bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I dose-escalation and immune biomarker study of intravenous FF-10832, liposomal gemcitabine, in patients with advanced solid tumors.
Authors: Borazanci Erkut Hasan , Falchook Gerald Steven , Abbas Atif , Wheeler Catherine A. , Maier Gary , Johansen Mary , Sedivy Paula , Subach Ruth Ann , Sen Shiraj , Jones Suzanne Fields , Ioroi Tadaaki , Matsumoto Takeshi , Suzuki Takeaki , Madden Timothy , Hamilton Erika Paige 
Published: May 2019

TPS3163 Background: FF-10832 (832) is a liposomal formulation of gemcitabine (GEM) that demonstrates a prolonged half-life and preferential uptake in tumor vs normal tissues and marrow in pre-clinical models. Macrophage uptake has been shown in the tumor microenvironment (TME), with subsequent GEM release in tumor cells. This relative selectivity and anti-tumor immunological changes observed in the TME may lead to decreased toxicity and increased efficacy compared to GEM. Ferumoxytol (FMX) may be a surrogate for nanoparticle penetration into tissue and is being examined as a potential correlate for activity. Methods: This ongoing Phase 1, 3+3 dose-escalation study of 832 will determine the safety profile, maximum tolerated dose, dose-limiting toxicities (DLT) and recommended Phase 2 dose, and will be followed by expansion. Enrollment of up to 60 patients (pts) with advanced solid tumors is planned. Pre-treatment (tx) FMX MRI scans are performed, followed by 832 administration on Days 1 &15 of each 28-day cycle until disease progression or unacceptable toxicity. In addition to standard biomarker and imaging evaluations, change in macrophage polarity, myeloid-derived suppressor cell (MDSC) and regulatory T cell populations are being investigatedin peripheral blood and tumor tissue. Clinical trial information: NCT03440450.
CA224-060: A randomized, open label, phase II trial of relatlimab (anti-LAG-3) and nivolumab with chemotherapy versus nivolumab with chemotherapy as first-line treatment in patients with gastric or gastroesophageal junction adenocarcinoma.
Authors: Feeney Kynan , Kelly Ronan , Lipton Lara Rachel , Chao Joseph , Acosta-Rivera Mirelis , Earle Dennis , Lei Ming , Kollia Georgia , Tebbutt Niall C. 
Published: May 2019

TPS4143 Background: Blockade of the immune checkpoint receptor programmed death-1 (PD-1) has shown clinical benefit in multiple tumor types. Nivolumab (anti–PD-1) has demonstrated a survival advantage versus (vs) placebo in patients (pts) with advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) (Kang YK et al. Lancet 2017;390:2461–71). Lymphocyte activation gene 3 (LAG-3) is an immune checkpoint molecule that negatively regulates effector T-cell function and is a marker of T-cell exhaustion. Preliminary data in melanoma suggest that combining nivolumab with relatlimab (anti–LAG-3) could improve efficacy without substantially increasing toxicity vs nivolumab especially, but not exclusively, in LAG-3-expressing pts (Ascierto PA et al. Ann Oncol 2017;28(S5):LBA18). Furthermore, LAG-3 expression was as high as 33% in an analysis of solid tumors including GC (Edwards R et al. J Immunother Cancer 2017;5(S3):P510). Study CA224-060 will assess the clinical efficacy and safety of relatlimab and nivolumab with chemotherapy for first-line treatment of GC or GEJC. Methods: This is a randomized, open-label, multicenter, phase 2 study of relatlimab and nivolumab with oxaliplatin-based chemotherapy vs nivolumab with oxaliplatin-based chemotherapy. Approximately 250 adult pts with untreated, locally advanced, unresectable or metastatic GC or GEJC will be enrolled. To be randomized, pts must have tumor tissue for analysis of biomarkers, LAG-3 status, and PD-L1 combined positive score. Key exclusion criteria include HER2-positive status, untreated CNS metastases, or significant cardiovascular disease. The primary endpoint is objective response rate (ORR) using RECIST v.1.1 by blinded independent central review in LAG-3-expressing pts. Other endpoints include investigator-assessed ORR, ORR in LAG-3-negative pts, duration of response, overall survival, progression-free survival, and safety and tolerability. Efficacy signals in biomarker subgroups will be explored. Currently, 26 sites are activated with 15 randomized pts. Clinical trial information: NCT03662659.
NET-02: A multi-center, randomised, phase II trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC).
Authors: McNamara Mairead Geraldine , Swain Jayne , Craig Zoe , Wadsley Jonathan , Reed Nicholas , Faluyi Olusola Olusesan , Lamarca Angela , Hubner Richard , Mansoor Wasat , Sarker Debashis , Howard Helen C , Cairns David A. , Meyer Tim , Valle Juan W. 
Published: May 2019

TPS4158 Background: The prognosis for pts with PD-EP-NEC is poor. First-line treatment for advanced disease is etoposide/platinum-based chemotherapy, analogous to that of high grade lung NEC, with no standard second-line treatment, and is an area of unmet need. Methods: This is a multi-centre, randomised, phase II trial of nal-IRI; 80mg/m2 intravenously (IV) over 90 mins, prior to 5-FU; 2400 mg/m2 infusion over 46 hrs and folinic acid, Q14 days, or docetaxel; 75mg/m2 IV over 60 mins, Q21 days, as second-line therapy in pts with progressive PD-EP-NEC (Ki-67 > 20%), with the overall aim of selecting a treatment for continuation to a phase III trial. The standard arm is that used in high-grade lung NEC, of which docetaxel is a second-line therapy option (NCCN guidelines) and combination regimens such as Irinotecan/5-FU are a second-line therapy option currently used without trial evidence for this subset of pts. Pts must have had prior treatment with first-line platinum-based chemotherapy, have documented disease progression and have an ECOG performance status of ≤2. This study plans to recruit 102 pts from 16 UK centres (over 37 mths). Primary endpoint is 6-mth progression-free survival (PFS) rate; trial is designed to have an 80% chance of demonstrating that the one-sided 95% confidence interval of the 6 mth PFS rate excludes 15%, if the true rate is at least 30%, where 30% is the required level of efficacy, and a rate of < 15% would give grounds for rejection. If both treatment arms exceed the required level of efficacy to warrant further evaluation in a phase III trial, treatment with the higher PFS rate at 6 mths will be selected. Secondary endpoints include overall survival, objective response rate, toxicity, quality of life, serum neuron-specific enolase. Exploratory endpoints include quantification of circulating tumour cells (CTCs), circulating tumour deoxyribonucleic acid (ctDNA) and molecular profiling of CTCs, ctDNA and tumour tissue, and generation of CTC-derived xenografts. This trial is open and has enrolled 6 pts at time of submission. Clinical trial information: 10996604.
Phase II multi-institutional study of nivolumab (Nivo), cabiralizumab (Cabira), and stereotactic body radiotherapy (SBRT) for locally advanced unresectable pancreatic cancer (LAUPC).
Authors: Cohen Deirdre Jill , Medina Benjamin , Du Kevin Lee , Coveler Andrew L. , Manji Gulam Abbas , Oberstein Paul Eliezer , Perna Serena K , Miller George 
Published: May 2019

TPS4163 Background: Treatment of LAUPC most commonly involves chemotherapy +/- RT. Patients(pts) who can be downstaged and undergo R0 resection have significant improvement in overall survival, but conventional chemoRT converts < 10% of patients with LAUPC. If the effects of RT can be augmented then higher R0 resection rates may be achieved and improve survival. In pre-clinical models, RT leads to increased expression of M-CSF from pancreatic tumor cells and marked immune suppression within the tumor microenvironment via expansion of tumor associated macrophages (TAMs). Concurrent blockade of M-CSF with RT reduces TAM infiltration, prevents the generation of tumor promoting T cell populations, and increases the therapeutic effect of RT. RT also induces up-regulation of PD-L1 in TAMs, another mode of immune suppression that can account for RT resistance in LAUPC. (Seifert et al. 2016). These data suggest the efficacy of RT in LAUPC is limited by its promotion of innate and adaptive immune suppression. CSF1R blockade with Cabira combined with PD-1 blockade with Nivo may enhance the efficacy of SBRT by reprogramming the TAM compartment in tumors, thereby preventing an immune suppressive phenotype and augmenting T-cell mediated anti-tumor response. Methods: Single arm phase II study designed to evaluate safety, tolerability, and surgical resection rate in LAUPC pts treated with concurrent Nivo, Cabira, and SBRT. Exploratory endpoints include immune changes within blood and tissue following treatment and correlation with clinical endpoints. Key eligibility: completion of 2- 6 months standard induction chemotherapy, normal organ and marrow function, pre- and on-treatment biopsy, and PS ≤ 1. Following initial biopsy and placement of fiducials, Cabira 4mg/kg and Nivo 240mg are given D1 of every 14 day cycle. SBRT 6.6 Gy x 5 consecutive fractions starts D8. After 2 cycles, repeat biopsy and imaging is performed. Treatment with Cabira and Nivo continues every 2 weeks and imaging is done every 8 weeks, at which time pt is assessed for surgical resection. If pt is downstaged, treatment is discontinued and pt proceeds to surgery. Preliminary 6 pt safety cohort is monitored for unacceptable toxicities. If < 3 unacceptable toxicities in the first 6 subjects enrolled, then plan for expansion phase with 14 more pts. As of abstract submission, 3 pts have been enrolled. Clinical trial information: NCT03599362.
An open label phase I/IIa study to evaluate the safety and efficacy of CCS1477 as monotherapy and in combination in patients with advanced solid/metastatic tumors.
Authors: De Bono Johann S. , Cojocaru Elena , Plummer Elizabeth Ruth , Knurowski Tomasz , Clegg Karen , Ashby Fay , Pegg Neil , West William , Brooks Anthony Nigel 
Published: May 2019

TPS5089 Background: CCS1477 is a potent, selective and orally bioavailable inhibitor of the bromodomain of p300 and CBP, two homologous and critical co-activators of the androgen receptor (AR) and its variant forms, including mutated, amplified and spliced AR, as well as c-Myc. CCS1477 represents a new therapeutic option for prostate cancer patients who have progressed after failure of anti-androgen therapy and in combination with anti-androgens such as enzalutamide or abiraterone. Methods: This is a Ph I/IIa study to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose and schedule(s) of CCS1477 and investigate clinical activity of CCS1477 monotherapy and CCS1477 in combination with abiraterone or enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC). The trial aims to enrol approximately 150 patients and is currently recruiting in the UK with plans to open additional sites in the USA (NCT03568656). Key inclusion criteria (for the mCRPC) require previous treatment with abiraterone and/or enzalutamide, taxane as well as evidence of disease progression (PCWG-3 guidelines). Single dose and steady state pharmacokinetics will be determined along with changes in plasma PSA, LDH and ALKP and in circulating tumour cell number. Anti-tumour activity will be determined by standard imaging according to PCWG-3 guidelines. Paired tumour biopsies for biomarker assessment are being collected. Cohort 1 of the monotherapy dose-escalation (rolling 6 design; 3-6 patients/cohort) has completed. Enrolment to cohort 2 began in January 2019. Dose finding in combination (CCS1477 + abiraterone; CCS1477 + enzalutamide) will be open once monotherapy dose escalation completes. Following definition of a recommended phase 2 dose and schedule for monotherapy and in combination, three expansion arms in patients with mCRPC will be opened in parallel (25 patients/arm); CCS1477 monotherapy; CCS1477 + abiraterone; CCS1477 + enzalutamide. A further expansion in patients with advanced solid tumours with a mutation in p300 or CBP will also be opened. Clinical trial information: NCT03568656.
Nivolumab and ipilimumab treatment in prostate cancer with an immunogenic signature (NEPTUNES).
Authors: Wong Yien Ning Sophia , Sankey Peter , Josephs Debra Hannah , Jones Robert J , Crabb Simon J. , Beare Sandy , Duggan Marian , White Laura , Charlaftis Nikolaos , Wheeler Graham , Linares Josep , Quezada Sergio A. , Ensell Leah , Flanagan Cliona , Kularatne Bihani Yoshana , Chung Moon , Pritchard Colin C. , Freeman Alex , Marafioti Teresa , Linch Mark David 
Published: May 2019

TPS5090 Background: Responses to checkpoint inhibitor (CPI) monotherapy in patients with metastatic castration resistant prostate cancer (mCRPC) have been limited. This is in part attributed to low tumour mutational burden (TMB) and low tumour infiltrating lymphocytes (TILs). Previously ~20% patients with prostate cancer have demonstrated high TILs or TMB1. We hypothesize that patients with higher TMB due to mismatch repair deficiency (dMMR) or defective DNA damage response (dDDR) and patients with high TILs are more likely to respond to combination CPI with anti PD-1 and anti CTLA-4 therapy. Methods: NEPTUNES is a single arm phase II trial designed to assess the efficacy of nivolumab and ipilimumab in biomarker selected patients with mCRPC that have progressed following ≥1 line of therapy. The immunogenic signature (ImS) biomarker is defined by ≥1 of the following: 1) dMMR by immunohistochemistry (IHC); 2) dDDR detected by the UW-OncoPlex sequencing assay and; 3) high TILs on multiplexed IHC. The UW-OncoPlex assay detects mutations in >260 genes and provides an estimation of TMB. Assuming an ImS+ rate of 20%, we aim to pre-screen 175 patients in order to enrol 35 patients into the main study. The primary endpoint is composite response rate (CRR), achieved if ≥1 of the following criteria are satisfied: 1) radiological response by RECIST 1.1; 2) PSA response ≥50%; 3) conversion of circulating tumour cells (CTC) count from ≥5 cells at baseline to <5 cells at week 9. The treatment will be deemed ineffective if the CRR is <20%. Nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) is dosed every three weeks for up to 4 times, followed by a 480mg flat dose of nivolumab every 4 weeks for up to one year. Baseline biopsies are mandated and paired biopsy at week 12 is encouraged. The secondary endpoints include safety, overall survival, and radiological and PSA progression free survival. Exploratory biological markers including TMB, mutational profiles, change in TILs and liquid biomarkers will be correlated with the primary clinical endpoint. Since opening in February 2018, 126 patients have been pre-screened with 25 ImS+. To date, 9/25 ImS+ patients have been enrolled into the main study. The trial is ongoing, with patient accrual expected to complete by late 2019. References: 1Linch, M., Goh, G., Hiley, C., Shanmugabavan, Y., McGranahan, N., Rowan, A., . . . Swanton, C. (2017). Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters. Ann Oncol, 28(10), 2472-2480. doi:10.1093/annonc/mdx355. Clinical trial information: NCT03061539.
DUO-O: A randomized phase III trial of durvalumab (durva) in combination with chemotherapy and bevacizumab (bev), followed by maintenance durva, bev and olaparib (olap), in newly diagnosed advanced ovarian cancer patients.
Authors: Harter Philipp , Bidziński Mariusz , Colombo Nicoletta , Floquet Anne , Rubio Pérez Maria Jesús , Kim Jae-Weon , Lheureux Stephanie , Marth Christian , Nyvang Gitte-Bettina , Okamoto Aikou , Reuss Alexander , Scambia Giovanni , Trillsch Fabian , Vardar Mehmet Ali , Van Nieuwenhuysen Els , Lichfield Jasmine , Rugman Paul , Twumasi-Ankrah Philip , Aghajanian Carol 
Published: May 2019

TPS5598 Background: Ovarian cancer (OC) is the leading cause of death from gynecologic cancers in US women. Despite high response rates to first-line treatment, ~70% of patients (pts) relapse within 3 years and then remain largely incurable. First-line treatment needs to be improved to achieve long-term remission in pts and improve the cure rate. The Phase III SOLO1 trial showed a meaningful clinical benefit for olap maintenance therapy in newly diagnosed OC pts with a BRCA mutation (Moore et al N Engl J Med 2018). Preliminary data suggest that combining a PD-L1 inhibitor, anti-angiogenic and PARP inhibitor (triplet therapy) may achieve a synergistic antitumor effect. The DUO-O study (NCT03737643) evaluates the efficacy and safety of treatment combinations involving standard-of-care platinum-based chemotherapy (chemo), VEGF inhibitor bev, anti-PD-L1 antibody durva and PARP inhibitor olap, in women with newly diagnosed advanced OC. Methods: Eligible pts for this double-blind, randomized, Phase III study must have newly diagnosed, advanced, high-grade epithelial OC and either have completed primary surgery or plan to have interval debulking surgery. Depending on their tumor BRCA mutation (tBRCAm) status (determined by central test), pts will join one of two independent cohorts. Pts in the non-tBRCAm cohort (n~906) will be randomized (1:1:1) before cycle 2 to: a) chemo + bev + placebo (for 6 cycles) followed by bev (15 mg/kg [total 15 months]) + placebo maintenance treatment (IV and tablets); b) chemo + bev + durva (6 cycles) followed by bev + durva (1120 mg q3w [total 15 months]) + placebo (tablets) maintenance treatment; or c) chemo + bev + durva (6 cycles) followed by bev + durva + olap (300 mg bd tablets [24 months]) maintenance treatment. Pts in the open-label tBRCAm cohort (n~150) will receive 6 cycles of chemo + durva followed by durva + olap maintenance therapy, with optional use of bev. The primary endpoint of progression-free survival will be assessed by modified RECIST 1.1. Key secondary endpoints include overall survival, overall response rate and duration of response. Enrollment began in January 2019. Clinical trial information: NCT03737643.
ENGOT-OV44/FIRST study: A randomized, double-blind, adaptive, phase III study of platinum-based therapy with dostarlimab (TSR-042) + niraparib versus standard-of-care (SOC) platinum-based therapy as first-line treatment of stage 3/4 non-mucinous epithelial ovarian cancer (OC).
Authors: Hardy-Bessard Anne-Claire , Moore Kathleen N. , Mirza Mansoor Raza , Asselain Bernard , Redondo Andres , Pfisterer Jacobus , Pignata Sandro , Provencher Diane M. , Cibula David , Reyners Anna K.L. , Bodnar Lubomir , Glasspool Rosalind Margaret , Papadimitriou Christos A. , Eitan Rami , Han Sileny , Duska Linda R. , Rimel Bj , Hazard Sebastien , Chen Jian , Pujade-Lauraine Eric 
Published: May 2019

TPS5600 Background: Despite surgery and SOC therapy (paclitaxel and carboplatin ± bevacizumab[bev]), 5-year survival rates remain low for patients (pts) with FIGO stage 3/4 OC. Niraparib (ZEJULA) is the first selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved in the US and Europe for maintenance treatment in pts with recurrent OC regardless of BRCAmut status. Preclinical data suggest synergy with PARPi + anti-PD-1 blockade. Niraparib + pembrolizumab has shown clinical efficacy in pts with platinum-resistant or secondary refractory OC regardless of biomarker status. Dostarlimab is an anti–PD-1 humanized monoclonal with clinical activity as monotherapy in early phase trials. The primary objective of the currently enrolling FIRST trial is to compare PFS (per RECIST v1.1) in pts treated with SOC + dostarlimab + niraparib to SOC. Methods: Eligible pts (up to 912) are FIGO stage 3 (with residual disease, CC0 high risk, or planned neoadjuvant therapy) or stage 4, non-mucinous epithelial OC and ECOG score < 2. After 1 cycle of SOC, pts are stratified by concurrent bev use, BRCAmut/HRR status, and disease burden then randomized as 1:1:2 to 1 of 3 arms (Table). An innovative feature of ENGOT-OV44/FIRST (NCT03602859; EUDRACT 2018-000413-20) is the pre-planned adaptive study design to adapt the control arm to the evolving SOCs in OC, allowing pts in the control arm to receive up to date SOC. These adaptations will occur when practice-changing data are released. Following publication of SOLO1 results, BRCAmut pts will only be randomized to arm 2 or 3 to ensure they receive niraparib. Further adaptations may be incorporated as new data become available, leading to stop randomization in arm 1 or 2 of pts based on their biomarker status. Clinical trial information: NCT03602859. [Table: see text]
NATALEE: Phase III study of ribociclib (RIBO) + endocrine therapy (ET) as adjuvant treatment in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) early breast cancer (EBC).
Authors: Slamon Dennis J. , Fasching Peter A. , Patel Ravindranath , Verma Sunil , Hurvitz Sara A. , Chia Stephen K. L. , Crown John , Martin Miguel , Barrios Carlos H. , Spera Gonzalo , Lopez Céline , Hor Inès , Pelov Diana , Hughes Gareth , Nawinne Moditha , Hortobagyi Gabriel N. 
Published: May 2019

TPS597 Background: RIBO is a selective inhibitor of CDK4/6 with demonstrated efficacy and is well tolerated when combined with ET in pre-/peri- and postmenopausal women with HR+, HER2– advanced breast cancer. Given these findings and considering the role of CDK4/6–Rb–E2F pathway dysregulation in ET resistance, there is a rationale for evaluating whether RIBO + ET prevents, or delays acquired resistance to ET in the adjuvant setting, to improve invasive disease-free survival (iDFS). Methods: The phase 3 multicenter, randomized, open-label NATALEE trial will evaluate the efficacy and safety of RIBO + ET as adjuvant treatment in patients with HR+, HER2– EBC. Eligible women (any menopausal status) and men aged ≥ 18 years will be randomized to RIBO 400 mg/day (3 weeks on/1 week off) + ET or ET alone. In both arms, ET will comprise daily continuous letrozole 2.5 mg/day or anastrozole 1 mg/day; men and premenopausal women will also receive goserelin 3.6 mg once every 28 days. Treatment with RIBO will last 36 months whereas treatment with ET (in both arms) will last 60 months. Patients must have had American Joint Committee on Cancer (8th ed.) Anatomic Stage II (either N0 with grade 2-3 and/or Ki67 ≥ 20% or N1) or III EBC, with an initial diagnosis ≤ 18 months prior to randomization, and completed chemotherapy and radiotherapy (if indicated). Patients receiving standard (neo)adjuvant ET are eligible only if this treatment was initiated within 12 months of randomization. Key exclusion criteria include previous CDK4/6 inhibitor treatment and clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality. The primary endpoint is iDFS using STEEP (Standardized Definitions for Efficacy End Points) criteria as assessed by the investigator; secondary endpoints include recurrence-free survival, distant DFS, overall survival, patient-reported outcomes, and RIBO pharmacokinetics. Safety and tolerability will also be evaluated. Estimated enrollment is 4000 patients from 425 sites in 21 countries. Recruitment is ongoing. Clinical trial information: NCT03701334.