjuvant therapy in subjects with muscle-invasive urothelial carcinoma (AURA trial).
Authors: Martinez Chanza Nieves , Roumeguere Thierry Andre , Sideris Spyridon , Gil Thierry , Peltier Alexandre , Awada Ahmad 
Published: February 2018

TPS535 Background: Avelumab, a fully human anti-PD-L1 IgG1 monoclonal antibody, is approved in monotherapy for the advanced disease. For patients with non metastatic muscle-invasive bladder cancer (MIBC) the preferred treatment nowadays consists of a multimodal approach comprising neoadjuvant cisplatin-based chemotherapy followed by surgery. However, the benefit of the neoadjuvant chemotherapy (NAC) is modest and an important proportion of patients do not benefit providing unnecessary toxicity. In addition, forty per cent of this population is ineligible for platinum-based therapies and currently no medical alternative option exist. This trial will attempt to answer several open questions: what is the role of the immunotherapy in the neoadjuvant setting? Is efficacy of immunotherapy influenced by the association with cytotoxic agents? Which agents (anthracyclins, platin or taxanes)? Do cisplatin-ineligible patients benefit from this approach? Is there any predictive biomarker for chemotherapy and/or immunotherapy? Methods: This is a randomized phase 2 study in subject candidates for a NAC followed by surgery (EudraCT Number: 2017-002758-35). The study will recruit cisplatin eligible and ineligible patients. For the group of cisplatin-eligible, chemotherapy with high dose of Metotrexate-Vinblastin-Adriamycin-Cisplatin or Cisplatin-Gemcitabine will be associated with Avelumab. For the group of cisplatin-ineligible, Avelumab as monotherapy or associated with Paclitaxel-Gemcitabine will be used. Four cycles of treatment are provided. A radiological evaluation will be performed after 2 cycles and if evidence of progressive disease exists the neoadjuvant treatment will be stopped and the surgery will be performed (Table 1 represents the study design). The primary objective is to determine the pathologic complete response as well as to assess the toxicity profile. Blood, urine and stool samples will be collected at different points to perform translational researches. Clinical trial information: 2017-002758-35.