bluuebunny/crossref_metadata_2025 huggingface dataset:
PROTEUS: A randomized, double-blind, placebo (PBO)-controlled, phase 3 trial of apalutamide (APA) plus androgen deprivation therapy (ADT) versus PBO plus ADT prior to radical prostatectomy (RP) in patients with localized high-risk or locally advanced prostate cancer (PC).
Authors: Taplin Mary-Ellen , Gleave Martin , Evans Christopher P. , Efstathiou Eleni , Kantoff Philip W. , Ross Ashley , Shore Neal D. , Briganti Alberto , Hadaschik Boris A. , Heidenreich Axel , Rooney Oliver Brendan , Tian Shaozhou Ken , Wetherhold Lisa , Xu Weichun , Cheng Shinta , Kibel Adam S.
Published: May 2019

TPS5100

Background: Patients (pts) with localized high-risk PC experience disease progression rates of approximately 50% after RP (Kane et al. J Urol. 2007). With the approval of next-generation androgen receptor inhibitors, neoadjuvant studies have shown that 6 months of androgen blockade may improve local disease control at the time of RP (McKay et al. Prostate Cancer Prostatic Dis. 2017; Taplin et al. JCO. 2014). The purpose of this study is to determine if treatment with APA plus ADT before and after RP in pts with localized high-risk or locally advanced PC results in an improvement in pathologic complete response (pCR) rate and metastasis-free survival (MFS) compared with PBO plus ADT. Methods: This international multicenter trial is enrolling pts with localized high-risk or locally advanced PC who are candidates for RP. Eligibility criteria: Any Gleason score (GS) ≥ 4 + 3 with ≥ 6 positive systematic biopsies (SB); any GS ≥ 4 + 3 with ≥ 3 SB and prostate-specific antigen (PSA) ≥ 20 ng/mL; GS ≥ 9 in ≥ 1 SB or targeted biopsies (TB); or ≥ 2 SB or TB with continuous GS ≥ 8, each with ≥ 80% involvement. Stratification: GS (7 or ≥ 8), cN0 or N1, and region (North America, Europe, or rest of world). Randomization: 1:1 to APA (240 mg) plus ADT (LHRHa) or PBO plus ADT. Pts will receive 6 treatment cycles, followed by RP, followed by an additional 6 cycles. Dual primary end points: pCR rate (to be assessed by blinded independent central pathology review) and MFS (to be assessed by blinded independent central radiology review [BICR]). Secondary end points: PSA-free survival and progression-free survival. Imaging with CT or MRI and bone scan will be conducted at baseline and then every 6 months following biochemical failure until documented distant metastasis by BICR, or death. Approximately 1500 pts will be enrolled globally over 3.0 years in 240 sites in 19 countries. An independent data monitoring committee is commissioned to review trial data. Clinical trial information: NCT03767244.
Randomized prospective phase 3 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: May 2019

TPS5101

Background: Salvage radiotherapy (SRT) for prostate cancer (PCa) recurrence after prostatectomy offers long-term biochemical control in about 50–60% of patients. SRT is commonly initiated in patients with serum PSA levels < 1 ng/mL, a threshold at which standard-of-care imaging is insensitive for detecting recurrence. As such, SRT target volumes are usually drawn in the absence of radiographically visible disease. 68Ga-PSMA-11 (PSMA) PET/CT molecular imaging is highly sensitive and may offer anatomic localization of PCa biochemical recurrence. However, it is unclear if incorporation of PSMA PET/CT imaging into the planning of SRT could improve its likelihood of success. The purpose of this trial is to evaluate the success rate of SRT for recurrence of PCa after prostatectomy with and without planning based on PSMA PET/CT. Methods: We will randomize 193 patients to proceed with standard SRT (control arm 1, n = 90) or undergo a PSMA PET/CT scan (free of charge for patients) prior to SRT planning (investigational arm 2, n = 103). The primary endpoint is the success rate of SRT measured as biochemical progression-free survival (BPFS) after initiation of SRT. Biochemical progression is defined by PSA ≥ 0.2 ng/mL and rising. The randomization ratio of 1:1.13 is based on the assumption that approximately 13% of subjects randomized to Arm 2 will not be treated with SRT because of PSMA-positive extra-pelvic metastases. These patients will not be included in the primary endpoint analysis but will still be followed. The choice of treating the prostate bed alone vs prostate bed and pelvic lymph nodes, with or without androgen deprivation therapy (ADT), is selected by the treating radiation oncologist. The radiation oncologist may change the radiation plan depending on the findings of the PSMA PET/CT scan. Any other imaging is allowed for SRT planning in both arms if done per routine care. Patients will be followed until either one of the following conditions occur: 5 years after the date of initiation of randomization, biochemical progression, diagnosis of metastatic disease, initiation of any additional salvage therapy, death. Discussion: This is the first randomized phase 3 prospective trial designed to determine whether PSMA PET/CT molecular imaging can improve outcomes in patients with PCa early BCR following radical prostatectomy. Clinical trial information: NCT03582774.
KEYNOTE-826: A phase 3, randomized, double-blind, placebo-controlled study of pembrolizumab plus chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer.
Authors: Shapira-Frommer Ronnie , Alexandre Jerome , Monk Bradley , Fehm Tanja N. , Colombo Nicoletta , Caceres Maria V. , Hasegawa Kosei , Dubot Coraline , Li Jerry Jing , Stein Karen , Keefe Stephen Michael , Tewari Krishnansu Sujata
Published: May 2019

TPS5595

Background: Cervical cancer arises in the setting of persistent infection with high-risk human papillomavirus subtypes. Many patients with early-stage and locally advanced carcinoma can be salvaged with radical surgery and chemoradiation, respectively. However, women with recurrent/metastatic disease represent a poor prognostic group with high unmet clinical needs. Incorporation of anti-angiogenesis therapy has emerged as a therapeutic option, but the survival benefit of 3.7 months over chemotherapy (CT) alone is modest (Tewari et al. NEJM 2014). Because viral tumor antigen-specific T cells reside predominantly in programmed cell death 1–expressing T-cell compartments, checkpoint inhibition may unleash a diverse antitumor T-cell response. Based on the 14.3% objective response in KEYNOTE-158, the US FDA granted accelerated approval to pembrolizumab (pembro) in June 2018 for second-line therapy and beyond. Methods: KEYNOTE-826 is a phase 3, randomized, double-blind, placebo-controlled, multinational trial of CT with pembro or with placebo for first-line treatment of recurrent, persistent, or metastatic cervical cancer. Patients not previously treated with CT for recurrence who are not amenable to curative treatment will be randomized 1:1 to CT + pembro 200 mg or placebo every 3 weeks. The CT regimen (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5, with or without bevacizumab 15 mg/kg) will be selected by the investigator before randomization. Stratification factors include metastasis status at diagnosis, bevacizumab use (yes/no), and tumor PD-L1 status (combined positive score <1, 1 to <10, or ≥10). Treatment will continue until disease progression, unacceptable toxicity, or voluntary patient withdrawal for up to 35 cycles (~2 years). Primary endpoints are progression-free survival (PFS) per RECIST v1.1 assessed by blinded independent central review and overall survival. Secondary endpoints are objective response, duration of response, 12-month PFS, patient-reported quality of life, and safety. Enrollment is ongoing. Clinical trial information: NCT03635567.
ENGOT-Ov41/GEICO-69-O/ANITA trial: A phase III randomized, double-blinded trial of platinum-based chemotherapy (CT) with or without atezolizumab (ATZ) followed by niraparib maintenance with or without ATZ in patients with recurrent ovarian, tubal or peritoneal cancer (OC) and platinum treatment-free interval (TFIp) >6 months.
Authors: González-Martín Antonio , Colombo Nicoletta , Heitz Florian , Christensen Rene dePont , Selle Frédéric , Vergote Ignace , Oaknin Ana
Published: May 2019

TPS5599

Background: Platinum-based CT is the treatment of choice for OC patients (pts) with TFIp > 6 months suitable for platinum. Niraparib is an oral PARP inhibitor that significantly prolongs the progression-free survival (PFS) of OC pts when given as maintenance therapy after a response to platinum-rechallenge (both in gBRCA and non-gBRCA mutated pts). Atz is a humanized monoclonal antibody targeting PD-L1 that showed activity in heavily pretreated OC pts. Combination of anti-PD-L1 and CT may improve the activity of the anti-PD-L1 antibody by increasing the amount of antigens released after immunogenic cell death induced by CT. Combination of PARPi and anti-PD-L1/PD-1 has shown synergy in preclinical models and promising clinical activity in certain indications. Methods: ANITA (NCT03598270) is a phase III, randomized (1:1), double-blinded, multi-center study to assess the efficacy of the addition of Atz to platinum-based doublet CT followed by maintenance niraparib in patients with recurrent high grade serous or endometrioid OC with a TFIp > 6 months. Approximately 414 patients with ECOG 0-1, known BRCA status, at least one measurable lesion and ≤ 2 prior lines will be randomized to placebo of Atz (Arm A) or Atz (Arm B) in combination with one of three possible standard platinum-based CT regimens (investigator’s choice) followed by maintenance niraparib in combination with placebo or Atz, according to randomization, if experiencing response or stable disease by RECIST after CT. Stratification factors: 1) Platinum-based regimen (paclitaxel-carboplatin vs gemcitabine-carboplatin vs PLD-carboplatin); 2) Platinum-free interval (6-12 vs > 12 months); and 3) BRCA status (mutated vs non-mutated). Dose of Atz is 1200 mg q3 weeks or 840 mg q2 weeks depending on the platinum-based regimen selected. Niraparib initial dose (300 vs 200 mg) is decided based on body weight and platelet counts after CT according to RADAR analysis. Primary endpoint is PFS based on investigator assessment by RECIST v1.1. Clinical trial information: NCT03598270.
ENGOT-OV43/KEYLYNK-001: A phase III, randomized, double-blind, active- and placebo-controlled study of pembrolizumab plus chemotherapy with olaparib maintenance for first-line treatment of BRCA-nonmutated advanced epithelial ovarian cancer.
Authors: Vergote Ignace , Sehouli Jalid , Salutari Vanda , Zola Paolo , Madry Radoslaw , Wenham Robert Michael , Korach Jacob , Pautier Patricia , Cibula David , Lheureux Stephanie , Hasegawa Kosei , Kim Byoung-Gie , Lai Chyong-Huey , González-Martín Antonio , Liu Qi , Keefe Stephen Michael , Puglisi Martina , Topuz Samet
Published: May 2019

TPS5603

Background: There is a significant unmet need to develop new regimens for BRCA1/2-nonmutated advanced ovarian cancer (OC). The PARP inhibitor olaparib is approved for women with platinum-sensitive, recurrent OC regardless of BRCA1/2 status and, more recently, for newly diagnosed women with BRCA-mutated OC. In the TOPACIO/KEYNOTE-162 study, the combination of the PD-1–blocking antibody pembrolizumab (pembro) and niraparib demonstrated efficacy in platinum-resistant relapsed OCirrespective of BRCA1/2 status. ENGOT-OV43/KEYLYNK-001 (ClinicalTrials.gov, NCT03740165) is a phase 3, randomized, double-blind, active- and placebo-controlled study of pembro plus paclitaxel-carboplatin chemotherapy (CT) followed by olaparib maintenance for first-line treatment of patients with BRCA1/2-nonmutated advanced epithelial OC (EOC). Methods: Patients with stage III or IV BRCA-nonmutated EOC, primary peritoneal cancer, or fallopian tube cancer will be stratified by surgery status (no residual tumor after primary debulking surgery [PDS], residual tumor after PDS, or planned interval debulking), bevacizumab use, and PD-L1 status (combined positive score < 10 or ≥10). After one lead-in cycle of CT, patients will be randomized 1:1:1 to receive: CT + pembro followed by olaparib maintenance; CT + pembro followed by placebo; or CT + placebo followed by placebo. The CT regimen will be administered for 5 cycles, and pembro 200 mg Q3W will be administered for 35 infusions. Olaparib 300 mg BID maintenance therapy will start after the end of CT as concomitant treatment with pembro until discontinuation or for 2 years if the patient has a complete response. Bevacizumab use is permitted at investigator’s discretion and determined prerandomization. Primary endpoints are investigator-assessed progression-free survival (PFS) per RECIST 1.1 criteria and overall survival. Key secondary endpoints are PFS per RECIST 1.1 assessed by blinded independent central review, PFS after next-line treatment, and safety. Enrollment is currently ongoing. Clinical trial information: NCT03740165.
Phase I (safety assessment) of durvalumab (MEDI4736) with focal sensitizing radiotherapy in platinum resistant ovarian, primary peritoneal or fallopian tube epithelial carcinoma.
Authors: Tinker Anna , Lim Peter , Aquino-Parsons Christina , Hoskins Paul , Khalaf Daniel , Lheureux Stephanie , Han Kathy , Liu Mitchell , Lum Julian J
Published: May 2019

TPS5604

Background: Radiation (RT) of malignant neoplasms can induce immunogenic tumor cell death, alter the tumor micro-environment and enhance recruitment of anti-tumor T cells. Co-administration of focal RT and an immune checkpoint-inhibiting agent may overcome immune-suppressive signals and potentiate systemic responses. A phase I study is underway to assess the safety of RT combined with PD-L1 inhibition in patients with recurrent epithelial ovarian/fallopian tube/peritoneal carcinomas (OV). Methods: Women with platinum resistant epithelial OV, ECOG PS 0/1 and ≤ 2 lines of treatment in the platinum-resistant setting are eligible. 1 lesion evaluable by RECIST criteria (v 1.1) and 2 additional lesions suitable for RT (minimal treatment volume 4cc) are required. Pre- and on-treatment biopsies for correlative studies are mandatory. The primary objectives are to assess the safety and tolerability of the focal RT combined with the immune checkpoint inhibitor, durvalumab (D), as defined by dose-limiting toxicities (DLTs), and to define the maximum tolerated RT dose and treatment schedule. The secondary objectives are to evaluate the clinical activity of focal RT and D [RECIST (v 1.1), GCIG CA-125, and immune-related response criteria], progression free survival and overall survival. D 1500 mg delivered intravenously every 28 days = one cycle. RT to the 2 selected target lesions is delivered 24-36 hours prior to the infusion of D. The RT starting dose-level is 24Gy (in 4 fractions) per lesion (given Days -1, 1 and 28 of Cycle 1 and Day 1 of Cycle 2). A 3+3+3 design will permit more extensive exploration of toxicity if DLTs are observed (Table). Investigator assessed DLTs are defined by CTCAE v. 4.03 and include the following: any grade ≥3 adverse event suspected to be related to D or RT (necrosis or recall reactions at previously irradiated sites, RT induced bowel perforation, any unexpected grade 3 or greater toxicity at the site of RT), any grade ≥2 allergic or autoimmune event that involves vital organ function, and any other grade 3 allergic or autoimmune events that do not resolve to grade 1 before the next scheduled dose of D. Treatment may continue up to 12 months. Enrollment began August 2018. To date, no DLTs have been observed at dose level 1 (n= 3) and enrollment is ongoing. Clinical trial information: NCT03283943. [Table: see text]
NRG GY012: A randomized phase II study comparing single-agent olaparib, single agent cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent or metastatic endometrial cancer.
Authors: Mackay Helen , Rimel Bj , Bender David
Published: May 2019

TPS5609

Background: The Cancer Genome Atlas and others identified genomic events suggesting that endometrial cancer (EC) should be susceptible to DNA repair inhibition. Mutations in classical homologous recombination genes occur in 22% of EC, ARID1A 41% and PTEN loss occurs in 55% of EC. Data from pre-clinical models suggest poly ADP-ribose polymerase (PARP) inhibitors alone or in combination may be an effective therapeutic strategy in EC (Hansen 2016). Combinations of angiogenic inhibitors and PARP inhibitors have demonstrated synergistic effects and have been well tolerated in other tumor types. This study has been designed to compare 2 experimental arms exploring DNA repair inhibition versus cediranib alone which has previously shown promising activity in GOG 229J (Bender 2015). Methods: This is a multicenter randomized three arm study for patients with recurrent, metastatic or persistent EC. Patients are randomized 1:1:1 to cediranib PO 30 mg OD; olaparib 300 mg PO BID or the combination of cediranib 20 mg PO OD with olaparib 300 mg PO BID. All treatment cycles are 28 days. Primary endpoint is progression free survival (PFS). The study is powered to detect an increase in median PFS from 3.6 (based on cediranib alone) to 7.2 months with 90% power, using a one-sided test with α = 0.05 per comparison. Forty patients will be enrolled per arm, with an interim futility analysis planned. Eligibility includes endometroid, serous, and mixed histology EC; at least 1 prior line of chemotherapy (no more than 2 lines for metastatic disease), prior endocrine or immunotherapy is allowed; ECOG PS ≤ 2; adequate hepatic, bone marrow, coagulation and renal function. Archival tumor tissue and blood samples are being collected for translational studies. The study is open across the NRG network; 24 patients are enrolled to date . Amendments are planned to include additional arms investigating combination strategies targeting DNA repair and angiogenesis. Clinical trial information: 03660826.
A multicenter, randomized, double-blind, placebo-controlled phase III study of anlotinib or placebo in combination with gemcitabine and cisplatin (GP) as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (R/M NPC).
Authors: Yang Yunpeng , Huang Yan , Fang Wenfeng , Ma Yuxiang , Cai Qingqing , Li Zhi-Ming , Zhao Hongyun , Zhao Yuanyuan , Zhou Ting , Hong Shaodong , Zhang Yaxiong , Zhang Li
Published: May 2019

TPS6089

Background: GP is the standard first-line chemotherapy for R/M NPC. However, the outcome of patients who are refractory to first-line chemotherapy is poor. There remains an unmet need for more effective first-line treatment. Overexpression of vascular endothelial growth factor (VEGF) is common in NPC and the higher expression is related to lower OS. This feature makes NPC potentially suitable for antiangiogenic treatment. Anlotinib is a novel multitarget tyrosine kinase inhibitor that targets VEGFR 1 to 3, fibroblast growth factor receptor 1 to 4, and platelet-derived growth factor receptor α and β. Our phase I study of anlotinib in R/M NPC patients who failed from standard treatment had shown a manageable safety profile and promising antitumor activity with an ORR of 25%. This phase 3 trial aims to compare the efficacy and safety of anlotinib versus placebo in combination with GP in patients with R/M NPC in the first-line setting. Methods: Key eligibility criteria of this study are that the patient has metastatic disease after curative radiotherapy, or is primarily metastatic; has an ECOG PS of 0 or 1; has adequate organ function; and has at least 1 measurable lesion according to RECIST 1.1. Eligible patients will be randomized in a 1:1 ratio to receive intravenous gemcitabine at 1 g/m² on days 1 and 8, cisplatin at 75 mg/m² on day 1, plus anlotinib or placebo 12 mg daily orally on days 1–14 every 3 weeks for a maximum of 6 cycles followed by anlotinib or placebo 12 mg daily on days 1–14 every 3 weeks as maintenance therapy. The primary endpoint is PFS. Secondary endpoints include OS, ORR, quality of life and safety profile. Independent Data Monitoring Committee and Independent Review Committee will be used in this study. We assume that the median PFS will be 10 mos in anlotinib group and 7 mos in placebo group. To detect a 3-month improvement of PFS in anlotinib group at a two-sided significant level of 0.05 and power of 0.8, allowing for a dropout rate of 10%, a total of 336 patients will be enrolled. From August 2018, 58 patients have been enrolled. Clinical trial information: NCT03601975.
Reproductive health in cancer.
Authors: Radeke Erika K , Lee Ju-Whei , Patel Ashlesha , Zaren Howard A. , Fisch Michael Jordan , Wagner Lynne I.
Published: May 2019

TPS6649

Background: Reproductive health needs of females ages 15 to 55 with cancer are poorly understood and overlooked, despite their importance to patients. Uncertainties regarding fertility and pregnancy are intricate and challenging for a patient and a cancer care team. The goals of reproductive health care may come in conflict with the primary objective of cancer care. However, with appropriate counseling and preventive measures, this conflict can be absolved to unify objectives. The primary objective of this trial is to evaluate the success of the implementation of reproductive health programming among reproductive aged females with cancer. To expand knowledge on this subject, the NCI approved the ECOG-ACRIN EROS trial: Engendering Reproductive Health within Cancer Survivorship, with two ancillary studies: Endocrine Disruption in Cancer Care and Sexuality in the first 5 years after Cancer Diagnosis. Methods: The primary study is a multicenter, cluster randomized control trial, with NCI Community Oncology Research Programs randomized to either the non-intervention arm (usual standard practice related to reproductive health) or the intervention arm (using study-specific training and tools). The accrual goal is 668 patients based on the expectation that the intervention can increase the adoption of appropriate reproductive health management within 3 months from the baseline visit from 50% to 80%, with the first 200 to consent to the endocrine disruption substudy. All patients participate in the sexuality part. Pre-menopausal female patients ages 15 to 55 with an initial diagnosis of any type of cancer who have not initiated treatment of any type are eligible to participate. Patients are asked to complete 2 questionnaires at 8 timepoints regarding their reproductive health interests. Providers are also asked to complete questionnaires regarding their healthcare practice in general as well as specific to patients enrolled in this study. The reproductive health management rate at each time point will be summarized, by arm, with frequency and percentage along with its 95% confidence interval. The comparison between the two arms, using a GEE model, can evaluate the intervention effect. EROS was activated in September 2015. To date, 264 patients have been enrolled to the main study and half of these patients are participating in the endocrine disruption correlative. Outcomes pertaining to management and treatment implementation and modification are the cornerstones of this study. It should inform organizations in cancer care to improve guidelines and to include a reproductive health assessment for all young females with cancer. Clinical trial information: NCT01806129.
Digitally captured step counts for evaluating performance status in advanced cancer patients: A single cohort, prospective trial (Digi-STEPS).
Authors: Gresham Gillian , Hendifar Andrew Eugene , Gong Jun , Asher Arash , Walsh Christine S. , Rimel BJ , Posadas Edwin M. , Diniz Marcio , Herring Maurice , Woubeshet Bethy , Baynes Rachel , Figlin Robert A. , Spiegel Brennan , Freedland Stephen J.
Published: May 2019

TPS6651

Background: Advanced cancer patients undergo dynamic changes in their functionality and physical activity over the course of their treatment. Monitoring patient function is important because it can inform treatment decisions and allow for timely and appropriate intervention. Current scales that assess patient function, such as the ECOG Performance Status (PS), are limited in their ability to capture the wide range in activity that cancer patients can experience on a daily basis outside of the clinic setting. Given recent technological advances in wearable activity monitors, we can collect real-time, objective information about a patient’s daily activity including steps, stairs, heart rate, sleep, and activity intensity. Thus, the primary objective of this study is to determine whether longitudinal changes in objectively-assessed activity are associated with change in physician-rated ECOG PS. Methods: This is a prospective, single cohort trial being conducted at Cedars-Sinai Medical Center. Stage 3/4 cancer patients who are English or Spanish-speaking, ambulatory (assistive walking devices are allowed) and expected to be seen for treatment or follow-up with their oncologist at least every 8 weeks are eligible for study. Consenting patients will be asked to wear a Fitbit Charge HR continuously for 8 weeks during the study period and for one week prior to the 6 month and 1 year follow-up visits. Primary outcomes are change in average daily step counts and ECOG PS at 8 weeks from baseline. Secondary outcomes include: 1) Change in NIH PROMIS patient-reported outcomes (physical function, pain, sleep, emotional distress, and fatigue), 2) Change in frailty status at 8 weeks, 3) Occurrence of adverse events, and 4) 6-month and 1-year survival outcomes. Baseline assessments include a physical exam, medical history, and frailty assessment. The attending oncologist will rate the patient's ECOG PS at baseline and at the end-of-study visit. Weekly NIH PROMIS questionnaires will be administered online over the 8-week study and again at 6 months and 1 year follow-up. The occurrence of serious cancer-related adverse events, chemotherapy-associated toxicities, and hospitalizations will be documented up to 12 weeks from baseline. Survival will be assessed at 6 months and 1 year. Accrual is ongoing with 20 patients currently enrolled of a target sample size of 60 patients. Clinical trial information: NCT03757182.
Lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with advanced melanoma previously exposed to anti–PD-1/PD-L1 agents: Phase 2 LEAP-004 study.
Authors: Arance Fernandez ANA Maria , Ascierto Paolo Antonio , Carlino Matteo S. , Daud Adil , Eggermont Alexander M. , Hauschild Axel , Kluger Harriet M. , Taylor Matthew H. , Smith Alan , Chen Ke , Krepler Clemens , Diede Scott J. , O'Day Steven
Published: May 2019

TPS9594

Background: Pembro, a PD-1 inhibitor, has shown effective antitumor activity, deep and durable responses, and survival benefit in treatment-naive pts and those with previously treated metastatic melanoma. Len, a potent inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, combined with a PD-1 inhibitor showed antitumor activity superior to either agent alone in preclinical models of colorectal and lung cancer. Additionally, len plus pembro showed anti-tumor activity and was well-tolerated (24-wk ORR, 47.6%; TRAE: gr 3/4, 67%; gr 5, 0%) in pts with advanced melanoma previously treated with 0-2 therapies in the phase 1b/2 KEYNOTE-146 trial. The efficacy and safety of len plus pembro combination therapy will be evaluated in an open-label, phase 2 trial of pts with advanced melanoma that progressed on PD-1/PD-L1 inhibitor therapy (NCT03776136). Methods: Key inclusion criteria: age ≥18 years, histologically/cytologically confirmed unresectable stage III-IV melanoma that progressed (per iRECIST) within 12 weeks of last dose of an approved PD-1/PD-L1 inhibitor therapy (≥2 doses as monotherapy or combined with other therapies), measurable disease, ECOG PS 0/1, no active autoimmune disease, and adequate organ function. Pts must provide a baseline tumor sample. Pts will receive len 20 mg/day orally plus pembro 200 mg IV Q3W for approximately 2 years (35 doses of pembro), after which they may receive len alone until PD or unacceptable toxicity. Response will be assessed per RECIST v1.1 based on blinded independent central review (BICR) Q9W until week 54, Q12W until week 102, and Q24W thereafter. Pts with CR may discontinue treatment after ≥24 weeks of therapy; eligible pts may continue treatment beyond initial RECIST- or iRECIST-defined PD. AEs will be assessed throughout treatment and for 90 days (120 days for serious AEs) after last dose and graded per NCI CTCAE v4.0. Pts will be followed-up for survival status Q12W. The primary efficacy end point is ORR per modified RECIST v1.1 (BICR). Key secondary end points are PFS and DOR per modified RECIST v1.1 (BICR), OS, and safety; an exploratory biomarker analysis is planned. Clinical trial information: NCT03776136.
ILLUMINATE 301: A randomized phase 3 study of tilsotolimod in combination with ipilimumab compared with ipilimumab alone in patients with advanced melanoma following progression on or after anti-PD-1 therapy.
Authors: Butler Marcus O. , Robert Caroline , Negrier Sylvie , In Gino Kim , Walker John WT , Krajsova Ivana , Atkinson Victoria , Hansson Johan , Kapiteijn Ellen , Loquai Carmen , Shaw Heather May , Cheng Tina , Mansard Sandrine , Grob Jean Jacques , Guidoboni Massimo , Mehta Minal , Ascierto Paolo Antonio , Diab Adi
Published: May 2019

TPS9599

Background: Tilsotolimod (IMO-2125) is a Toll-like receptor (TLR) 9 agonist with potent immunostimulating activity. In an ongoing Phase 1/2 clinical study in patients with advanced melanoma who progressed on or after anti-PD-1 therapy (NCT02644967), intratumoral (IT) tilsotolimod with ipilimumab was well-tolerated, demonstrating durable responses (including complete response > 21 months), dendritic cell activation, type I interferon response, CD8+ T-cell proliferation in responders, and an abscopal effect. Methods: ILLUMINATE 301 (NCT03445533) is a randomized phase 3 global, multi-center, open-label study of IT tilsotolimod (8 mg) in combination with ipilimumab (3 mg/kg) versus ipilimumab monotherapy in patients with advanced melanoma and progression on or after anti-PD-1 therapy. Eligible patients are ≥18 years with histologically confirmed unresectable Stage III or Stage IV melanoma, ≥1 measurable lesion accessible for injection (superficial or visceral, the latter with image guidance), ECOG PS ≤1, and adequate organ function. Exclusion criteria include prior TLR agonists, prior ipilimumab (except adjuvant ≥12 weeks before progression), and CNS disease other than stable brain metastases. Patients are randomized 1:1 and stratified by duration of prior anti-PD-1 (≥12 weeks vs <12 weeks), stage (M1c vs other), and BRAF status/prior targeted therapy (TT) (BRAF wildtype vs BRAF mutation+ with TT vs BRAF mutation+ without TT). Primary endpoints are overall response rate (RECIST v1.1) by independent central review and overall survival. Secondary endpoints include durable response rate, time to response, progression-free survival, patient-reported outcomes, and safety. Patients are enrolling at sites in the United States, European Union, Australia, and Canada. References: (1) Haymaker C. Society for Immunotherapy of Cancer Annual Meeting, November 2017, National Harbor, MD; (2) Diab A, et al. European Society of Molecular Oncology Annual Meeting, October 2018, Munich, Germany. Clinical trial information: NCT03445533.
An open label, multicenter, phase II study of KRT-232, an oral small molecule inhibitor of MDM2, for the treatment of patients with Merkel cell carcinoma (MCC) who have failed treatment with anti-PD-1/L1 immunotherapy.
Authors: Hanna Glenn J. , DeCaprio James A. , Mei John Hai Ming , McGreivy Jesse S.
Published: May 2019

TPS9602

Background: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a poor prognosis in patients with advanced disease, with mortality as high as 46%. An oncogenic Merkel cell polyomavirus (MCPyV) is present in about 80% of MCC tumors, which inactivates tumor suppressors p53 and RB. Virus-positive MCC has proven to be an immunologically responsive disease and the recently approved PD-L1 inhibitor avelumab (March 2017) has improved the prognosis of patients with advanced MCC. However, despite the addition of immune checkpoint inhibitors to the treatment paradigm, a lack of response or disease progression occurs in up to two-thirds of avelumab patients previously treated with chemotherapy, and 32-44% of first-line patients treated with the PD-1 inhibitors nivolumab or pembrolizumab. KRT-232 is a potent and selective small molecule targeted drug that binds to murine double minute chromosome 2 (MDM2) and inhibits the MDM2/tumor protein 53 (p53) protein-protein interaction. Inactivating mutations in p53 have rarely been found in MCC, and the majority of MCCs with the presence of MCPyV express p53WT. The purpose of this study is to evaluate the tolerability and efficacy of KRT-232 in p53WT MCC patients who have been treated with anti-PD-1/L1 immunotherapy. Methods: The primary objective is ORR by RECIST v1.1 after 2 cycles (42 days) as determined by independent review. A Simon two-stage design is employed. In Stage 1, up to 13 eligible patients will be enrolled and treated with 240 mg KRT-232 once daily (QD) on Days 1-7 of a 21-day cycle. If the predesignated efficacy threshold is reached in Stage 1, enrollment for Stage 2 will include an additional 14 patients (for a total of 27 patients). The study is enrolling in the U.S. Clinical trial information: NCT03787602.
Analgesic Benefit of Pectoral Nerve Block II Blockade for Open Subpectoral Biceps Tenodesis: A Randomized, Prospective, Double-Blinded, Controlled Trial
Authors: Reynolds J. Wells , Henshaw Daryl S. , Jaffe J. Douglas , Dobson Sean W. , Edwards Christopher J. , Turner James D. , Weller Robert S. , Graves Benjamin R. , Freehill Michael T.
Published: May 2019

BACKGROUND:

Axillary pain is common after arthroscopic shoulder surgery with an open subpectoral biceps tenodesis. We hypothesized that adding a pectoral nerve block II (Pecs II) to an interscalene block (ISB) would improve postoperative analgesia in this surgical population.

METHODS:

Forty patients were enrolled in this prospective, randomized, observer and patient-blinded, single-institution trial. All 40 patients received a single-injection ISB with 20 mL of 0.25% bupivacaine with 1:400,000 epinephrine and 1:600,000 clonidine. The intervention arm (ISB + Pecs II) consisted of 20 patients who also received a Pecs II block using 30 mL of 0.25% bupivacaine with 1:400,000 epinephrine and 1:600,000 clonidine. The 20 control group patients (ISB) received a sham Pecs II block. The primary outcome was postoperative pain scores at 6 hours using the numeric rating scale (NRS; range, 0–10) and was analyzed using the Mann-Whitney U test. Secondary outcomes included the presence of axillary pain at 6 hours, the need for postanesthesia care unit (PACU) opioids, PACU length of stay (LOS) (minutes), NRS pain scores at 24 hours, cumulative opioid usage postdischarge through 24 hours, the presence of nausea or vomiting during the first 24 hours, and Pecs II block duration (in hours, based on time to onset of axillary pain). Data were analyzed using a modified intention-to-treat (ITT) methodology.

RESULTS:

Pain scores (NRS, 0–10) at 6 hours differed significantly between groups: ISB 3.0 (0.25–5.0) (1.7–4.3) versus ISB + Pecs II 0.0 (0–2.0) (0.0–1.1) (median [IQR] [95% CI]); P = .026. Hodges–Lehmann estimator of the difference was 2.0 (95% CI, 0.0–4.0). Fewer patients in the ISB + Pecs II group reported axillary pain at 6 hours and fewer required opioids in the PACU. There were no differences in any of the remaining secondary outcomes.

CONCLUSIONS:

The addition of a Pecs II block to an ISB for patients undergoing arthroscopic shoulder surgery with an open subpectoral biceps tenodesis significantly improved postoperative analgesia and reduced the need for opioids in the PACU.
Consistent Definitions of Clinical Practice Guidelines, Consensus Statements, Position Statements, and Practice Alerts
Authors: Joshi Girish P. , Benzon Honorio T. , Gan Tong J. , Vetter Thomas R.
Published: May 2019

An evidence-based approach to clinical decision-making for optimizing patient care is desirable because it promotes quality of care, improves patient safety, decreases medical errors, and reduces health care costs. Clinical practice recommendations are systematically developed documents regarding best practice for specific clinical management issues, which can assist care providers in their clinical decision-making. However, there is currently wide variation in the terminology used for such clinical practice recommendations. The aim of this article is to provide guidance to authors, reviewers, and editors on the definitions of terms commonly used for clinical practice recommendations. This is intended to improve transparency and clarity regarding the definitions of these terminologies.
A indústria do petróleo e gás natural e o desenvolvimento nacional
Authors: Pansieri Flávio
Published: May 2019

The oil and natural gas industry and national development O presente artigo analisa a indústria nacional do petróleo e gás natural em seus níveis histórico, econômico e jurídico. Embora alguns fatores contribuam para que o setor esteja em crise, o objetivo é apresentar como esta indústria é referencial à economia brasileira, tendo como enfoque a política de concessão somada ao conteúdo local como um mecanismo para o desenvolvimento nacional. Por meio de análise normativa, revisão bibliográfica e dados oficiais, conclui-se que o conteúdo local é um elo importante para o desenvolvimento industrial, econômico e social do Brasil. This article analyses the Brazilian oil and gas industry in historic, economics and law outlook. Although some factors have launched this sector in downturn, the aim is show how this industry is referential to the economy, focusing on the concessions and local content policy as a national development factor. Through a systematic analysis of the legislation, relevant literature, and official statistics, the article concludes that the local content policy is crucial for industrial, economic and social developments of Brazil.
O processo civil no estado constitucional e seus reflexos nas ações de improbidade administrativa
Authors: Vedovato Luís Renato , Lopes Thiago Henrique Teles
Published: May 2019

Civil procedure in a constitutional state and its reflexes in administrative misconduct actions O objeto da pesquisa é analisar a estrutura lógica-racional estabelecida na Lei de Improbidade Administrativa, com ênfase na avaliação dos impactos de normas fundamentais, consagradas no novo CPC, na ação de improbidade administrativa, além da aplicabilidade do regime de revelia à ação de improbidade administrativa, o princípio da congruência e a ciência e a manifestação prévia das partes a fim de se evitar decisão surpresa. A Lei de Improbidade Administrativa (Lei no 8.429/1992), entre outros mecanismos legislativos, instituiu um sistema normativo que visa sancionar a prática de condutas ímprobas pelos agentes públicos e terceiros a eles aderentes. Com tal finalidade, essa sistematização criou a ação de improbidade administrativa de natureza cível (entendimento adotado no presente trabalho). Consequentemente, as alterações promovidas no direito processual civil, principalmente em virtude de sua nova fase metodológica (processo civil no Estado Constitucional), que se baseia num modelo cooperativo, trouxeram diversos reflexos nas ações de improbidade administrativa, tanto em seu modelo de constatação para a formação da convicção judicial quanto em alguns aspectos processuais de igual relevância. O método utilizado é o dedutivo e o procedimento é a investigação bibliográfica e documental, legislativa e jurisprudencial. The aim of this paper is to analyze the logical-rational structure established in the Administrative Misconduct Law, with emphasis on its procedural model of evidence and the legislative reflexes irradiated. The Act of Administrative Misconduct (n. 8.429/1992), among other legislative mechanisms, established a normative system that aims to punish the practice of misconduct conduct by public agents and third parties. For this purpose, the systematization created the action of administrative misconduct with civil nature (understanding adopted in the present paper). Consequently, the changes promoted in civil procedural law, mainly due to its new methodological phase (civil process in the Constitutional State), which is based on a cooperative model, brought several reflexes in the actions of administrative misconduct, both in its model of verification for the judicial conviction, and in some procedural aspects of equal importance. The method used is the deductive and the procedure is the bibliographical and documentary, legislative and judicial decision investigation.
Anotações sobre a ausência de limitação temporal para anulação de ato administrativo perpetrado com má-fé
Authors: Prado Safira Orçatto Merelles do
Published: May 2019

Annotations about absence of a time limit for annulment of an administrative act perpetrated with bad-intention Neste artigo, apresentamos os posicionamentos doutrinários a respeito da aplicação dos institutos da preclusão e da coisa julgada na esfera administrativa, levando em consideração o prazo decadencial de cinco anos para a anulação de atos administrativos praticados com boa-fé. Além disso, buscou-se demonstrar a necessidade de regulamentação legislativa federal no tocante ao prazo para a anulação dos atos administrativos praticados com má-fé do beneficiário, tendo como embasamento a proporcionalidade como metodologia de interpretação. In this article, we present the doctrinal positions regarding the application of the institutes of debarment and res judicata in the administrative sphere, taking into consideration the decadential period of five years for the annulment of administrative acts practiced with good intention. In addition, it was sought to demonstrate the need for federal legislative regulation regarding the deadline for annulment of administrative acts performed in bad intention by the beneficiary, based on Proportionality as a methodology of interpretation.
Intimações judiciais via WhatsApp
Authors: Santana Conselheira Daldice
Published: May 2019

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Teoria da Cultura do Consumo: possibilidades, limitações e caminhos em estudos de marketing no Brasil
Authors: Vera Luciana Alves Rodas , Gosling Marlusa de Sevilha , Shigaki Helena Belintani
Published: May 2019

Em uma cultura em que os consumidores passam a ser representados e compreendidos como sujeitos em busca de uma identidade reflexiva e empoderada, o tema Consumer Culture Theory ou Teoria da Cultura do Consumo (CCT) ganha relevância. Este ensaio teórico tem por objetivo a discussão sobre as possibilidades, as críticas e os caminhos dessa tradição teórica em estudos de Marketing no Brasil. Os resultados deste ensaio teórico apontam que tal abordagem tem ganhado crescente atenção no campo do comportamento do consumidor, com estudos desenvolvidos em vários sentidos, como padrões sócio-históricos de consumo, culturas de mercado, identidade do consumidor e apropriações do uso de mídias. Igualmente, nota-se que a CCT apresenta muitas possibilidades em pesquisa de marketing, tanto no contexto brasileiro quanto estrangeiro e que suas poucas críticas podem ser solucionadas e revertidas por meio do contexto interdisciplinar que este novo campo de estudo propõe.
Avaliação de segurança em empresas da construção civil: uma aplicação da lógica Fuzzy
Authors: Araujo Aloisio Celso de , Santos João Alberto Neves dos , Lima Gilson Brito Alves , Nichioka Julio , Gavião Luiz Octávio
Published: May 2019

A Indústria da Construção (IC) é uma das atividades produtivas de maior perigo para os trabalhadores, especialmente por ocorrência de acidentes de trabalho fatais e não fatais. Estimativas da OIT para o ano de 2012 mostram que são 2,3 milhões de mortes a cada ano, decorrentes de falta de treinamento. Estima-se que, também a cada ano, ocorram pelo menos 60.000 acidentes fatais na IC em todo o mundo, um óbito a cada 10 minutos, sendo um em cada seis acidentes fatais na IC. Este estudo tem por objetivo estabelecer um modelo de mecanismo gerencial de indicadores para a gestão de segurança de empresas de construção civil, baseado em programas nacionais de premiação e modelos de gestão, com aplicação da lógica Fuzzy. O modelo elaborado com base nesta lógica apresenta dimensões e critérios cujos resultados apontaram a adequação do processo escolhido.
The New Logic of William van Orman Quine and Its Significance for the Development of Logic in Brazil
Authors: Stern Julio Michael
Published: May 2019

Review of the book: Willard Van Orman Quine, The Significance of the New Logic, edited and translated by Walter Carnielli, Frederique Janssen-Lauret and William Pickering, Cambridge Univ. Press, 2018, 224 pages, Online ISBN: 9781316831809. DOI:  http://dx.doi.org/10.1017/9781316831809
Physical activity, sedentary time and bone tissue: effects of an 8-months interdisciplinary program with overweight/obese children
Authors: Mello Júlio Brugnara , Lemos Luís Filipe Gomes Barbosa Pereira de , Aires Luísa Maria , Silva Gustavo , Tassitano Rafael Miranda , Mota Jorge Augusto , Gaya Anelise Reis , Martins Clarice Maria De Lucena
Published: May 2019

Moderate to vigorous physical activity plays a recognized osteogenic effect on bone. Moreover, sedentary time, and fat accumulation are unfavorable to bone health. Our study aimed (1) to examine changes in body composition, bone tissue, physical activity, and sedentary time; and (2) to explore whether changes in physical activity intensities and in sedentary time are associated with changes in bone outcomes after a school-based interdisciplinary intervention program. A total of 53 overweight/obese students (10.6 ± 3.5 year-olds; 26 girls) participated in physical activity classes. Bone area, bone mass, and bone mineral density z-score, body composition (fat mass, fat lean mass), physical activity, sedentary time and potential confounders (vitamin D and maturational status) were assessed at baseline, and 8 months later. General Linear Models were carried out and significance level was set at 5%. Changes in moderate to vigorous physical activity were positively correlated with changes in all bone mass indicators. We observed a significant overall effect of the intervention on bone mineral density z-score changes, however after adjustments for changes in sedentary time and moderate to vigorous physical activity, no effect was observed. Finally, variations in sedentary time and in moderate to vigorous physical activity play an important role in bone mass density in those participants of the interdisciplinary program.
La creación de eventos integrados: El caso Cervezas Victoria en el Carnaval de Málaga
Authors: Cristófol-Rodríguez Francisco-Javier , Galmés-Cerezo María , Cristófol-Rodríguez Carmen
Published: May 2019

Los eventos se han convertido en la mejor forma de acercarse a los consumidores y usuarios de marcas. En la presente investigación se exponen los antecedentes y la metodología sobre la creación de eventos integrados, propuesta por Galmés y Argudo (2016) así como la evolución de las estrategias de comunicación de marketing hacia la integración de canales y la creación de experiencias. Se pretende exponer dicha tendencia a través del ejemplo del caso de la Cervezas Victoria en el Carnaval de Málaga analizando la campaña llevada a cabo por la cervecera en 2019. Dicha campaña combina medios off con medios on, que se convierten una vez más en los grandes difusores y transmisores de los valores de la marca. Dichos valores se trasladan de la marca al acontecimiento de la ciudad y viceversa, fusionándose y dotándose mutuamente de nuevos matices comunicacionales. Dichos matices y resultados se exponen en las conclusiones de esta investigación.