bluuebunny/crossref_metadata_2025_split huggingface dataset:
Perioperative trastuzumab and pertuzumab in combination with FLOT versus FLOT alone for HER2 positive resectable esophagogastric adenocarcinoma: Petrarca—A phase II trial of the German AIO.
Authors: Hofheinz Ralf , zur Hausen Gerrit , Borchert Kersten , Kretzschmar Albrecht , Ebert Matthias Philip , Ettrich Thomas Jens , Koenigsmann Michael , Haag Georg Martin , Hagen Volker A. , Hoehler Thomas , Homann Nils , Kroening Hendrik , Reichardt Peter , Rieger Michael , Teschendorf Christian , Goekkurt Eray , Lindig Udo , Schmiegel Wolff H. , Pauligk Claudia , Al-Batran Salah-Eddin 
Published: September 2018

TPS4133 Background: Neoadjuvant or perioperative chemotherapy has become a standard of care for locally advanced, resectable gastric cancer and adenocarcinoma of the GEJ. However, patient’s outcome is still unsatisfactory and 5-year survival, even in prospective trials, has been below 40%. Targeting HER2 with Trastuzumab and Pertuzumab prolonged survival in patients with HER2-positive advanced breast cancer as did Trastuzumab in patients with HER2-positive advanced gastric cancer. This provides a rationale for the evaluation of anti-HER2 treatment for resectable patients. Methods: This is a prospective, multicenter, randomized, investigator initiated phase II trial. Patients with HER2-positive locally advanced adenocarcinoma of the stomach and GEJ (i.e. ≥cT2 any N or any T N-positive) with exclusion of distant metastases are enrolled. HER2 status is centrally assessed. Patients are randomized 1:1 to 4 pre-operative 2-week cycles (8 weeks) of FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m²) followed by surgery and 4 additional cycles of FLOT (arm A); or the same therapy in combination with Trastuzumab 8/6 mg/kg and Pertuzumab 840 mg every 3 weeks pre- and postop, followed by a total of 9 additional cycles of Trastuzumab/Pertuzumab monotherapy (arm B). Primary endpoint of the phase II part (n = 100) of the trial is to show numerical improvement of the rate of pathological complete remission to approx. 25% with antibodies compared to approx. 16% with FLOT alone as assessed by a centralized pathology. Main secondary endpoints are safety and tolerability. Once results from phase II become available, study transition into phase III will be evaluated based on de facto results and current medical standards. Recruitment has already started; by February 2017 a total of 19 patients have been randomized. EudraCT: 2014-002695-86 Clinical trial information: NCT02581462.
A phase II, open-label, randomized study to evaluate the efficacy and safety of GS-5745 combined with nivolumab versus nivolumab alone in subjects with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma.
Authors: Shah Manish A. , Metges Jean-Philippe , Chun Patrick Youngwhan , Smith Victoria , Maltzman Julia D. , Wainberg Zev A. 
Published: September 2018

TPS4141 Background: GS-5745 is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. Inhibiting MMP9 is expected to block paracrine signaling and metastasis and to alter the immune microenvironment within the tumor. Results from the ATTRACTION-2 Phase III trial showed the PD-1 inhibitor nivolumab significantly improved overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) in patients with heavily pre-treated advanced gastric or gastroesophageal junction cancer. Preclinical studies indicate that selective inhibition of MMP9 can inhibit immune-suppressive myeloid cell polarization, regulatory T cell generation, desmoplasia, and the destruction of ligands for CXCR3 (a critical chemokine receptor that enables effector T cell trafficking). In combination with a checkpoint inhibitor, CD8+, CD4+ and CD44+ cytotoxic T cells are significantly increased in a checkpoint-refractory model, suggesting that MMP9 inhibition could relieve immune suppression. Methods: This phase 2, open-label, randomized study investigates the efficacy and safety of GS-5745 combined with nivolumab versus nivolumab alone in patients with unresectable or recurrent gastric or gastroesophageal adenocarcinoma. 120 patients will be randomized to either GS-5745 800mg IV + nivolumab 3mg/kg IV, or nivolumab alone. Treatment will be administered every 2 weeks and stratified by PD-L1 status. CT will be performed every 8 weeks to evaluate response. The primary endpoint of the study is ORR; secondary endpoints include PFS, OS, and occurrence of adverse events. Key inclusion criteria: metastatic or inoperable adenocarcinoma of the stomach or GEJ which has progressed after ≥1 prior systemic therapy, ECOG performance status ≤1, RECISTv1.1 measureable disease, archival tissue adequate for PD-L1 evaluation. Exploratory biomarkers correlated with study drug response will also be evaluated. Enrollment opened September 2016. Clinical trial information: NCT02864381.
S1605: Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer.
Authors: Singh Parminder , Catherine Tangen , Lerner Seth P. , McConkey David , Plets Melissa , Lucia M. Scott , Woods Michael , Bivalacqua Trinity , Kassouf Wassim , Bangs Richard Carlton , Thompson Ian Murchie , Black Peter C. 
Published: September 2018

TPS4591 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. Results: 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). Conclusion: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 information: NCT02844816.
Avelumab plus axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma: Phase 3 study (JAVELIN Renal 101).
Authors: Choueiri Toni K. , Rini Brian I. , Larkin James M. G. , Bjarnason Georg A. , Gravis Gwenaelle , Gurney Howard , Lee Jae-Lyun , Keizman Daniel , Haanen John B. A. G. , Tomita Yoshihiko , Uemura Hirotsugu , Albiges Laurence , Schmidinger Manuela , Atkins Michael B. , Mariani Mariangela , Shnaidman Michael , di Pietro Alessandra , Motzer Robert J. 
Published: September 2018

TPS4594 Background: The combination of a checkpoint inhibitor with an anti-VEGF agent is a promising treatment strategy for advanced renal cell carcinoma (aRCC). Avelumab is a fully human IgG1 anti–PD-L1 antibody with clinical activity in aRCC and other tumor types (eg, Apolo et al. ASCO 2016; Gulley et al. ECC 2015). Axitinib is an anti-VEGF receptor tyrosine kinase inhibitor approved for second-line treatment of aRCC (Rini et al. Lancet 2011) that has also shown clinical activity as a first-line (1L) therapy (Hutson et al. Lancet Oncol 2013). In an ongoing phase 1b study in treatment-naïve patients (pts) with aRCC, avelumab + axitinib administered at standard monotherapy doses showed a tolerable safety profile and encouraging antitumor activity (Larkin et al. ESMO 2016). JAVELIN Renal 101 is a randomized, multicenter, phase 3 study (NCT02684006) comparing avelumab + axitinib vs sunitinib in pts with treatment-naïve aRCC. Methods: The primary objective is to demonstrate superiority of avelumab + axitinib vs sunitinib in prolonging progression-free survival (PFS) in the 1L treatment of pts with aRCC. Eligibility criteria include: aRCC with a clear cell component, ECOG PS ≤1, no prior systemic therapy for advanced disease, and measurable disease per RECIST v1.1. Approximately 583 pts will be randomized 1:1 and stratified based on ECOG PS (0 vs 1) and region (US vs Canada/Europe vs rest of the world). Pts receive either avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID continuously (cycle length 6 weeks) or sunitinib 50 mg orally once daily for 4 weeks followed by 2 weeks off. Treatment is discontinued for unacceptable toxicity or if any other criteria for withdrawal are met. Pts may continue treatment beyond progression (RECIST v1.1) if investigator-assessed clinical benefit is achieved and treatment is well tolerated. PFS is assessed by blinded central review. Secondary efficacy assessments include overall survival, objective response, disease control, duration of response, and time to response. Safety, PK, and biomarker analyses will also be performed. The trial is currently active at 103 sites across 12 countries and as of Feb 2017, more than 40% of patients have been enrolled. Clinical trial information: NCT02684006.
A randomized study of enzalutamide in patients with localized prostate cancer undergoing active surveillance (ENACT).
Authors: Shore Neal D. , Vourganti Srinivas , Silberstein Jonathan L. , Brown Bruce A. , Wilson Samuel , Hollowell Courtney M.P. , Cooperberg Matthew , Shang Gwendoline , Fleshner Neil Eric 
Published: September 2018

TPS5097 Background: Prostate cancer (PC) patients (pts) who select active surveillance (AS) are a heterogeneous population with varying risks for disease progression. Studies have estimated that approximately 31–42% of pts electing AS have experienced disease progression (pathological or therapeutic) over 1.8 and 2.3 years. There is no evidence-based pharmacological intervention which has effectively lessened this progression event. Pharmacological intervention with enzalutamide (ENZ), an androgen receptor inhibitor approved for treatment of metastatic castration-resistant PC, may lessen this progression. The aims of this study are to evaluate the efficacy of ENZ versus AS alone for delaying time to progression in pts with clinically localized PC undergoing AS. This study examines the effects of ENZ on progression in a subset of pts with low- or intermediate-risk PC who would otherwise elect an AS protocol. Methods: This is a multicenter, randomized, open-label study (NCT02799745). Eligibility criteria include histologically confirmed prostate adenocarcinoma within 6 months of screening, low or intermediate risk PC (T1c−T2c, prostate-specific antigen [PSA] < 20, N0, M0, Gleason score ≤7 [3+4 pattern only]), Eastern Cooperative Oncology Group status ≤2 and estimated life expectancy > 5 years. Exclusion criteria include any prior PC intervention. Pts will be randomized to receive open-label oral ENZ 160 mg/day once daily or to AS during the 1-year study treatment period. After the first year, all pts will be followed for one additional year with no other intervention. All pts will undergo prostate biopsy at 1 and 2 years. The primary end point is time to PC progression (pathological or therapeutic). Secondary end points include safety, incidence of negative biopsies for cancer at 1 and 2 years, percentage of cancer positive cores at 1 and 2 years, time to PSA progression, incidence of secondary rise in serum PSA, and quality-of-life questionnaires. Exploratory end points include biomarker assessment and genomic analysis. Study enrolment commenced in June 2016, with study completion expected in March 2019. Planned total enrolment is 222 pts from ~60 United States/Canadian sites. Clinical trial information: NCT02799745.
ARIEL4: An international, multicenter randomized phase 3 study of the PARP inhibitor rucaparib vs chemotherapy in germline or somatic BRCA1- or BRCA2-mutated, relapsed, high-grade ovarian carcinoma.
Authors: Oza Amit M. , Lorusso Domenica , Oaknin Ana , Safra Tamar , Swisher Elizabeth , Bondarenko Igor , Huzarski Tomasz , Klat Jaroslav , Póka Róbert , Viola Luciana Spillari , Tankersley Chris , Maloney Lara , Goble Sandra , Unger Caro , Giordano Heidi , Kristeleit Rebecca Sophie 
Published: September 2018

TPS5603 Background: In high-grade epithelial ovarian carcinoma (OC), ≈18% of patients (pts) have tumors with a germline BRCA1 or BRCA2 mutation; ≈7% have tumors with a somatic BRCA1 or BRCA2 mutation (Pennington et al. Clin Cancer Res. 2014;20:764-75). The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib is approved in the United States for treatment of pts with OC associated with a deleterious BRCA1 or BRCA2 mutation (germline and/or somatic) who have received ≥2 chemotherapies. Although PARP inhibitors have demonstrated clinical activity in OC in both treatment and maintenance settings, comparison to standard of care (SOC) has only been evaluated in the maintenance setting. Randomized studies are needed to assess the benefit-risk profile of PARP inhibitors vs current SOC as treatment for BRCA1- or BRCA2-mutated, relapsed, high-grade OC. Methods: ARIEL4 (NCT02855944) is evaluating rucaparib vs chemotherapy as treatment for pts with germline or somatic BRCA1- or BRCA2-mutated, relapsed, high-grade OC (regardless of histology) who have received ≥2 prior chemotherapy regimens. Approximately 345 pts will be randomized 2:1 to receive rucaparib (600 mg BID) (n = 230) or chemotherapy (n = 115) and stratified by progression-free interval after their most recent platinum regimen. Pts with platinum-resistant (progressive disease [PD] 1– < 6 mo after last platinum) or partially platinum-sensitive disease (PD 6– < 12 mo after last platinum) will be randomized to rucaparib or weekly paclitaxel; pts with platinum-sensitive disease (PD ≥12 mo after last platinum) will be randomized to rucaparib or platinum-based therapy (single-agent or doublet at the discretion of the investigator). Pts receiving chemotherapy have the option to cross over to rucaparib upon radiographic disease progression. The primary endpoint is progression-free survival. Secondary endpoints include investigator-assessed objective response rate (ORR) (RECIST version 1.1), ORR/CA-125 response, duration of response, overall survival, and pt-reported outcomes. Safety will be summarized descriptively using standard adverse event reporting. Clinical trial information: NCT02855944.
PAOLA-1: An ENGOT/GCIG phase III trial of olaparib versus placebo combined with bevacizumab as maintenance treatment in patients with advanced ovarian cancer following first-line platinum-based chemotherapy plus bevacizumab.
Authors: Ray-Coquard Isabelle Laure , Harter Philipp , Gonzalez Martin Antonio , Cropet Claire , Pignata Sandro , Fujiwara Keiichi , Marth Christian , Vergote Ignace , Mirza Mansoor Raza , Colombo Nicoletta , Rosenberg Per , Maenpaa Johanna Unelma , Pujade Lauraine Eric 
Published: September 2018

TPS5605 Background: Olaparib (Lynparza) is an oral PARP inhibitor indicated in the EU for the maintenance treatment of patients (pts) with platinum-sensitive relapsed BRCA-mutated high grade serous ovarian cancer (HGSOC). Bevacizumab is an anti-VEGF monoclonal antibody indicated in the EU in first line or relapse for the treatment of OC in combination with specific chemotherapeutic agents. Bevacizumab treatment is associated with increasing hypoxia-induced homologous recombination repair deficiencies in tumor cells, and is hypothesized to increase ovarian tumor sensitivity to olaparib. Methods: PAOLA-1 (ENGOT-ov25) is a randomized, placebo-controlled trial evaluating the efficacy and safety of olaparib (tablet formulation) in pts with advanced HGSOC receiving bevacizumab maintenance therapy. Eligible pts are those in complete or partial response following first-line platinum chemotherapy plus bevacizumab, and for whom bevacizumab maintenance therapy is planned. Approximately 762 European and 24 Japanese pts will be randomized 2:1 to olaparib 300 mg twice daily or placebo for up to 24 months. All pts will receive standard maintenance care of bevacizumab (15 mg/kg every three weeks) for up to 15 months. Primary objective: PFS1 according to RECIST 1.1 Secondary objectives: PFS2, OS, Safety, PRO/QoL, TFST, TSST All pts will undergo tumor BRCA testing prior to randomization. Central BRCA testing (tumor) will be performed in five screening platforms in France. Tumor BRCA test results have to be available within two months of sample provision. PFS will be evaluated using a log-rank test stratified by response to first-line treatment and BRCA mutation status. Treatment effect hazard ratio of 0.7 is expected and final PFS1 analysis will be performed after 372 events. The first pt from eight ENGOT groups plus Japan (10 participating countries) was randomized in July 2015. As of 31 January 2017, 549 pts have been randomized. The median period between the provision of a tumor sample and returned BRCA test result is 40 days. Accrual is expected to be complete before July 2017. Clinical trial information: NCT02477644.
Towards omitting breast cancer surgery in select patient groups: Assessment of pathologic complete response after neoadjuvant systemic therapy using biopsies—The MICRA trial.
Authors: Van Der Noordaa Marieke , van Duijnhoven Frederieke , Loo Claudette , van der Vijver Koen , Sonke Gabe S. , Van Der Pol Carmen , Francken Anne Brecht , Vrancken Peeters Marie-Jeanne 
Published: September 2018

TPS593 Background: Improvements in systemic treatments for breast cancer patients has led to increasing rates of pathologic complete response (pCR). In addition, the identification of a pCR has been greatly improved with magnetic resonance imaging (MRI). In patients with a pCR, surgical resection of (part of) the original tumor area is performed to confirm the absence or presence of pCR and is not likely to contribute to locoregional control. With the MICRA trial (Minimally Invasive Complete Response Assessment) we aim to omit breast surgery in breast cancer patients achieving pathologic complete response (pCR) after neoadjuvant systemic therapy (NST) using biopsies, thus preventing overtreatment and improving quality of life. Methods: The MICRA trial is a multi-center observational prospective cohort study. In all breast cancer patients receiving NST, a marker is placed in the center of the tumor area before NST. 440 patients with radiologic complete response or partial response (0.1-2.0 cm residual contrast enhancement, ≥30% decrease in tumor size according to RECIST criteria) on contrast enhanced MRI will be included in the MICRA trial. Patients with hormone receptor positive, triple negative and Human Epidermal growth factor Receptor 2 tumors are eligible. After NST, 8 ultrasound-guided biopsies are obtained in the region surrounding the marker, while the patient is under general anesthesia. Immediately hereafter, breast surgery is performed and pathology results of the biopsies and resected specimens are compared. The primary endpoint is specificity of post-NST biopsies. In addition, sensitivity and positive and negative predictive value will be calculated. We will perform a multivariable analysis using data on MRI and ultrasound findings, pre-NST pathology parameters and post-NST biopsy results to determine what the most reliable method is to assess pCR and how many biopsies are needed for this purpose. Conclusion: With the MICRA-trial we aim to select a group of breast cancer patients in whom surgery of the breast after NST can be omitted, by predicting the presence of a pCR on biopsies. Clinical trial information: NTR6120.
A feasibility study of neoadjuvant talazoparib for early-stage breast cancer patients with a germline BRCA pathogenic variant: NCT02282345.
Authors: Litton Jennifer Keating , Scoggins Marion , Whitman Gary J , Barcenas Carlos Hernando , Moulder Stacy L. , Murthy Rashmi Krishna , Abouharb Sausan , Adrada Beatriz , Helgason Thorunn , Schwartz-Gomez Jill , Mittendorf Elizabeth Ann , Thompson Alastair Mark , Arun Banu 
Published: September 2018

TPS595 Background: Poly-(adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a family of enzymes responsible for DNA repair via base excision repair as well as maintenance of genetic stability. BRCA mutation carriers appear to have significant sensitivity to PARP inhibitors, not only from synthetic lethality but also potentially PARP trapping in the metastatic setting. A 2-month window study of talazoparib was reported at ESMO in 2016. In 13 patients treated, the median % tumor shrinkage by ultrasound was 88% (range 30-98%) and the study was halted early to allow for this expansion of neoadjuvant talzoparib as the only treatment prior to surgery to evaluate pathologic response. Primary Objective: Evaluate the rate of pathologic complete response (pCR)/RCB-0 + residual cancer burden (RCB)-I responses in patients with early stage breast cancer and a known BRCA pathogenic variant. Methods: 20 patients with stage I-III breast cancer and a known BRCA mutation will be accrued on this IRB-approved study. Patients will receive 4-6 months of neoadjuvant talazoparib and then proceed to surgery. Radiation, chemotherapy and endocrine therapy will be given when appropriate in teh adjuvant setting. Brief Eligibility Criteria: Patients with an identified BRCA pathogenic variant and diagnosed with a stage I-III breast cancer at least 1 cm in size are eligible. Tumors can have any ER or PR status but HER2 over-expressed cancers were excluded. Prior systemic or radiation therapy for previous breast cancer is excluded, but prior surgical treatment for contralateral DCIS is allowed. Correlative Science: Blood and biopsies prior to initiation of therapy will be collected to evaluate biomarkers of therapy efficacy as well as to initiate patient derived xenograft (PDX) models. Other studies will include: immunohistochemistry, targeted or whole exome sequencing for BRCA pathway mutations and other somatic and germline alterations; RNA sequencing; immune response; transcriptional profiles to assess TNBC subtype, reverse phase protein array (RPPA); generation of PDX models and mammosphere cultures. Clinical trial information: NCT02282345.