bluuebunny/crossref_metadata_2025_split huggingface dataset:
NUC-1031 in combination with cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121).
Authors: Knox Jennifer J. , McNamara Mairead Geraldine , Goyal Lipika , Doherty Mark , Springfeld Christoph , Park Joon Oh , De Gramont Aimery , Verdaguer Helena , Zalcberg John Raymond , Palmer Daniel H. , Evans T.R. Jeffry , Ross Paul J. , Valle Juan W. 
Published: February 2020

TPS602 Background: Biliary tract cancer (BTC) carries a poor prognosis and has no approved treatments. Although gemcitabine + cisplatin (GemCis) is accepted as the global standard of care (SoC) for 1st-line treatment, the reported unconfirmed ORR and OS from randomized studies of this combination are low at 18.5-26.1% and 11.2-11.7 months, respectively. NUC-1031, a phosphoramidate transformation of gemcitabine, is designed to overcome key cancer resistance mechanisms associated with gemcitabine. Promising signs of efficacy have been observed with single-agent NUC-1031 in a Phase I study in advanced solid tumors (Blagden et al 2018) and in the Phase Ib ABC-08 study of NUC-1031 + cisplatin 25 mg/m2 on days 1 and 8 of a 21-day cycle for the 1st-line treatment of advanced BTC. Of 14 patients (pts) enrolled in 2 cohorts (NUC-1031: 625 mg/m2 and 725 mg/m2), 1 pt achieved a CR and 6 pts achieved PR, giving an unconfirmed ORR of 50% and representing an approximate doubling of ORR over SoC. The combination was well-tolerated with no unexpected adverse events or dose-limiting toxicities. The RP2D of NUC-1031 in combination with cisplatin is 725 mg/m2. The tolerability profile together with robust efficacy signals suggested NUC-1031 + cisplatin may represent a more effective therapy than GemCis for BTC and led to initiation of a global Phase III study. Methods: A Phase III, open-label, randomized head-to-head study of NUC-1031 + cisplatin versus GemCis for 1st-line treatment of advanced BTC will include pts ≥18 years with histologically- or cytologically-proven BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease. A total of 828 pts will be randomized (1:1) to either 725 mg/m2 NUC-1031 + 25 mg/m2 cisplatin or 1000 mg/m2 gemcitabine + 25 mg/m2 cisplatin, administered on days 1 and 8 of a 21-day cycle. Primary objectives are OS and ORR. Secondary objectives include further measurements of efficacy, safety, pharmacokinetics, and patient-reported quality of life. The study will be conducted at approximately 120 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT04163900.
Phase II HEPANOVA trial of tumor treating fields concomitant with sorafenib for advanced hepatocellular carcinoma.
Authors: Grosu Anca , Gkika Eleni , Brunner Thomas B. , Thimme Robert 
Published: February 2020

TPS603 Background: Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of glioblastoma and malignant pleural mesothelioma by the FDA. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of hepatocellular carcinoma (HCC), leading to a significant increase in cell death. The Phase 2 HEPANOVA [NCT03606590] study is the first trial testing TTFields in HCC patients, and is designed to test the safety and efficacy of adding TTFields to sorafenib in advanced HCC. Methods: (N = 25) with unresectable HCC who are not amenable to any local treatment will be enrolled in this prospective, single-arm study. The study enrolls patients with ECOG score of 0-2 and Barcelona clinic liver cancer (BCLC) stage 0-C. Patients must have a measurable disease per RECIST Criteria. Having implanted electronic devices in the torso is exclusionary. Sorafenib will be administered at standard dose (400 mg twice daily). TTFields (150 kHz) will be delivered for 18 hours/day until local disease progression per RECIST Criteria. Clinical follow up will be performed q4w, and a CT/MRI scan q12w. Following disease progression in the liver, patients will discontinue TTFields and be followed monthly for survival. Overall response rate will be the primary endpoint and in-field control rate, progression-free survival rate at 12 month (PFS12), OS rate at 1 year and toxicity will all be secondary endpoints. Sample size was calculated using an Exact test for proportions considering the weighted average of ORR of patients who had either complete or partial response per RECIST criteria in historical studies with sorafenib is 4.5%. A sample size of 25 patients was required to achieve a power of approximately 80% at a one-sided alpha level of 0.05 using a single sample Exact test for proportions. Clinical trial information: NCT03606590.
Apartinib in combination with S-1 for the second-line treatment of advanced pancreatic cancer (APC).
Authors: Hang Junjie , Wu Lixia , Yin Ruohan , Liu Muhan , Xu Kequn 
Published: February 2020

TPS781 Background: The prognosis for patients with advanced pancreatic cancer (APC) is extremely dismal. First-line treatment for APC is gemcitabine/5-FU-based chemotherapy with no standard second-line treatment. Anti-angiogenic therapy combined with chemotherapy have showed its effects in improving the outcomes in a variety of cancers. Apatinib is an oral tyrosine kinase inhibitor that selectively targets VEGFR2. Some preclinical studies and several case reports showed the anti-tumor effect of apatinib in pancreatic cancer, but there is no evidence from clinical trial to confirm it. This study aims to evaluate the efficacy and safety of apartinib in combination with S-1 as the second-line therapy for patients with APC. Methods: In this open-label, single-arm, randomized phase II study, we will recruit 30 patients with pathologically proven advanced pancreatic cancer after the failure of first-line chemotherapy. All patients are aged 18-70 years with ECOG PS 0-2 and will receive apatinib at an initial dose of 500mg/d on a continuous basis, and oral S-1 (60mg/d for BSA < 1.25m2, 80mg/d for 1.25<BSA < 1.5m2, and 100mg for BSA >1.5m2, orally) twice a day on days 1-14 of a 21-day cycle. Primary endpoint is PFS. Secondary endpoints include OS, duration of response, ORR and DCR. The safety of apartinib + S-1 will be evaluated by CTCAE v4.0. Translational research will be performed in blood (before and on-treatment): cytokine panel to explore predictive and prognostic biomarkers. Clinical trial information: NCT03662035.
A phase I study to evaluate the safety and tolerability of AB680 combination therapy in participants with gastrointestinal malignancies.
Authors: Bendell Johanna C. , Manji Gulam Abbas , Pant Shubham , Lai Dominic W. , Colabella Jill , Berry Wade , Paoloni Melissa Constance , Grossman William J. , O'Reilly Eileen Mary 
Published: February 2020

TPS788 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) expresses very high levels of CD73 among tumor types, and CD73 expression level is a known poor prognostic factor in PDAC. Adenosine, a product of AMP breakdown by CD73, is highly immunosuppressive against effector T & NK cells in the tumor microenvironment. AB680 is the first clinical-stage small-molecule CD73 inhibitor, which is highly potent, pharmacodynamically active, and safe in healthy volunteer dose escalation studies. Targeting the adenosine pathway in combination with standard of care regimens may have a more profound effect on activating and inducing sustained anti-tumor immunity. Methods: This is a Phase 1/1b, open-label, dose-escalation, and dose-expansion study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of AB680 in combination with AB122 (anti-PD-1 antibody) and standard chemotherapy (nab-paclitaxel [NP] and gemcitabine [Gem]) in participants with first line (1L) mPDAC. In the dose-escalation Ph1 portion, increasing dose levels of AB680 are administered every 2 weeks (Q2W) in combination with AB122 (240 mg Q2W) and NP/Gem (Gem 1000 mg/m2 + NP 125 mg/m2 IV on Days 1, 8, and 15 of each 28-day cycle). Up to 30 participants may be evaluated in Ph1 dose-escalation. In the dose-expansion Ph1b portion, AB680 will be administered at the recommended dose for expansion in combination with AB122 and NP/Gem in up to 40 participants. Adverse events will be graded according to NCI CTCAE 5.0 and antitumor activity assessed using RECIST v1.1. Conclusions: This Ph1/1b study will be the first to target the adenosine axis using a highly potent small-molecule inhibitor of CD73, AB680, in 1L mPDAC in combination with standard of care chemotherapy (NP/Gem) and a PD-1 antibody (AB122). Future results will be shared in upcoming scientific conferences. Clinical trial information: NCT04104672.
A phase II trial of pharmacological ascorbate, gemcitabine, and nabpaclitaxel for metastatic pancreatic cancer.
Authors: Kasi Pashtoon Murtaza , Bodeker Kellie , Berg Daniel James , Chandrasekharan Chandrikha , Sharif Saima , Smith Brian J. , Vollstedt Sandy , Brown Heather , Chandler Meghan , Cullen Joseph J. 
Published: February 2020

TPS791 Background: FOLFIRINOX or gemcitabine/nab-paclitaxel are both frontline chemotherapy options for patients with metastatic pancreas cancer. For most who cannot tolerate the triplet, the latter doublet is the preferred option. Through previous work by our group, pharmacologic ascorbate is known to synergize with gemcitabine; preliminary in vitro data from our group suggests a similar synergistic response with paclitaxel. Though ascorbate has been utilized in cancer therapy, few robust trials have investigated intravenous delivery of ascorbate to deliver plasma concentrations that are cytotoxic to tumor cells. Our prior studies have demonstrated ascorbate induces oxidative stress and cytotoxicity in pancreatic cancer cells; this cytotoxicity appears to be greater in tumor vs. normal cells. We hypothesize that production of hydrogen peroxide mediates the increased susceptibility of pancreatic cancer cells to ascorbate-induced metabolic oxidative stress, resulting in improved treatment outcomes, which has led to the development of the clinical trial (NCT02905578). Methods: All participants receive gemcitabine (1000 mg/m2 weekly) and nab-paclitaxel (125 mg/m2) on cycle days 1, 8, and 15 of a 28-day cycle. Participants are randomized to ± pharmacologic ascorbate (75-gram infusion 3x weekly) in addition to chemotherapy. Study therapy continues until tumor progression. The primary objective is to determine overall survival in patients when treated with combination gemcitabine, nab-Paclitaxel and high-dose ascorbic acid compared to gemcitabine and nab-paclitaxel in patients with non-resectable pancreatic cancer. Secondary objectives include determining objective response rate as well as progression free survival using RECIST 1.1 criteria employing a blinded reviewer for RECIST measurements. The study opened to accrual in 2018 with a goal of enrolling 65 participants. Oversight.Study is conducted under IND 105715 (J. Cullen, sponsor). The University of Iowa Biomedical IRB (IRB-01) serves as the IRB of record. Clinical trial information: NCT02905578.
PANOVA-3: A phase III study of tumor treating fields with nab-paclitaxel and gemcitabine for front-line treatment of locally advanced pancreatic adenocarcinoma (LAPC).
Authors: Picozzi Vincent J. , Macarulla Teresa , Philip Philip Agop , Becerra Carlos Roberto , Dragovich Tomislav 
Published: February 2020

TPS792 Background: Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of glioblastoma. TTFields at specific frequency (150-200 kHz) are delivered via transducer arrays placed on the skin in proximity to the tumor site. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of pancreatic cancer. The Phase 2 PANOVA study, the first trial testing TTFields in pancreatic cancer patients, demonstrated the safety and preliminary efficacy of TTFields when combined with nab-paclitaxel and gemcitabine in both metastatic and LAPC. The Phase 3 PANOVA-3 trial (NCT03377491) is designed to test the efficacy and safety of adding TTFields to nab-paclitaxel and gemcitabine combination in LAPC. Methods: Patients (N = 556) with unresectable, LAPC (per NCCN guidelines) will be enrolled in this prospective, randomized trial. Patients should have an ECOG score of 0-2 and no prior progression or treatment. Patients will be stratified based on their performance status and geographical region, and will be randomized 1:1 to TTFields plus nab-paclitaxel and gemcitabine or to nab-paclitaxel and gemcitabine alone. Chemotherapy will be administered at standard dose of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2 once weekly). TTFields (150 kHz) will be delivered at least 18 hours/day until local disease progression per RECIST Criteria V1.1. Follow up will be performed q8w, including a CT scan of the chest and abdomen. Following local disease progression, patients will be followed monthly for survival. Overall survival will be the primary endpoint and progression-free survival, objective response rate, rate of resectability, quality of life and toxicity will all be secondary endpoints. Sample size was calculated using a log-rank test comparing time to event in patients treated with TTFields plus chemotherapy with control patients on chemotherapy alone. PANOVA-3 is designed to detect a hazard ratio 0.75 in overall survival. Type I error is set to 0.05 (two-sided) and power to 80%. Clinical trial information: NCT03377491.
Association of an RNA signature (RS) with emergence of ICOS hi CD4 T cells and efficacy outcomes for the ICOS agonist vopratelimab (vopra) and nivolumab (nivo) in patients (pts) on the ICONIC trial.
Authors: Yap Timothy A , Gainor Justin F. , Burris Howard A. , Kummar Shivaani , Pachynski Russell Kent , Callahan Margaret K. , LoRusso Patricia , Tykodi Scott S. , Gibney Geoffrey Thomas , Falchook Gerald Steven , Rahma Osama E. , Seiwert Tanguy Y. , Papadopoulos Kyriakos P. , Mier James Walter , Hashambhoy-Ramsay Yasmin , Felitsky Daniel , Lee David Y. , McGrath Lara , Harvey Christopher , Hooper Ellen 
Published: February 2020

14 Background: ICOS is a costimulatory molecule upregulated on activated T cells. Vopra is an investigational ICOS agonist antibody that results in activation and proliferation of primed CD4 T effector cells. Vopra was assessed in heavily pretreated patients with advanced solid tumors as monotherapy (mono) or in combination with nivolumab (nivo) in the Phase 1/2 ICONIC trial (NCT02904226). Emergence of a distinct ICOS high (hi) population of peripheral CD4 T effector cells, not seen with PD-1 inhibitors alone, was associated with improved ORR, PFS and OS with vopra mono and combo therapy (AACR 2019). Baseline tumor and blood biomarkers were assessed for ability to predict ICOS hi CD4 T cell emergence and clinical outcomes. Methods: Fresh pre-treatment tumor biopsies were assessed by RS, a gene signature describing immune cell infiltration, and other biomarkers, including PD-L1 TPS by IHC. Pts were classified as RS1 and RS2 based on medium and high cutoffs. Associations between potential predictive biomarkers, ICOS hi CD4 T cell emergence and clinical outcomes were evaluated. Results: Baseline RS is significantly higher in patients with emergence of ICOS hi CD4 T cells. High RS was associated with increased emergence of ICOS hi CD4 T cells, accompanied by improved RECIST response, PFS, and OS. In contrast, no association was noted with PD-L1 IHC. Clinical trial information: NCT02904226. Conclusions: In this retrospective subset analysis, the RS score, but not PD-L1, in baseline tumor biopsies was predictive of emergence of an ICOS hi CD4 T cell population and improved RECIST response, PFS, and OS in patients treated with vopra alone and in combination with nivo. Clinical evaluation of vopra and investigational PD-1 inhibitor JTX-4014 in cancer patients with RS selection is planned. [Table: see text]
A phase Ib study of the anti-CD47 antibody magrolimab with the PD-L1 inhibitor avelumab (A) in solid tumor (ST) and ovarian cancer (OC) patients.
Authors: Lakhani Nehal J. , Patnaik Amita , Liao John B. , Moroney John William , Miller David S. , Fleming Gini F. , Axt Matt , Wang Yan V. , Agoram Balaji , Volkmer Jens-Peter , Maute Roy , Schroeder Andreas , Chico Isagani , Chao Mark , Takimoto Chris H.M. , Moore Kathleen N. 
Published: February 2020

18 Background: Magrolimab (M, Hu5F9-G4) is an antibody targeting CD47, a “don’t eat me” signal for macrophages that enhances ovarian cancer cell phagocytosis in preclinical models in combination with the PD-L1 inhibitor avelumab. CD47 blockade can also enhance cross-priming of T cells. Methods: In Part 1 (P1) M+A doses were escalated in ST patients (pts) while Part 2 (P2) enrolled platinum-resistant or refractory OC pts. All received a 1 mg/kg Day 1 priming dose of M to mitigate on-target anemia due to macrophage-mediated extravascular hemolysis followed by 30 or 45 mg/kg maintenance doses in P1 or 45 mg/kg in P2, in combination with 800 mg of A Q2 wks. Results: In the 34 total pts (13 in P1 and 21 in P2), median age was 66 years (range 47-88), and median # of prior therapies was 5 (range 1-10). In P1, no dose limiting toxicities occurred. In P1+P2, no Grade (G) 4 or 5 treatment-related adverse events (TRAEs) occurred. TRAEs of any G in > 20% pts included headache 62%, fatigue 47%, infusion related reaction 44%, pyrexia 38%, chills 35%, nausea 35%, anemia 24%, and vomiting 21%. In P1, a patient (pt) with metastatic papillary adenocarcinoma of the finger on 45 mg/kg of M had a confirmed partial response (PR) lasting for 4 months before progressing. In P2, 1 pt had an unconfirmed PR but progressed per RECIST v1.1 on the next scan achieving a best response of stable disease (SD). In the 18 OC P1+P2 pts with at least one response evaluation, 56% had SD and 44% had progression. Analysis of tumor biopsies for immune cells infiltration and CD47, PD-L1, and other marker expression is ongoing. In the 13 OC tumors analyzed to date, only 2 were PD-L1 positive. One PD-L1+ tumor had PD-L1 expression only on infiltrating immune cells. The other PD-L1+ had tumor cell expression and was the only OC pt with tumor shrinkage. This supports the potential importance of PD-L1 expression for this combination. Pharmacokinetic profiles will be presented. Conclusions: M+A is a novel, well-tolerated combination treatment regimen with 1 observed PR in a ST pt and a 56% SD rate in OC pts. Tumor shrinkage was noted in the only OC pt with tumor cell expression of PD-L1 which warrants further evaluation in PD-L1+ OC pts. Clinical trial information: NCT03558139.
PD-L1 profiling of circulating tumor cells for immune checkpoint inhibitor therapy in gastroesophageal cancers.
Authors: Devhare Pradip , Patil Revati , Akolkar Dadasaheb B. , Patil Darshana , Srivastava Navin , Fulmali Pooja , Patel Shoeb , Shejwalkar Pradyumna , Datta Vineet , Sims Cynthe , Srinivasan Ajay , Datar Rajan 
Published: February 2020

29 Background: Selection of Immune Checkpoint Inhibitor (ICI) therapies in Gastroesophageal cancers are based on IHC based detection of PD-L1 expression in tumor tissue. Invasive biopsy to obtain tumor tissue for IHC is associated with procedural risks, sequelae and expenses. Prior efforts at PD-L1 profiling of Circulating Tumor Cells (CTCs) have been constrained by low CTC yields. We employed a novel approach for harvesting sufficient CTCs from Gastroesophageal cancers that permit PD-L1 profiling by Immunocytochemistry (ICC). Methods: 15 ml peripheral blood was collected from 106 patients among whom 20 were diagnosed with gastric adenocarcinomas (AD) and 86 with either esophageal AD or esophageal squamous cell carcinomas (SCC). CTCs were enriched from PBMCs via an epigenetically acting stabilization process which induced apoptosis in non-malignant cells and conferred survival privilege on apoptosis-resistant CTCs, which were harvested and confirmed by immunostaining for EpCAM and pan-CK positivity. Deep ICC profiling of CTCs was performed with organ-specific markers as well as PD-L1:22c3 and PD-L1:28-8 clones. Results: Viable CTCs could be enriched and harvested in 103 out of 106 samples (97.2%) regardless of metastatic or treatment status. Deep ICC and PD-L1 profiling could be performed in all 103 samples (100%). PD-L1 expression was quantitatively assigned as ‘Low’, ‘Moderate’ or ‘High’. Among the 19 gastric ADs, 5 (26.3%) samples were positive for PD-L1:22c3 and 2 (10.5%) were positive for PD-L1:28-8; all gastric ADs were ‘Low’ for either PD-L1 subtype. Among the 84 esophageal carcinomas (AD+SCC), 32 samples (38.1%) were positive for PD-L1:22c3 (26 Low + 5 Moderate + 1 High) and 16 (19.1%) were positive for PD-L1:28-8 (11 Low + 5 Moderate). Conclusions: CTCs in Gastroesophageal cancers can be considered for evaluating PD-L1 expression in patients where ICI therapies are otherwise viable.
Increased risk of hypothyroidism in patients with primary head and neck cancer compared to non-head and neck primary malignancies.
Authors: Alaber Omar A. , Chander Apoorva K. , Jain Prantesh , Rajpal Aman , Patel Monaliben , Hoimes Christopher J. , Mendiratta Prateek , Lavertu Pierre , Mangla Ankit 
Published: February 2020

37 Background: Immune related thyroiditis is a common adverse effect of Immune checkpoint inhibitors (ICI). We sought to determine if the incidence of hypothyroidism (HT) in patients with primary head and neck cancers (pHNC) who received ICI, is increased compared to other primary cancers (lung, gastrointestinal (GI), skin melanoma or urinary system(GU). Methods: Data were obtained from a commercial de-identified database (IBM Explorys Solutions, IBM, Inc.). Cases included patients ≥ 18 years with a diagnosis of pHNC and controls included patients with a diagnosis of lung, GI, skin melanoma or GU cancer. All patients received one of 5 ICI (Avelumab, Atezolizumab, Durvalumab, Nivolumab or Pembrolizumab). Incidence of HT was defined as patient with a new diagnosis of HT at least 1 day following initiation of ICI. All patients with diagnosed HT, thyroid cancer (previous/concurrent), lymphomas were excluded. Odds ratios (OR) and confidence intervals (CI) were calculated using chi-square test. Results: There were 238,490 patients with a diagnosis of pHNC, and 616,850 patients with a diagnosis of other cancers in the database. Out of 710 pHNC patients, 80 patients (18.6%) and out of 7420 patients with other primary cancers, 850 (12.57%) had a new diagnosis of HT. When compared to non-HNC patients, HNC cases had a 1.6 (CI = 1.23 - 2.05) times higher odds of developing HT. In subgroup analyses, HNC cases were significantly more likely to develop HT compared to patients with GI or lung cancer, but not with skin melanomas or GU cancers. Overall, male cases and adults aged 18 - 65 years were significantly more likely to develop HT. (Table). Conclusions: The risk of developing HT after ICI is higher in patients with HNC compared to other primary cancers. Men and patients between the ages 18-65 years with pHNC were more likely to become HT. [Table: see text]