bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase Ib trial of pembrolizumab and XL888 in patients with advanced gastrointestinal malignancies.
Authors: Akce Mehmet , Alese Olatunji B. , Shaib Walid Labib , Wu Christina Sing-Ying , Lesinski Gregory B , El-Rayes Bassel F.
Published: January 2019

TPS526

Background: Heat shock protein 90 (HSP90) has a central role in modulating tumor microenvironment, inflammatory signaling pathways (NF-κB, HIF-1α and Jak-STAT), tumor antigen presentation and expression, PD-L1 expression and macrophage migration inhibitory factor (MIF) as well as cytokine production. Inhibitors of HSP90 have been shown in preclinical studies and in patient samples to exert anti-tumor effects and modulate signaling pathways. XL888 is a selective inhibitor of HSP90. Based on this preclinical rationale, we have developed a phase Ib/II trial to determine the recommended phase II dose, evaluate the safety, toxicity profile, preliminary antitumor activity, and immunogenicity of the XL888 and Pembrolizumab combination in previously treated patients with advanced gastrointestinal tumors. Methods: The phase Ib trial design is standard 3+3. XL888 is administered orally (PO) in three dose levels of 45 (DL1), 90 (DL2), 60 (only if DLT on DL2) mg twice weekly with pembrolizumab at 200 mg IV on day 1, in 21-day cycles. Eligible patients must have stage IV or locally advanced unresectable gastrointestinal adenocarcinomas who have failed at least one prior therapy (patients with colorectal adenocarcinoma must have previously received oxaliplatin, irinotecan, and fluoropyrimidine), age ≥18 years, ECOG PS 0-1, no prior anti PD-1 or anti-PD-L1 agent. After recommended phase II dose is established, an expansion phase will enroll 16 patients with pancreatic adenocarcinoma (Arm A) and 16 patients with colorectal adenocarcinoma (Arm B). Primary endpoint response rate. In the expansion phase patients will receive initial cycle (3 weeks) treatment with either pembrolizumab or pembrolizumab plus XL888 and then starting cycle 2 all patients receive the combination. Blood will be collected pre-treatment, post 1st and 2nd cycle. Eight patients in each arm will undergo pre and post treatment tumor biopsies. This design will enable us to evaluate the effects of pembrolizumab alone versus the combination. This study was activated in June 2017 and to date 4 patients were enrolled in dose escalation phase. The dose expansion phase is expected to start accrual in December 2017. Clinical trial information: NCT03095781.
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.
SWOG S1505: A randomized phase II study of perioperative mFOLFIRINOX versus gemcitabine/nab-paclitaxel as therapy for resectable pancreatic adenocarcinoma.
Authors: Sohal Davendra , McDonough Shannon L , Ahmad Syed A. , Gandhi Namita , Beg Muhammad Shaalan , Wang-Gillam Andrea , Guthrie Katherine A , Lowy Andrew M. , Philip Philip Agop , Hochster Howard S.
Published: January 2019

TPS547

Background: Clinical outcomes after curative therapy for resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. Series show that 70-85% of patients die of systemic recurrence. Improved overall survival (OS) in the metastatic setting with the use of multi-agent chemotherapy regimens (FOLFIRINOX, gemcitabine/nab-paclitaxel) holds the promise of progress in the curative setting as well. However, aggressive systemic therapy is usually not feasible after major pancreatic surgery. Therefore, early control of systemic disease by increased preoperative chemotherapy may improve outcomes. Furthermore, the perioperative platform facilitates early identification of patients with chemotherapy-resistant tumors and allows prospective biomarker studies in the future. Methods: This is a randomized phase II study intended to choose the most promising perioperative regimen to test in a larger trial. Eligibility requirements include adult patients with an ECOG PS of 0 or 1, a confirmed histopathologic diagnosis of PDA, and resectable disease as confirmed by central radiology review: no involvement of the celiac, common hepatic, or superior mesenteric arteries (and, if present, variants); no involvement, or < 180° interface between tumor and vessel wall, of the portal or superior mesenteric veins; patent portal vein/splenic vein confluence; no metastases. Treatment includes 12 weeks [either 6 doses of mFOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin – without bolus 5-FU and leucovorin), or 9 doses of gemcitabine/nab-paclitaxel, on standard schedules] of preoperative chemotherapy, followed by surgical resection and 12 weeks of identical postoperative chemotherapy. Primary outcome is 2-year OS, using a “pick the winner” design with minimum two-year OS of 40% assuming a 58% alternative hypothesis, 88% power, and a 1-sided α of 0.05, providing 90% probability of selecting the better regimen with a total sample size of 150 patients. Correlative studies are planned. The study opened through the National Clinical Trials Network (NCT02562716), and is supported by NIH/NCI/NCTN grants CA180888, CA180819, CA180821, CA180833. Clinical trial information: NCT02562716.
AGITG nabnec: A randomised phase II study of nab-paclitaxel in combination with carboplatin as first line treatment of gastrointestinal neuroendocrine carcinomas.
Authors: Chantrill Lorraine A. , Lipton Lara Rachel , Hofman Michael , Gebski Val , Gill Anthony , Markman Ben , Yip Sonia , Karapetis Christos Stelios , Pavlakis Nick , Wong Shu Fen , Ransom David Turner , Sjoquist Katrin Marie , Nagrial Adnan , Michael Michael , Rayani Uzma , Oostendorp Martinus , Simes John , Khasraw Mustafa
Published: January 2019

TPS548

Background: Neuroendocrine carcinomas (NEC WHO grade 3) are rare and aggressive cancers. There are no randomised trials to date to establish standard therapy for advanced gastrointestinal (GI) NECs. Extrapolating from small cell lung cancer data, standard practice is to treat GI-NECs with etoposide and carboplatin. Paclitaxel is also active in NECs however there is no data on the role of nab-paclitaxel. NABNEC aims to establish if the carboplatin and nab-paclitaxel combination is an effective and tolerable treatment for advanced GI-NECs and to enhance our understanding of the biology and imaging characteristics of NECs. Methods: Design: Randomised, non-comparative, stratified, multicentre phase 2 trial. Primary endpoint (n=70): objective response rate (RR) by RECIST 1.1 at 6 months. Secondary endpoints: progression free survival, overall survival, adverse events by NCI-CTCAE V4.03 and quality of life (EORTC QLQC30, QLQ-GINET21 questionnaires). Translational endpoints include 1) blood and tissue biomarkers (prognostic and/or predictive) correlated with clinical endpoints including circulating tumour cells, mutation profile (whole exome sequencing), DNA methylation profile; 2) correlation of 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) to early response and other clinical endpoints. Sample Size: 70 patient’s gives 80% power and 95% confidence to rule out a 30% RR in favour of a clinically relevant RR of 50% at 6 months. Population: Adults with advanced or metastatic non-resectable GI-NEC (includes small cell and large cell NEC). Treatment: Randomisation 2:1 to Arm A IV nab-paclitaxel 100 mg/m2 on Day (D) 1 weekly and IV carboplatin AUC=5 on D1, 3 weekly; and Arm B IV etoposide 100mg/m2 on D1-3, and IV carboplatin AUC=5 on D1, 3 weekly to continue until disease progression or unacceptable toxicity. Assessments: 68Ga Octreotate PET at baseline, CT scan at baseline and every 9 weeks, FDG PET at baseline, 9 weeks then every 18 weeks and QOL questionnaires every 9 weeks until disease progression. NABNEC is enrolling patients at 12/20 planned study sites in Australia and New Zealand. ANZCTR #. Clinical trial information: 12616000958482.
Safety of trifluridine/tipiracil (TAS-102) in combination with temozolomide for metastatic neuroendocrine tumors.
Authors: Uboha Nataliya Volodymyrivna , Deming Dustin A. , Lubner Sam Joseph , Mulkerin Daniel , Eickhoff Jens C. , LoConte Noelle K.
Published: January 2019

TPS549

Background: Low and intermediate grade neuroendocrine tumors (NETs) are incurable once they metastasize. Cytoreductive surgery and locoregional therapies play an important role in their management, but ultimately most patients are treated with systemic therapies. In clinical studies, combination of temozolomide (TMZ) and capecitabine (CAP) demonstrated significant response rates (> 50%) in patients with advanced pancreatic NETs. Trifluridine/tipiracil (FTD/TPI), also known as TAS-102, is a new anti-metabolite agent that is non-cross resistant with 5-fluorouracil (5-FU) and CAP and that has a different toxicity profile from CAP. In clinical trials, FTD/TPI has been associated with limited toxicities in patients with chemotherapy refractory (including 5-FU and CAP) metastatic colorectal cancer. Given that CAP has demonstrated activity in metastatic NETs, we hypothesize that FTD/TPI in combination with TMZ will be well tolerated and will be efficacious in metastatic NETs. Methods: This is a two-part investigator-initiated phase IB clinical trial (NCT02943733). Part 1 is a dose escalation portion of the study that will determine maximum tolerated doses of FTD/TPI administered in combination with TMZ in patients with advanced NETs. Patients with low and intermediate grade NETs of any origin are eligible for part 1. This part follows a classical “3+3” design to establish the phase 2 doses. Both drugs are oral agents that are administered on a 28 day cycle. FTD/TPI is taken twice a day on days 1-5 and days 8-12. TMZ is taken daily on days 8-12. This schedule was selected based on the pre-clinical data demonstrating schedule-dependent synergism between 5-FU and TMZ. Because of concern for overlapping bone marrow toxicities between the two agents, TMZ is started at the dose of 100 mg/m2 and escalated to a goal dose of 200mg/m2 daily if no dose limiting toxicities are observed. FTD/TPI is started at a goal dose of 35 mg/m2. Part 2 of the study will enroll estimated 15 patients with metastatic pancreatic NETs. Primary endpoint of part 2 is overall response rate, and secondary endpoints are progression free survival, disease control rate and overall survival. Part 1 of the trial is currently open to enrollment. Clinical trial information: NCT02943733.
Adjuvant FOLFOX-Nab-paclitaxel (FOLFOX-A) for pancreatic cancer: A phase II Brown University Oncology Research Group (BrUOG) trial.
Authors: Safran Howard , Charpentier Kevin , Mantripragada Kalyan C. , Breakstone Rimini , Miner Thomas J. , DiPetrillo Thomas A. , Marks Eric I , Rosati Kayla , Mitchell Kristen , Rossiter Rachael , Luppe Denise , Rago Molly , Schumacher Andrew , Cavanagh Lindsey
Published: January 2019

TPS550

Background: The FOLFOX-A regimen was developed by BrUOG, in response to the activity of nab-paclitaxel (nP) in metastatic pancreatic cancer (mPC), by substituting nP for irinotecan in FOLFIRINOX. In a phase I/II study of FOLFOX-A in mPC, median overall survival (OS) was 15 months (Safran H, et al. Am J Clin Oncol, 2016 Dec;39(6):619-622), which motivated evaluation of the tolerability and efficacy of this aggressive regimen in the adjuvant setting. Therefore, a phase II study of FOLFOX-A was initiated for patients with resected pancreatic cancer. Methods: Eligibility criteria included potentially curative resection of pancreatic adenocarcinoma (positive margins allowed if all gross tumor was removed), pathologic stages T1-3/N0-1/M0, interval between surgery and registration of 21-70 days and post resection serum CA19-9 ≤ 180 units/mL. All patients received nab-paclitaxel 150mg/m2, oxaliplatin 85mg/m2 and leucovorin 400mg/m2, followed by fluorouracil 2400mg/m2 infused over 46 hours. Cycles were repeated every 2 weeks. The primary objective is to assess the feasibility of administering at least 10 of 12 planned cycles of FOLFOX-A without unacceptable toxicity in 25 patients. Secondary endpoints include progression-free survival and OS. Results: Between June 2014-August 2017, 19 patients have been enrolled, 8 male and 11 female. Median age is 63 (43-68). Fifteen patients had positive lymph nodes on pathology with stages T1N0(n = 2), T3N0(n = 2), T1N1(n = 1), T3N1(n = 14) [AJCC Cancer Staging Manual, 7th Edition (2010)]. Conclusions: This study is testing the tolerability of administering adjuvant FOLFOX-A to patients with resected pancreatic cancer. Accrual is expected to be complete by January 2018. Clinical trial information: NCT02022033.
Prospective multicenter study of the impact of the 12-gene assay recurrence score on adjuvant chemotherapy treatment recommendations for stage II/III colon cancer in the post-IDEA era: SUNRISE-Decision Impact study.
Authors: Yamanaka Takeharu , Sato Takeo , Nakashima Sayoko , Yoshino Takayuki
Published: January 2019

TPS868

Background: The results of IDEA collaboration study in ASCO 2017 suggested that adjusting the duration of adjuvant chemotherapy (CTx) for stage III colon cancer may be possible according to patient’s risk (T and N factors) and treatment regimen (FOLFOX and CAPOX) in order to balance the benefit and neurotoxicity of oxaliplatin-based CTx. The 12-Gene Assay Recurrence Score (12-gene RS), known as Oncotype DX, has been validated to predict the recurrence risk of stage II/III colon cancer patients through several studies, including our SUNRISE study (J Clin Oncol, 2016), and thus to personalize adjuvant CTx taking account of individual recurrence risk. The objective of this SUNRISE-DI study is to determine the impact of the 12-gene RS on adjuvant CTx treatment recommendations, including the decision for the duration of oxaliplatin-based CTx in stage III patients as well as that for oxaliplatin-based CTx versus 5FU-based monotherapy in stage II/III patients. This study enables us to evaluate how physicians employ the IDEA collaboration results combined with the 12-gene RS to determine the regimen. Methods: Patients who have a curatively resected Stage II/IIIA/IIIB colon cancer, an age of more than 20, and an ECOG PS of 0-1 are eligible. Treating physicians will formulate a treatment recommendation and complete a pre-assay questionnaire, and the 12-gene assay will be performed. Following receipt of the RS result, the treatment recommendation will be revised and a post-assay questionnaire completed. The primary endpoint is the proportion of changes in treatment recommendations between pre- and post-assay across all patients. Secondary endpoints include the proportion of changes by stage; the proportion of changes in the duration of oxaliplatin-based CTx (3 months vs 6 months); the proportion switched to observation only, 5-FU mono, or 5-FU plus oxaliplatin; and changes in expressed physician confidence level. The enrollment target is 200 patients with stage IIIA/IIIB and 100 patients with stage II from 15 centers in Japan. Clinical trial registry number: UMIN000028784
Phase I/IIb trial: In-situ vaccine for metastatic colorectal cancer.
Authors: Kundranda Madappa N. , Dragovich Tomislav , Price Andrew , Lanauze Philippe , Bloch Miriam , Bishop Michael , Chang John , Har-Noy Michael
Published: January 2019

TPS871

Background: Except for MSI-H tumors, CRC does not respond to immunotherapy. CRC does respond to the graft vs. tumor (GVT) immune effect that occurs after allogeneic stem cell transplantation. GVT is associated with GVHD toxicity which limits the clinical application. A bioengineered allograft (BAG) has been developed which can elicit host-mediated GVT-like effects without GVHD toxicity, chemotherapy conditioning or a HLA-matched donor. BAG are Th1 memory cells derived from blood of healthy donors with CD3/CD28 microbeads attached. These cells have immunomodulatory properties which enable modulation of Th1/Th2 balance and dysregulation of immunosuppressive circuits. We are evaluating the safety and efficacy of BAG in third-line mCRC. Methods: The study uses a standard 3+3 design followed by an expansion phase with the optimal dosing pattern. The protocol has four components: (A) priming; (B) in-situ vaccination; (C) extravasation and trafficking; and (D) counter immune suppression/avoidance. Priming involves intradermal injections of BAG cells which activates NK cells and develops allo-specific Th1/Tc1 immunity. In-Situ vaccination involves tumor cryoablation to release endogenous HSP which chaperone tumor neoantigens, followed immediately by the intralesional injection of BAG cells as adjuvant. Released HSP are engulfed and processed by immature dendritic cells (DC) attracted to the tissue damage. The inflammatory microenvironment created by the BAG and the subsequent allo-rejection response amplified by the priming induces DC maturation. These DC display processed tumor antigens on upregulated MHCI/II and express co-stimulatory CD80/86 enabling priming of a tumor-specific Th1/Tc1 response. CD40L and interferon-gamma expressed by BAG activates allo-specific and tumor-specific memory cells upon intravenous infusion, permitting trafficking to tumor. The host rejection of BAG releases endogenous danger signals creating a sustained systemic inflammatory cytokine release which serves to counter-regulate immunosuppressive mechanisms. Longitudinal CT scans biopsies, PBMC and serum samples are collected for analysis to verify immune events within each phase of the protocol. Clinical trial information: NCT02380443.
PIER trial: Neoadjuvant therapy with panitumumab (P) and mFOLFOX-6 in an enriched population of patients with T3 rectal adenocarcinoma of the middle third with clear mesorectal fascia.
Authors: Fernandez-Martos Carlos , Aparicio Jorge , Ayuso Juan , Capdevila Jaume , Gallego Javier , Losa Ferran , Maas Monique , Maurel Joan , Pericay Carles , Rodriguez Salas Nuria , Safont Maria Jose , Tobeña Maria , Valladares Manuel , Vera Ruth
Published: January 2019

TPS875

Background: Retrospective data suggest that patients with advanced colorectal carcinoma wild-type (WT) for RAS, BRAF or Pi3K achieve increased response rates from anti-EGFR therapy as compared with mutated tumors. Neoadjuvant chemotherapy with oxaliplatin/fluoropyrimidine combination has shown to induce encouraging pathological complete response (pCR) in clinically staged T3 rectal cancer tumours (Schragg et al, JCO 2014 and Fernandez-Martos et al, The Oncologist 2014). We hypothesize this efficacy could be improved in a selected population (quadruple WT [4WT]) combining chemotherapy and anti-EGFR therapy. The objective is to assess the feasibility, efficacy and safety of neoadjuvant therapy with mFOLFOX-6 + P in rectal adenocarcinoma patients of intermediate risk and 4WT. Methods: PIER is a prospective, phase II, single-arm, multicentre, open-label clinical trial (NCT03000374). Key eligibility criteria include patients < 75 years with rectal adenocarcinoma in the middle third , clear mesorectal fascia, candidate for R0 resection with sphincter preservation surgery and absence of mutations in KRAS (exon 2 [codons 12/13], exon 3 [codons 59/61] and exon 4 [codon 117/146]), NRAS ( exon 2 [codons 12/13], exon 3 [codons 59/61] and exon 4 [codons 117/146]), BRAF (exon 15 [codon 600]) and PI3KCA in exons 9 and 20. All pre- and post-treatment MRI scans are centrally reviewed. Treatment: 6 induction cycles of mFOLFOX6 + P every 14 days. After the last cycle, a CT-scan, MRI and rectal endoscopy will be performed and patients will undergo TME surgery within 4 weeks +/- 1 week after the last dose. In case of progression patients will receive standard preoperative chemoradiation. The primary end point is pCR; key secondary end points include R0 resection rate, and clinical complete response. Statistical design: 42 evaluable patients (assuming a P0 of 16% and a P1 35%, with 0.1 alfa and 0.1 beta); 2-stage Simon’s optimal design. Enrolment in PIER is ongoing. Clinical trial information: NCT03000374.
INNOVA: A phase II randomized study comparing INterval versus NeOadjuVAnt chemotherapy in magnetic resonance imaging-defined high risk rectal cancer.
Authors: Seshadri Ramakrishnan Ayloor , Ganesan Trivadi S. , M N Arunkumar , Sundersingh Shirley
Published: January 2019

TPS879

Background: Patients with rectal cancers treated with neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy are not exposed to systemic doses of chemotherapy until very late in the treatment schedule. Preoperative chemotherapy, either in the neoadjuvant or interval setting can lead to early treatment of micrometastasis, improve the tumor response and possibly the overall survival. Phase II studies of neoadjuvant chemotherapy in rectal cancer have shown good response to chemotherapy with no tumor progression and good compliance. A phase II study evaluating the effect of giving chemotherapy in the interval waiting period between chemoradiation and surgery has shown acceptable toxicity and high pathological complete response rates. Methods: This single centre, randomized, open label, phase II trial compares the safety and efficacy of two pre-operative regimens in locally advanced MRI defined high-risk rectal cancers. Based on the Simon optimal two-stage design, 94 patients will be randomised to either Arm A [3 cycles of neoadjuvant chemotherapy (capecitabine and oxaliplatin) followed by chemoradiation (50.4 Gy with capecitabine) and then surgery] or Arm B [neoadjuvant chemoradiation followed by 3 cycles of interval chemotherapy and then surgery]. Patients in both arms receive 3 cycles of adjuvant chemotherapy. The primary end-point is the pathological complete response rate. Secondary end-points include frequency and severity of adverse events, RO resection rates, tumor regression grading and compliance to treatment. The inclusion criteria: age 18 to 70 years; ECOG performance status 0-2; non-metastatic, locally advanced rectal cancer with any one of the following features on high-resolution thin slice MRI: any T3/T4 tumor in the lower rectum, T3c/T3d/T4 tumor in the mid rectum, N2 disease, threatened mesorectal fascia, or extramural vascular invasion. Patients are randomly assigned to one of the two intervention arms in a 1:1 ratio. Prespecified activity goal for the first stage of accrual was met; second stage accrual began in July 2017. Clinical trial information: CTRI/2015/01/005385.
Toca 511 and Toca FC in patients with gastrointestinal tumors in the Toca 6 study.
Authors: Merchan Jaime R. , Ostertag Derek , Jolly Douglas J. , Tejera Dalissa , Gruber Harry E. , Shorr Jolene
Published: January 2019

TPS880

Background: Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV). RRVs selectively infect cancer cells due to defects in innate and adaptive immune responses found in cancers that support virus replication, and the requirement for cell division for virus integration into the genome. Toca 511 spreads through tumors, stably delivering an optimized cytosine deaminase (CD) gene that converts the prodrug, Toca FC (investigational, extended-release 5-FC) into 5-FU. 5-FU kills infected dividing cancer cells and diffuses and kills surrounding cancer cells, myeloid derived suppressor cells, and tumor associated macrophages, thus reestablishing tumor immunity (Cloughesy et al. Neuro Oncol 2016). In a Phase 1 study, resected high grade glioma tumors expressed CD protein following intravenous (IV) Toca 511.1 In animal models of metastatic colorectal cancer, IV Toca 511 infected metastatic sites, and subsequent 5-FC treatment resulted in decreased tumor size and improved survival (Yagiz et al. Mol Therapy 2015). Methods: Toca 6 is a Phase 1b, multicenter, open-label study (NCT02576665) that aims to investigate changes in immune activity after treatment with Toca 511 & Toca FC in patients with solid tumors, including gastrointestinal tumors. A total of 30 patients who have advanced malignancies, including colorectal and pancreatic cancer, with molecular characteristics that may increase sensitivity to 5-FU or viral infection, or IDH1 mutated solid tumors (e.g., intrahepatic cholangiocarcinoma) will be enrolled. In these patients, Toca 511 is injected IV daily for 3 days, then intratumorally after biopsy. Oral Toca FC is started ~4 weeks later and repeated every 4-6 weeks. Changes from baseline in intratumoral immune activity (infiltrating T-cell subpopulations, B cells, monocytes) at 4 weeks after start of Toca FC are assessed. Contemporaneous peripheral blood is analyzed for effector, memory, Treg, and myeloid lineage cells. Viral RNA, DNA, and CD protein expression in tumor after IV Toca 511 are measured. Safety and efficacy will be determined. Concomitant checkpoint inhibitor therapy may be given following immune activity assessments. The study has enrolled 3 patients. Clinical trial information: NCT02576665.