bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pilot study of galunisertib (LY2157299) plus stereotactic body radiotherapy (SBRT) in advanced hepatocellular carcinoma (HCC).
Authors: Reiss Kim Anna , Ben-Josef Edgar , Damjanov Nevena , Hoteit Maarouf , O'Hara Mark H. , Karasic Thomas Benjamin , Teitelbaum Ursina R. , Schneider Charles , O'Dwyer Peter J. , Carpenter Erica L. , Mick Rosemarie , Vonderheide Robert H. 
Published: January 2019

TPS528 Background: Hepatocellular carcinoma (HCC) is a common and lethal malignancy with few effective treatment options. Inherently aggressive disease biology combined with the immunosuppressive hepatic microenvironment creates a unique therapeutic challenge. TGF-β, the strongest known immunosuppressive cytokine [1, 2], modulates the hepatic immune response to various antigens and to ionizing radiation [3, 4]. TGF-β is constitutively released by liver cells and plays a key role in the early and late pathogenesis of HCC [5-7] by dampening the local T-cell response to the oncogenic hepatitis B and –C viruses [4, 8-11]. TGF-β is activated by ionizing radiation, where it blocks the effector T-cell response to cellular destruction and the release of tumor-specific antigens [4]. Preclinical data demonstrate that neutralizing TGF-β during radiation therapy effectively generates a CD8+ T-cell response to multiple endogenous tumor antigens [4], thereby generating an in-situ vaccine against a tumor [12-17]. We hypothesize that the combination of TGF-β receptor inhibition plus radiation therapy will produce a potent and clinically effective antitumor immune response against HCC. Methods: We have enrolled 9 of 15 planned patients on study NCT02906397. Eligibility criteria include inoperable HCC, Childs Pugh score of ≤7, and either failure of or refusal to take sorafenib. Patients must be 4 weeks from prior therapy and may not be taking immunosuppressants. Patients with major cardiac disease or abnormalities or a predisposition toward aneurysm development are excluded. Patients receive galunisertib on days 1-14 of 28 day cycles. SBRT will be delivered in a single fraction of 18 Gy between days 15-28 of C1. Pre-treatment and on-treatment biopsies are obtained, as well as serial blood collections for circulating tumor material. Immunologic evaluation will include TCR deep sequencing to track T-cell receptor clones, analysis of serum inflammatory cytokines, analysis of myeloid and B cell activation, multiplex flow cytometry of PBMCs to measure percentages and absolute counts of T-cell subsets and tissue assessment of immune markers. Peripheral and tissue levels of TGF-β will be assessed. Clinical trial information: NCT02906397.
MORPHEUS: A phase Ib/II multi-trial platform evaluating the efficacy and safety of cancer immunotherapy (CIT)-based combinations in patients (pts) with gastric or pancreatic cancer.
Authors: Manji Gulam Abbas , Bendell Johanna C. , Oh Do-Youn , Kim Kyu-Pyo , Macarulla Teresa , Ponz-Sarvisé Mariano , Ajani Jaffer A. , Oberstein Paul , Janjigian Yelena Yuriy , Chau Ian , Abdullah Heba , He Xian , Zhang Xiaosong , Wang Jun , Barak Hila , Cha Edward , Grossman William , Bang Yung-Jue 
Published: January 2019

TPS530 Background: CIT has demonstrated significant survival benefits across multiple cancers. Despite remarkable success, only subsets of pts derive clinical benefit from CIT monotherapy. Thus, CIT combinations may be needed to address the mechanisms that allow cancers to escape antitumor immunity. However, a large number of potential combinations would have to be tested to identify an effective CIT combination regimen. The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to assess the impact of CIT combination therapies in pts with different tumor types. The randomized trial designs allow comparison of a single control arm vs multiple CIT combination arms. The trials will aid development of CIT combinations by identifying early signals and have the flexibility to open arms with new CIT combinations and close arms that show minimal clinical activity or unacceptable toxicity. Various CIT combinations that simultaneously enhance immune cell priming and activation, tumor infiltration and/or recognition of tumor cells for elimination will be evaluated. Here, we will describe Phase Ib/II trials in pts with gastric or gastroesophageal junction cancer (GC) and metastatic pancreatic ductal adenocarcinoma (mPDAC), both of which represent populations with high unmet medical need. Methods: MORPHEUS-GC (NCT03281369) will enroll 2 cohorts including pts with advanced unresectable or metastatic GC who have not received prior chemotherapy (chemo) or have progressed on platinum- or fluoropyrimidine-based chemo. MORPHEUS-PDAC (NCT03193190) will enroll pts with mPDAC who have progressed on prior chemo. Further eligibility criteria details will be provided. Pts will be randomized to one of the CIT combination arms or a control arm (up to 8 arms across 2 cohorts in GC; 4 arms in PDAC). Pts experiencing loss of clinical benefit or unacceptable toxicity may be eligible to continue on a different CIT combination arm. Primary endpoints are investigator-assessed ORR per RECIST v1.1 and safety. Secondary endpoints include PFS, OS, DCR and DOR. Multiple exploratory biomarkers will also be examined. Clinical trial information: NCT03281369, NCT03193190.
A pilot study to assess the efficacy, safety, and pharmacodynamic effects of pembrolizumab and BL-8040 in patients with metastatic pancreatic cancer.
Authors: Fogelman David R. , Townson Steven Matthew , Varadhachary Gauri R. , Javle Milind M. , Shroff Rachna T. , Wolff Robert A. , Overman Michael J. , Ho Linus , Vainstein Haras Abi , Lustig Tzipora M , Sorani Ella , Lane Maureen E. , Kaufman David Ross , Yao James C. 
Published: January 2019

TPS533 Background: Checkpoint inhibitors such as pembrolizumab are active against a variety of tumor types; however, pancreatic cancer patients generally do not see improvements in their disease from single agent treatment. Blocking CXCR4 may potentiate the activity of checkpoint inhibitors by (1) increasing mobilization of lymphocytes from bone marrow, (2) blocking production of SDF-1, in turn allowing better penetration of immune cells into the tumor, (3) reducing the entry of suppressor T cells into tumor, and (4) upregulating CCL20 in the tumor microenvironment, which may help attract dendritic cells into the tumor. We have launched a study combining BL8040, a CXCR4 antagonist, with pembrolizumab in order to determine the efficacy of this combination. Methods: Major inclusion criteria require patients with pancreatic adenocarcinoma whose tumors have progressed through at least one line of therapy. There must be sufficient disease to allow for pre- and post-treatment biopsy as well as measurement of response by RECIST criteria. Patients must be age 18 or older and ECOG 0-1. Liver function, renal, and hematologic criteria are fairly rigorous. Major exclusion criteria include patients with viral infections or those who require supraphysiologic steroid use. Treatment includes a two week cycle of single agent BL-8040 given on days 1-5 and 8-12. Cycles 2 and beyond include treatment on day 1 with pembrolizumab, 200 mg flat dose, plus BL-8040 given SQ on days 1,4,8, and 11 of a two week cycle. The primary endpoint is response rate; other major clinical objectives include progression free and overall survival. Scientific correlates include assessments of immune cell infiltrates into tumor via histology and immunoflourescence, histological assessment of stromal components, and gene expression signatures. Blood is likewise being collected for serum cytokine analysis, circulating free DNA analysis, circulating tumor cells, and exosome analysis. Clinical trial information: NCT02907099.
Trial in progress: A multicenter phase II study of pembrolizumab in patients with advanced small bowel adenocarcinomas.
Authors: Pedersen Katrina , Overman Michael J. , Foster Nathan R. , Kim Sunnie S. , Bekaii-Saab Tanios S. , Murphy Janet E. , Boland Patrick McKay , Hochster Howard S. , Halfdanarson Thorvardur Ragnar , Wilson Richard H. , Welch Jack , McWilliams Robert R. 
Published: January 2019

TPS535 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy, possibly because of the high rate of immunosurveillance in baseline small bowel function, and is frequently diagnosed in late stages. Due to these factors, there is no consistent standard of care for metastatic disease beyond first-line where several prospective studies have confirmed activity of FOLFOX/CAPOX. Historically, second-line treatment of SBA has been extrapolated from colon/gastric cancer. Recent studies suggest that SBA has a distinct genomic profile, including higher incidence of microsatellite instability, compared to gastric and colon cancers. Additionally, the tumor microenvironment reflects a greater degree of PD-L1 expression and infiltration by lymphocytes. Immune checkpoint inhibitors have not previously been tested in SBA unselected for MSI status. Methods: The study is a phase 2, multicenter, single-arm clinical trial of pembrolizumab (200 mg IV every 3 weeks) for patients with unresectable or metastatic SBA refractory to first-line chemotherapy. Forty patients with any tumor mismatch repair status will be enrolled at 8 US sites as part of the ACCRU network and International Rare Cancer Initiative (IRCI) with a primary objective to assess the confirmed response rate (H0 p < 10%, HA: p > 30%) to pembrolizumab. Secondary endpoints include PFS, OS, and adverse events. Correlative aims include assessing blood and tissue biomarkers (i.e. PD-L1, MSI-H/MSS status, cfDNA, mutation burden, etc.) for association with clinical benefit. An interim analysis will be performed to assess efficacy after 18 patients become evaluable. The study is open with 16 patients enrolled at time of submission. Clinical trial information: NCT02949219.
SPARC: A phase-I trial of pre-operative margin-intensified stereotactic radiotherapy for pancreatic cancer at high risk of positive resection margins.
Authors: Holyoake Daniel , Robinson Maxwell , Strauss Victoria Y , Reilly Gavin , McIntosh David , Grose Derek B , Radhakrishna Ganesh , Sebag-Montefiore David , Mukherjee Somnath , Hawkins Maria A 
Published: January 2019

TPS536 Background: Standard therapy for resectable and borderline resectable pancreatic cancer in the UK is surgery with adjuvant chemotherapy, but clear resection margins rates are unsatisfactory. Conventional neoadjuvant radiotherapy has limited efficacy, but stereotactic radiotherapy (SBRT) achieves accuracy and precision to enable dose escalation and margin-intensification, with the goal of achieving clear resection margins. This prospective multi-centre study aims to establish the maximum tolerated dose of margin-intensified pre-operative SBRT, for subsequent definitive comparison with other neoadjuvant treatment options. Methods: SPARC is a phase-I dose-escalation study (NCT02308722). A ‘rolling-six’ design is utilised to minimise delays and facilitate ongoing recruitment during dose escalation. Eligibility comprises histologically or cytologically proven borderline-resectable pancreatic cancer, or operable tumour in contact with vessels increasing the risk of positive margin. Up to 24 patients will be recruited from up to 5 treating centres. Radiotherapy is delivered in 5 daily fractions, with surgery planned to take place 5–6 weeks later. The margin-intense radiotherapy concept utilises a systematic method to define the target volume for a simultaneous integrated boost in the region of tumour-vessel infiltration. Up to 4 radiotherapy dose levels will be investigated, and the maximum tolerated dose is the highest dose at which no more than 1 of 6 patients or 0 of 3 patients experience a dose limiting toxicity. Secondary endpoints include resection rate, resection margin status, response rate, overall survival, and progression free survival at 12 and 24 months. Translational work will involve exploratory analyses of the cytological and humoral immunological responses to SBRT in pancreatic cancer. Radiotherapy quality assurance of target definition and radiotherapy planning is enforced with pre-trial test cases and on-trial review. Recruitment began in April 2015 and eleven patients have been treated to date. Cohort 1 was completed without DLT and recruitment to cohort 2 began in September 2016. Clinical trial information: NCT02308722.
A phase II open-label, single-centre, non-randomized trial of Y90 transarterial radioembolization in combination with nivolumab in Asian patients with intermediate stage hepatocellular carcinoma: An immunological study of radioembolization in combination with anti-PD1 therapy in HCC.
Authors: Chang Esther Wei Yin , Tai David Wai-Meng , Koo Si-Lin , Ng Matthew CH , Yeong Joe Poh Sheng , Zhai Wei Wei , Newell Evan , Chow Pierce K. H. , Lim Kiat Hon , Gogna Apoorva , Tong Aaron Kian Ti , Huang Hian Liang , Loke Kelvin Siu Hoong , Ng David Chee Eng , Hennedige Tiffany Priyanthi , Thng Choon Hua , Choo Su Pin 
Published: January 2019

TPS542 Background: In recent years, Yttrium-90 (Y90) trans-arterial radioembolization (TARE) has emerged as a therapeutic option for intermediate stage hepatocellular carcinoma (HCC). Cancer immunotherapy targeting tumour immune evasion has shown remarkable successes in various cancers. Nivolumab, an immune checkpoint inhibitor of programmed death 1 (PD1), has demonstrated encouraging activity in advanced stage HCC. Similarly, chronic hepatitis B virus (HBV) infection, a strong risk factor for HCC, is characterized by immune escape mechanisms. We hypothesize that TARE will stimulate tumor and/or HBV specific T cell responses that can be boosted using nivolumab. We thus propose an open label phase 2 trial investigating the combination of TARE with nivolumab in BCLC intermediate stage HCC. Methods: Eligible patients (pts) have ECOG performance status ≤ 2, Child-Pugh A score, intermediate stage HCC planned for TARE according to institutional practice with adequate organ function. Pts will be treated with TARE followed by nivolumab 240mg, 21 days after TARE and every 2 weeks thereafter. Pre- and on-treatment tumor biopsies will be taken. Primary end-point is response rate (RR) of combinational TARE and nivolumab. Key secondary end points are: progression free survival, overall survival, safety and quality of life using FACT-HEP score and EORTC QLQ-C30. Exploratory objectives are to evaluate how tumor PD L-1 expression, HCC mutational burden and blood lymphocyte activation/phenotypic profiles correlate with tumor response. Where possible, serial changes in antigen-specific T cell responses to HBV and/or tumour antigens will also be assessed. This study aims to enroll 40 pts as calculated using the Simon two-stage optimal design with 80% power and one sided significance level of 0.05. This will assess whether the addition of nivolumab improves the RR of TARE at 8 weeks from 21% to 41%. Patient accrual was initiated in December 2016 and as of September 2017, 9 pts have been treated. Clinical trial information: 03033446.
HALO 110-101: A phase Ib, randomized, open-label study of PEGPH20 (pegvorhyaluronidase alfa) in combination with cisplatin (CIS) + gemcitabine (GEM) (PEGCISGEM) or atezolizumab and CIS + GEM (PEGCISGEMATEZO) in hyaluronan-high subjects with locally advanced or metastatic cholangiocarcinoma and gallbladder cancer.
Authors: Borad Mitesh J. , Shroff Rachna T. , Abou-Alfa Ghassan K. , Hecht J. Randolph , Bullock Andrea J. , Ritch Paul S. , Chondros Dimitrios , Muhsin Mann , Oh Do-Youn 
Published: January 2019

TPS543 Background: Cholangiocarcinoma (CCA) is treated with CIS and GEM (CISGEM), but prognosis is poor. Hyaluronan (HA) accumulation in solid tumors may impede drug and immune cell access. PEGPH20 targets tumors that accumulate HA (HA-high). This study (NCT03267940) plans to enroll 70 subjects to evaluate the safety and activity of PEGPH20 + programmed cell death-ligand 1 (PD-L1) agent atezolizumab, (PEGCISGEMATEZO), & PEGPH20 + CISGEM (PEGCISGEM) in HA-high subjects with CCA and gallbladder cancer. Study will comprise initial run-in and expansion portions. Primary endpoints include incidence of AEs and other laboratory/safety parameters and ORR (RECIST v1.1). Secondary endpoints include PK parameters; DOR, DCR, PFS, and ORR (RECIST v1.1 and immune-modified RECIST); and OS and OS by PD-L1 expression. Methods: ~6 HA-high subjects will be enrolled in PEGCISGEM arm run-in portion and undergo at ≥1 cycle; subsequently, 6 HA-high subjects will enter the PEGCISGEMATEZO arm. Treatment period will be 21-day cycles. In the expansion portion, ~50 HA-high subjects will be enrolled and randomized in a 2:2:1 ratio into PEGCISGEMATEZO, PEGCISGEM, and CISGEM arms. PEGPH20 is planned to be administered at 3.0 μg/kg on Days 1, 8 and 15 of all cycles in both portions. ATEZO will be administered at 1200 mg 1–3 hours after PEGPH20 on Day 1 of each 21-day cycle in the PEGCISGEMATEZO arm in both portions. In the PEGCISGEM & PEGCISGEMATEZO arms, dosing schedule for CISGEM is the same during both portions, with administration of 25 mg/m2 CIS and 1000 mg/m2 GEM on Days 2 and 9 of each cycle. In CISGEM control arm (expansion only), dosing schedule will be on Days 1 and 8 of each cycle. Treatment will continue until death, withdrawal of consent, disease progression, or unacceptable toxicity. Tumor response will be evaluated using RECIST v1.1. AEs will be graded per NCI CTCAE v4.03. Tumor samples will be tested retrospectively for PD-L1 expression. Safety data will be periodically monitored by an independent data monitoring committee. Clinical trial information: NCT03267940.
ABC-08: A phase Ib, multi-centre, open-label study of a first-in-class nucleotide analogue NUC-1031 in combination with cisplatin in patients with locally advanced/metastatic biliary tract cancers.
Authors: McNamara Mairead Geraldine , Bridgewater John A. , Palmer Daniel H. , Wasan Harpreet Singh , Ryder David , Gnanaranjan Chathunissa , Ghazaly Essam Ahmed , Evans T.R. Jeffry , Valle Juan W. 
Published: January 2019

TPS544 Background: The UK ABC-02 study established cisplatin and gemcitabine as the reference regimen for first-line treatment of patients (pts) with advanced biliary tract cancers (BTCs) (median overall survival (OS): 11.7 months). No clinical studies since ABC-02 have reported an extension in OS, and therefore effective new agents/combinations are required. NUC-1031 was designed to improve on gemcitabine’s relatively poor efficacy by overcoming its associated key cancer resistance mechanisms, through cellular uptake independent of nucleoside transporters, activation independent of deoxycytidine kinase and protection from cytidine deaminase inactivation, resulting in over 200x the intracellular levels of the anti-cancer metabolite, dFdCTP, greater stability and reduction in the generation of toxic metabolites. NUC-1031 showed activity as monotherapy in a phase I/II study in 7 pts with BTC, refractory to all standard treatments (Blagden et al ASCO 2015; abstract 2514). Methods: ABC-08 is a multi-centre phase Ib study of NUC-1031 combined with cisplatin in pts with non-resectable or recurrent/metastatic cholangiocarcinoma, gallbladder or ampullary carcinoma, aged ≥18 years with an ECOG performance status of 0-1, who have received no prior systemic therapy. The starting dose for NUC-1031 is 625 mg/m2 administered IV on days 1 and 8 in combination with cisplatin (standard dose of 25 mg/m2) (21 day schedule). The dose will be escalated sequentially in cohorts of 3-6 pts using an accelerated titration procedure (725mg/m2, 825mg/m2, 925mg/m2). Treatment will continue until intolerable toxicity/progressive disease. The primary endpoints are safety and RP2D. Secondary endpoints are progression-free survival, OS, response rate and pharmacokinetic endpoints, including assessments of multiple plasma and intracellular analytes: NUC-1031, cisplatin, dFdC, dFdCMP, dFdCDP, dFdCTP and dFdU, and will be correlated with safety profile and clinical activity. Planned accrual is 15-24 pts over 2 years. Cohort 1 has been completed without dose-limiting toxicities. Enrolment to cohort 2 is on-going. Clinical trial information: NCT02351765.
A phase II trial of LEE011 in combination with everolimus in the treatment of advanced well differentiated neuroendocrine tumors of foregut origin.
Authors: Raj Nitya Prabhakar , Kelly Virginia , Chan Jennifer A. , Dasari A. , Capanu Marinela , Tang Laura , Reidy Diane Lauren 
Published: January 2019

TPS546 Background: Changes in the retinoblastoma (Rb) tumor suppressor pathway are believed to contribute to the development of well differentiated neuroendocrine tumors (WDNETs). In the pre-clinical setting, loss or downregulation of proteins that normally inhibit the cyclin dependent kinases Cdk4 and Cdk6 have contributed to NET development. Separately, rigorous investigation of everolimus in WDNETs has demonstrated a survival benefit in this patient (pt) population. Pre-clinical data suggests that the Cdk4/Cdk6 inhibitor LEE011 is synergistically active with everolimus. The aim of this study is to evaluate the efficacy and safety of LEE011 in combination with everolimus in pts with advanced WDNETs of foregut origin (thymic, bronchopulmonary, gastric, duodenal, pancreatic). Methods: This study is a multicenter, non-randomized, open-label phase II clinical trial using a Simon two stage optimal design. Main inclusion criteria include: adult patients with WDNET of foregut origin, low to intermediate grade, unresectable and/or metastatic, disease progression ≤ 12 months prior to enrollment, ECOG 0-1. Between 15 and 43 patients will be enrolled from three sites across the US. LEE011 300mg daily, 3 weeks on and 1 week off, in combination with everolimus 2.5mg daily (final dosing based on phase 1b clinical trial performed in metastatic breast cancer; LEE011X2106) will be administered orally until disease progression, unacceptable toxicity, investigator decision, or pt withdrawal. All enrolled pts will be followed by telephone contact for overall survival until death or consent withdrawal. The primary endpoint, progression free survival, will be assessed based on radiographic review by RECISTv1.1. Main secondary endpoints include establishing the safety of this drug combination in this patient population, objective response rate, clinical benefit rate, and overall survival. Correlative objectives include exploring the effect of this drug combination on biomarkers related to the Rb pathway and/or WDNET pathogenesis. This trial began enrollment in 2/27/2017, with 10 patients enrolled to date. Clinical trial information: NCT03070301.