bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular and clinical characterization of BRAF mutations in pancreatic ductal adenocarcinomas (PDACs).
Authors: Guan Michelle , Bender R Joseph , Pishvaian Michael J. , Halverson David Charles , Tuli Richard , Klempner Samuel Jacob , Wainberg Zev A. , Singhi Aatur D. , Petricoin Emanuel , Hendifar Andrew Eugene
Published: January 2019

214

Background: The activation of the RAS/RAF/MEK/ERK pathway is critical for the proliferation, survival, and tumorigenesis of PDACs. Oncogenic mutations in KRAS (90%) or BRAF (3%) are recurrent genomic alterations, but their co-occurrence is not well described. We reviewed BRAF alterations and clinical outcomes in consecutive PDAC patients (pts). Methods: Perthera, Inc. deploys an IRB-approved registry that was utilized in partnership with PanCAN’s “Know Your Tumor” program. Perthera uses CAP/CLIA accredited multi-Omic profiling, including next generation DNA sequencing (NGS, Foundation Medicine) and proteomics/immunohistochemistry (Neogenomics Inc. and Caris Life Sciences, Inc.). We used a Fisher's exact test with multiple testing correction to compare frequencies of mutations and protein over-/under-expression between BRAF-mutated (n = 21) and BRAF wild type pts (n = 745). Results: Of 766 pancreatic cancer pts, 21 pts were identified with BRAF mutations. 18 pts were diagnosed with PDAC, 1 pancreatoblastoma, 1 pancreatic acinar cell carcinoma, and 1 mixed acinar neuroendocrine carcinoma. Amongst the 18 PDAC pts with BRAF mutations, nine variations were found: V600E (5/18), BRAF fusion (4/18), N486_P490del (3/18), T310I (1/18), K601N (1/18), G596R (1/18), exon 2-10 deletions & S467L (1/18), equivocal amplification of BRAF (1/18), and a BRAF inframe deletion (1/18). KRAS was mutated in 6% of BRAF mutated PDACs, compared to 94% in BRAF wild type PDACs (p < 0.001). Amongst KRAS wild type PDACs, 53% of CDKN2A mutated pts had BRAF mutations vs. only 15% of CDKN2A wild type cases (p < 0.05). Two BRAF mutated pts from the database were given BRAF inhibitors. A sustained response to the combination dabrafenib and trametinib was observed in a BRAF V600E mutated PDAC pt, while no response was seen in a pt with concurrent KRAS G12A & BRAF K601N mutations who received trametinib. Conclusions: BRAF mutations are significantly and inversely correlated with KRAS alterations. The most common BRAF alteration, V600E mutation, was found to be mutually exclusive with the KRAS mutation. Clinical trials targeting BRAF alterations in KRAS wild type pancreatic cancer appears warranted.
Neutrophil-to-lymphocyte ratio as a prognostic marker for metastatic pancreatic cancer.
Authors: Desai Jasmin Radhika , Colton Bradley Scott , Wang Hongkun , Marshall John , Kim Sunnie S. , Pishvaian Michael J.
Published: January 2019

251

Background: Metastatic pancreatic cancer is a deadly disease, with a median survival that remains less than 12 months. However, more patients than ever before are surviving for more than 1 year, though it has been difficult to determine which patients have a better or worse prognosis. In the MPACT trial of gemcitabine + nab-paclitaxel vs gemcitabine alone, the neutrophil-to-lymphocyte ratio (NLR) prior to treatment was found to be a promising prognostic marker. However, the significance of NLR has not been confirmed. We examined our institutional experience with assessing the prognostic value of the NLR for patients with metastatic pancreatic cancer treated with standard chemotherapies. Methods: We performed an IRB approved retrospective chart review of patients with metastatic pancreatic adenocarcinoma. Patients were eligible if a routine blood count from which an NLR would be calculated was available prior to initiating any chemotherapy. 41 patients were identified who were treated with either FOLFOX (n = 9), FOLFIRINOX (n = 8) or gemcitabine + nab-paclitaxel (n = 24). Patients were stratified into two groups: NLR < 5 and NLR > 5. The median progression free survival and overall survival were determined, and statistical analyses performed to observe any correlation to NLR. Results: In this review, patients with an elevated NLR (NLR > 5) had an improved PFS and OS when compared with patients with a decreased NLR (NLR < 5). OS was 12.2 months in NLR > 5 and 11.0 months in NLR < 5. PFS was 4.7 months and 3.6 months, respectively. When comparing patients that were treated with 5-FU based regimens, the overall survival was similar with the NLR > 5 of 11.5 months and the NLR < 5 group of 11.0 months. However, those patients treated with gemcitabine and abraxane had more of a difference; patients with an NLR > 5 had an OS of 16.0 months and NLR < 5, the OS was 11.5 months. Conclusions: Our single institution experience suggests that NLR could be a marker for prognosis for metastatic pancreatic cancer. However, our data contradicts the results of the MPACT trial where an increased NLR was associated with a worsened overall survival. Therefore, additional confirmatory studies will need to be performed to find the true prognostic value of the NLR.
Evaluation of pharmacodynamic (PD) biomarkers in patients with metastatic pancreatic cancer treated with BL-8040, a novel CXCR4 antagonist.
Authors: Hidalgo Manuel M. , Epelbaum Ron , Semenisty Valeriya , Geva Ravit , Golan Talia , Borazanci Erkut Hasan , Stemmer Salomon M. , Borad Mitesh J. , Park Joon Oh , Pedersen Katrina , Wolpin Brian M. , Ramirez Robert A. , Becerra Carlos , Shaw Stephen Michael , Oberkovitz Galia , Sorani Ella , Lustig Tzipora M , Vainstein Haras Abi , Peled Amnon , Von Hoff Daniel D.
Published: January 2019

276

Background: BL-8040 is a novel CXCR4 antagonist being developed for multiple oncology indications. Preclinical studies demonstrated that BL-8040 increases the number of immune cells in peripheral blood and promotes CD8+ T cell infiltration into orthotropic pancreatic mouse tumors, reducing tumor load. BL-8040 is being evaluated in a Phase 2a, multicenter, open label trial in patients with metastatic pancreatic cancer (the COMBAT study). Patients are undergoing a 5-day period of monotherapy in which they receive daily doses of BL-8040, followed by 21-day cycles in which patients receive one dose of pembrolizumab and 3 doses/week of BL-8040 until disease progression or discontinuation. To date, 32 patients have been enrolled. Methods: On Day 1 and Day 5, blood samples were taken at pre- and post-dosing, to evaluate peripheral immune cell subset frequency by flow cytometry. In addition, core biopsies were taken from liver metastases, where possible, to assess immune cell infiltration into tumors and the tumor microenvironment (TME). Results: Here we present interim PD biomarker data from the BL-8040 monotherapy portion of the trial. Flow cytometry shows that BL-8040 monotherapy caused an approximately two-fold reduction in frequency of peripheral T regulatory cells, but had no effect on the frequency of T cells, NKT cells or cell populations that contain B cells (CD3- CD56-). Additionally, BL-8040 remained bound to CXCR4 on peripheral immune cells throughout the period of monotherapy. Analysis of available biopsies (N = 7) shows an up to 15-fold increase in the CD3+ population, and up to two-fold increase of CD8+ cells, in the tumor periphery and TME of 43% (3/7) of the patients after five days of BL-8040 monotherapy compared to baseline. Conclusions: In summary, the PD biomarker results in humans support the proposed mechanism of action for BL-8040 that was based on preclinical mouse models. Analysis of tumor biopsies is ongoing, with an emphasis on investigating the effects of BL-8040 on tumor-resident immune cells and the TME. Clinical trial information: NCT02826486.
An open label phase 1b/2 trial of TRC105 and sorafenib in patient with advanced/metastatic hepatocellular carcinoma (HCC) (NCT01806064).
Authors: Raghav Kanwal Pratap Singh , Mody Kabir , Greten Tim F. , Paluri Ravi Kumar , Lee Richard T. , Simpson Brian E , Adams Bonne J. , Theuer Charles P. , Kaseb Ahmed Omar
Published: January 2019

301

Background: Endoglin plays a critical role in angiogenesis and is implicated in resistance to VEGF inhibition. TRC105, an endoglin antibody potentiates anti-tumor activity of sorafenib (S) in preclinical HCC models. The combination of TRC105 and S demonstrated encouraging evidence of activity, including a 33% partial response rate (5/15 pts) by RECIST, at RP2D doses of TRC105 in HCC ( Clin Can Res 2017). Adverse events characteristic of each drug were not increased in frequency or severity when the two drugs were administered concurrently, and most commonly included epistaxis, fatigue, headache and anemia. Methods: Following dose escalation, 21 pts will be enrolled at the RP2D. Four objective responses are required to reject the null hypothesis that the true response rate probability is < 5% with an alpha level of 0.1 and 80% power. Secondary endpoints: DR, PFS, frequency and severity of AEs, PK, immunogenicity, angiogenic biomarkers. Key inclusion criteria: disease not amendable to surgical or local therapies, ECOG ≤ 1; Child-Pugh A or B (7 points) classification. Results: Four pts have been enrolled in phase 1b at TRC105 10 mg/kg (n=4) weekly for four doses and 15 mg/kg every other week thereafter + S 800 mg daily without DLT. One of 3 evaluable pts achieved PR (41% reduction), ongoing at month 4. Serum levels of TRC105 exceeded the target concentration following 4 weekly doses of TRC105 at 10 mg/kg (mean = 59 µg/ml, range 43-80). Mean trough concentration decreased following every other week dosing (mean = 21 µg/ml, range 17-31). Common TRC105 related AEs included ≤ G2 epistaxis and G1 headache. Common S related AEs included G3 hand foot syndrome, ≤G3 periodontal disease, G2 hypertension, ≤G2 increased lipase, ≤G2 fatigue and G1 epistaxis. Conclusions: TRC105 dosed by a hybrid schedule of 10 mg/kg weekly for four doses followed by every other week dosing at 15 mg/kg was tolerable and did not potentiate the toxicity of S. The combination of TRC105 + S demonstrated additional signs of activity, including a PR in 1/3 evaluable pts. 21 pts will be enrolled at the RP2D to assess the primary endpoint of ORR by RECIST. Clinical trial information: NCT01806064.
Quality of life study in patients with unresectable locally advanced or metastatic pancreatic cancer treated with gemcitabine in combination with nab-paclitaxel versus gemcitabine alone:ax-panc-sy001: A phase II randomized study.
Authors: Yalcin Suayib , Dane Faysal , Oksuzoglu Berna , Yildirim Nuriye , Isikdogan Abdurrahman , Ozkan Metin , Demirag Guzin , Coskun Hasan Senol , Karabulut Bulent , Evrensel Turkkan , Ustaoglu Mehmet Ali , Ozdemir Feyyaz , Turna Hande , Yavuzsen Tugba , Aykan Faruk , Sevinc Alper , Akbulut Hakan , Yuce Deniz , Hayran Mutlu , Kilickap Saadettin ,   Gastrointestinal Cancers Study Group
Published: January 2019

346

Background: Although clinical efficacy of gemcitabine in combination with nabpaclitaxel has been shown to be superior to single agent gemcitabine in a randomize phase 3 trial, data are lacking on the quality of life of this combination regimen as first-line therapy in patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma. Methods: We randomly assigned 125 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 to receive gemcitabine, 1000 mg/m2 plus nabpaclitaxel 125 mg/m2 or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Treatment continued until disease progression or unacceptable toxicity. The primary end point was 3-months deterioration-free rate (percentage of patients free from definitive deterioration) and quality of life of patients. Results: The median overall survival was 9.92 months in the gemcitabine plus nabpaclitaxel group as compared with 5.95 months in the gemcitabine group (hazard ratio for death, 0.642, 95% confidence interval, 0.422 to 0.866; p < 0.038). Median progression-free survival was 6.28 months in the combination group and 3.22 months in the gemcitabine group (hazard ratio for disease progression, 0.582; 95% CI, 0.391 to 0.866; p < 0.008). The objective response rate was 37.1% in the combination group versus 23.7% in the gemcitabine group (p < 0.009). Median time to deterioration was 3.68 months in the gemcitabine arm versus 5.36 months in the combination arm. More data on quality of life will be presented. Conclusions: As compared with gemcitabine, gemcitabine plus nabpaclitaxel was associated with an overall and progressive free survival advantage, with increased response rate, without increasing toxicity and deterioration of quality of life. Gemcitabine and nabpaclitaxel combination regimen with this form is a preferable option for the treatment of patients with advanced pancreatic cancer Clinical trial information: EudraCT: 2013-004180-32.
Efficacy of nab-paclitaxel plus gemcitabine (AG) vs. FOLFIRINOX as first line chemotherapy for metastatic pancreatic cancer (mPC): Real world experiences.
Authors: Hwang Inhwang , Kang Jihoon , Yoo Changhoon , Kim Kyu-Pyo , Jeong Jae Ho , Chang Heung-Moon , Ryoo Baek-Yeol
Published: January 2019

354

Background: AG and FOLFIRINOX have been established as standard first-line treatment in mPC patients based on the improved efficacy compared to gemcitabine monotherapy. Because there was no head-to-head comparison between these regimens, however, there is lack of data which regimen is preferable in patients with mPC. Therefore, we performed retrospective analysis comparing the efficacy of AG and FOLFIRINOX in daily practice setting. Methods: We analyzed a total of 308 patients with confirmed mPC who received AG (n = 149) or FOLFIRINOX (n = 159) as first-line treatment between 2013 and 2016 at Asan Medical Center, Seoul, Korea. Primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and overall response rates (ORR). Results: Median age was slightly older in AG group than FOLFIRINOX group (62 vs. 60 years, p = 0.02). Except this, there was no significant difference between the two groups in terms of baseline characteristics including sex (male, AG/FOLFIRNOX): 56%/67%, ECOG performance status (0-1): 97%/99%, pancreatic head location: 32%/40%, and baseline CA19-9 level ( > UNL): 77%/82%. ORR (28% vs. 31%) and disease control rate (74% vs. 74%) did not differ between two groups (p = 0.45, and p = 0.96, respectively). Although there was no significant difference in PFS between the two groups (AG: median 6.8 months [95% CI: 5.8-7.8] vs. FOLFIRINOX: 5.1 months [95% CI: 4.2-5.9]; p = 0.15), OS was significantly better in AG group compared to FOLFIRINOX group (median 12.3 months [95% CI: 11.0-13.7] vs. 9.7 months [95% CI, 8.1-11.4]; p = 0.001). Among the patients who showed progression, 81% (180/223) received second-line chemotherapy and there was no difference between the two groups (AG vs. FOLFIRINOX: 76% vs. 85%, p = 0.09). 5-FU monotherapy or combination with oxaliplatin were given in 97% (73/75) of patients in AG group and gemcitabine-based regimens (including 2 cases of AG) were given in 97% (102/105) of patients in FOLFIRINOX group. Conclusions: Both AG and FOLFIRINOX are feasible and active as first-line treatment for patients with mPC. In daily practice setting, AG showed comparable efficacy outcomes with FOLFIRINOX.
Deterioration of liver function after transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): An exploratory analysis of OPTIMIS—An international observational study assessing the use of sorafenib after TACE.
Authors: Kudo Masatoshi , Raoul Jean-Luc , Lee Han Chu , Cheng Ann-Lii , Nakajima Keiko , Peck-Radosavljevic Markus
Published: January 2019

368

Background: TACE is commonly used for patients (pts) with unresectable HCC, and appropriate pt selection is important to obtain optimal outcomes. However, there is no globally accepted consensus on unsuitability and refractoriness to TACE. Retrospective studies suggest that continuing TACE after refractoriness or failure is harmful and may cause pts to become ineligible for further treatments because of liver function deterioration. This exploratory analysis of OPTIMIS evaluated the real-world incidence of liver function deterioration by baseline liver characteristics after first TACE. Methods: OPTIMIS enrolled 1670 pts with HCC for whom a decision to treat with TACE was made at the time of study entry. Liver function deterioration was defined as worsening of CTCAE grade compared with baseline for any of these parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, albumin, and prothrombin international normalized ratio (INR). All analyses are descriptive. Results: A total of 977 pts received TACE. The incidence of liver deterioration was higher in pts with BCLC stage C vs stage B (52% vs 44%, respectively), in pts exceeding the up-to-7 criteria compared with those within (49% vs 43%, respectively), and in those deemed unsuitable for TACE at baseline versus those deemed eligible (53% vs 44%, respectively) (Table). Conclusions: Deterioration of liver function parameters was observed after TACE in pts with HCC in the real-world setting. Therefore, appropriate pt selection for TACE and preserving liver function are important to optimize the benefit of TACE and subsequent treatments. Clinical trial information: NCT01933945. [Table: see text]
Overall survival of PEGylated human IL-10 (AM0010) with 5-FU/LV and oxaliplatin (FOLFOX) in metastatic pancreatic adenocarcinoma (PDAC).
Authors: Hecht J. Randolph , Naing Aung , Falchook Gerald Steven , Patel Manish R. , Infante Jeffrey R. , Aljumaily Raid , Wong Deborah Jean Lee , Autio Karen A. , Wainberg Zev A. , Javle Milind M. , Bendell Johanna C. , Pant Shubham , Hung Annie , Van Vlasselaer Peter , Oft Martin , Papadopoulos Kyriakos P.
Published: January 2019

374

Background: The therapeutic options for 2nd line therapy PDAC remain unsatisfying with 5-FU/LV plus oxaliplatin or nal-irinotecan resulting in a mOS of 5-6 mo. PDAC has been largely refractory to immune-oncology approaches and CD8 T cells are rare in most PDAC. AM0010 stimulates survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Immune activation, durable stable disease and a 1yr survival of 22.5% was seen in salvage PDAC patients (pts) receiving AM0010 alone. AM0010 has synergistic anti-tumor activity with 5-FU/LV or oxaliplatin in preclinical models. Here we report on the safety, efficacy and overall survival of AM0010 + FOLFOX as 2nd and later line treatment in PDAC. Methods: PDAC progressing on a median of 2 prior therapies (range 1-5) were treated with AM0010 (5ug/kg SQ, qd) + FOLFOX (n = 21). The safety population (n = 25) included also 4 pts with prior oxaliplatin / 5-FU. The survival population included patients without prior platinum containing regimen. Tumor responses were assessed with irRC. Biomarkers evaluated the activation and clonality of peripheral T cells. Archival tumor tissues were evaluated for tumor infiltration by CD8 T cells, by whole exome sequencing and mRNA analysis. Results: AM0010 + FOLFOX, was generally well tolerated. G3/4 TrAEs included thrombocytopenia (52%), anemia (44%), neutropenia (36%) and fatigue (12%). Most cytopenias had a short duration, reaching retreatment criteria within 2-5 days after dose interruption. Dosing AM0010 for 5 days followed by a 2 days dose holiday avoided G3/4 cytopenias. As of 08/11/2017, 2 patients have remained on treatment for > 1 year. Of 19 evaluable pts, 2 had an irCR, 1 had irPR with 100% reduction in tumor burden, ORR is 15.8%, DCR is 78.9%. With median follow-up of 19.2 months (range 13.4-24.1), mPFS was 3.5 mo, mOS was 10.2 mo and 1-year survival was 43%. Transcriptional profiling and CD8 T cells in the archival tumor tissue may identify patients with longer OS. Conclusions: AM0010 in combination with FOLFOX is well tolerated in patients with metastatic PDAC. Immune activation, mOS and 1 year survival are encouraging in this advanced PDAC population. This regimen is currently being studied in a phase 3 trial Clinical trial information: NCT02009449.
Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer.
Authors: Wang-Gillam Andrea , Lockhart A. Craig , Tan Benjamin R. , Suresh Rama , Lim Kian-Huat , Ratner Lee , Morton Ashley , Huffman Jess , Marquez Samantha , Boice Nicolas , DeNardo David G
Published: January 2019

380

Background: Focal adhesion kinase (FAK) is consistently hyperactivated in multiple tumor types including pancreatic ductal adenocarcinoma (PDAC). Our preclinical work showed that FAK and PD-1 inhibitors elicit significant tumor regression, and a maximal response is achieved by combining FAK and PD-1 inhibitors with gemcitabine, suggesting the need for a cytotoxic agent to bolster antigen presentation (Jiang H et al, Nature Medicine 2016). Defactinib is an orally available, well-tolerated, potent ATP-competitive FAK inhibitor. Methods: Eligible patients are being treated according to the dose escalation schema (Table 1). A 3+3 design is being used. The study has an expansion portion for PDAC patients at the recommended phase 2 dose (RP2D). The primary endpoint is to determine the RP2D. Secondary endpoints include safety, toxicity, objective response rate, progression-free survival and overall survival. The exploratory endpoints include developing a molecular and immune profile for treatment response. Results: The dose escalation cohort has been completed with a total of 17 patients with refractory solid tumors being enrolled. The common treatment-related adverse events included fatigue (35%), nausea (29%), myalgia (29%), vomiting (24%), anorexia (24%), pruritus (24%) and fever (18%). No DLTs were observed, therefore the Level 5 dose was deemed to be the RP2D. Among the 13 patients evaluable for treatment response, 7 (54%) have stable disease. No partial or complete responses were observed to date. The median time on treatment was 127 days for all evaluable patients, and 104 days in the 6 PDAC patients with the longest time on treatment being 290 days. Paired biopsies in PDAC patients showed decreased p-FAK and changes in T cells infiltration and proliferation with treatment. Conclusions: The combination regimen is well tolerated. Dose Level 5 is the RP2D dose. The expansion cohort (PDAC only) is ongoing. Efficacy and correlative data is forthcoming. Dose LevelDefactinib D1-21 (BID)Pembrolizumab Gemcitabine (D1 and 8) Level 1 200 mg 200 mg- Level 2 400 mg 200 mg- Level 3 400 mg 200 mg 500 mg/m2 Level 4 400 mg 200 mg 750 mg/m2 Level 5 400 mg 200 mg 1,000 mg/m2 Clinical trial information: NCT02546531.
Phase II trial of pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC).
Authors: Kelley Robin Kate , Mitchell Emily , Behr Spencer , Hwang Jimmy , Keenan Bridget , Cheung Alexander , Gordan John Dozier , Ko Andrew H. , Cinar Pelin , Atreya Chloe Evelyn , Van Loon Katherine , Weber Thomas , Ngo Zoe , Quandt Zoe E. , Liu Chienying , Venook Alan P. , Fong Lawrence
Published: January 2019

386

Background: The efficacy of immune checkpoint inhibition (CPI) has not been established in ABC. GM-CSF modulates immune effector cells and has demonstrated safety and improved survival (OS) in combination with ipilimumab in melanoma. This phase 2 trial aims to evaluate the efficacy and safety of PEM in combination with GM-CSF in ABC. Methods: Design: Simon’s 2-stage. Key eligibility: ABC with progression/intolerance on ≥ 1 standard therapy, no prior CPI, bilirubin ≤1.5xULN. Treatment: PEM 200 mg IV Q21 days plus 2 cycles of GM-CSF 250 µg SC D1-14 Q21 days in cycles 2 and 3 (Stage 1 Safety Cohort) or in cycles 1 and 2 (Stage 2). Endpoints: 1◦: Progression-free survival at 6 months (PFS6) with H0 25% vs. H1 50%. Key 2◦: Safety, overall response rate (ORR) and duration (DOR), OS, PD-L1 expression. Exploratory: PBMC and tumor immune cell profiles, tumor genotype, microsatellite (in)stability (MSI or MSS). Results: Accrual has completed with 27 patients (pts) enrolled 5/2016-6/2017: F/M 13/14; median age 61 (range 37-77); intrahepatic 19 (70%), extrahepatic 7 (26%), mixed 1 (4%) cholangiocarcinoma; stage IVA/B 85%, II/III 15%; median prior therapies 2 (range 1-6). Adverse events (AE): Related grade(Gr) ≥3 AE occurred in 4/27 (15%) pts including immune-related (ir)AE of Gr4 diabetes mellitus and Gr3 thrombocytopenia in 1 pt each. Gr≤2 irAE in ≥5% were: arthralgia (33%), dry eye/mouth (15%), hyperthyroid/thyroiditis (15%), hypothyroid (15%), neuropathy (11%), rash (11%), and adrenal insufficiency (7%). Steroids were required in 3/27 (11%) pts. Disposition: 19 pts removed for PD, 1 for Gr2 irAE; 7 pts remain active on treatment. Median time on treatment: 6 cycles (range 2-22+). Best response by RECIST 1.1: Partial response (PR) in 5/24 (21%) evaluable pts (1 MSI, 4 MSS); minor regression and ≥50% CA 19-9 decline in 2 additional MSS pts for 11+ and 16+ months. PBMC analyses show changes in expression of activating and inhibitory markers including PD-1 on various immune cell populations. Conclusions: PEM plus induction GM-CSF is safe and tolerable in ABC. Durable radiographic and tumor marker responses including MSS pts warrant further study. PFS6, OS, and correlative analyses are ongoing. Clinical trial information: NCT02703714.
Pilot study of gemcitabine, nab-paclitaxel, PEGPH20, and rivaroxaban for advanced pancreatic adenocarcinoma: An interim analysis.
Authors: Yu Kenneth H. , Mantha Simon , Tjan Catherine , Kaufmann Erica S. , Brenner Robin , Lowery Maeve Aine , Ku Geoffrey Yuyat , Raj Nitya Prabhakar , Shcherba Marina , Goldberg Zoe , Li Jia , Zervoudakis Alice , Hamilton Audrey M. , Won Elizabeth , Ucar Antonio , Do Richard K. G. , O'Reilly Eileen Mary
Published: January 2019

405

Background: PEGPH20 (P) degrades hyaluronan (HA), a key component of pancreatic adenocarcinoma (PDAC) tumor microenvironment, leading to reduction of tumor interstitial pressure, decompression of tumor blood vessels and improvement in delivery of chemotherapeutics. A prior study of P with chemotherapy in PDAC (HALO-202) found an increased risk of thromboembolic (TE) events, 43%, effectively reduced with subcutaneous enoxaparin treatment. Rivaroxaban (R) is a safe and effective oral anticoagulant for treating cancer-related TE. Methods: 28 patients with advanced PDAC, KPS ≥ 70 and without prior TE were enrolled from January to June 2017. Patients received treatment with PAG (P; 3 µg/kg IV 2x/wk x 3 wks in C1, then 1x/wk x 3 wks in C2+, plus AG) every 28 days, with R (15 mg twice daily for 21 days, followed by 20 mg once daily). Primary endpoint is symptomatic TE event rate; secondary endpoints include PFS, OS, major bleeding rate and RR. Results: All 28 patients are evaluable for efficacy and safety. Key patient characteristics: age = 62 (range 45-76), M/F = 15/13, stage III/IV = 4/24, KPS 70/80/90 = 1/13/14. Median follow-up is 5.4 mo. No symptomatic and one grade 2, asymptomatic TE event (DVT) occurred (1/28 = 3.6%). Two grade 3 GI hemorrhages occurred. Best responses: partial response 11 (39%), stable disease 13 (46%), progressive disease 4 (14%), and overall disease control rate of 86%. Median PFS and OS have not been reached. Conclusions: Interim analysis shows R is safe and effectively prevents TE events in patients receiving PAG. Responses and disease control rate are encouraging in this tumor HA-level unselected patient population. Updated safety and efficacy data will be reported. Clinical trial information: NCT02921022.
A comparison of percutaneous and endoscopic-guided celiac plexus block/neurolysis in pancreatic cancer patients.
Authors: Kambhampati Swetha , Sugar Elizabeth A. , Herman Joseph , Erdek Michael A. , Shin Eun Ji , Laheru Dan
Published: January 2019

413

Background: Pancreatic Cancer is associated with severe pain and often intractable due to its multifactorial nature. Celiac plexus neurolysis (CPN) has been shown to be effective in controlling pain and conventionally was performed percutaneously (PC) with fluoroscopic or CT guidance. However EUS guidance is being increasingly used and has shown to provide effective analgesia. The aim of this retrospective study is to compare PC-guided and EUS-guided CPN for pain control. Methods: Our retrospective cohort study included pancreatic cancer patients who underwent CPN for pain control from 2008 to 2015 at Johns Hopkins. The primary outcome was a good pain response defined as a drop in NRS pain scores to less than 1 or drop of at least 3 post-procedurally or at 1 month. Secondary outcomes were changes in opiate usage (morphine equivalents), QOL (FACT-Hep) scores and opiate-related side effects. Results: 151 patients underwent PC-CPN and 49 patients underwent EUS-CPN. Patients had their procedure on average 5 months after diagnosis. At baseline, EUS patients had significant higher median baseline pain scores, 9 (4-10) compared to 6 (5-7). A good pain response was seen in 86% of PC patients compared to 73% of EUS patients post-procedurally (p = 0.01). However, at 1 month 43% of EUS patients had a good pain response compared to 28% of PC patients, which trended towards statistical significance (p = 0.08). Following the procedure at 1 month, opiate dosage increased in both groups and no reduction in the proportion of patients with opiate related side effects was seen. EUS patients had significantly higher QOL scores at 1 month, 86 (79-92) vs 72 (67-82) (p < 0.001). Median time from procedure to death was significantly higher in EUS patients than PC patients (HR: 0.63, 95% CI: 0.44, 0.89, p = 0.008). No differences in adverse events between the two groups were seen. Conclusions: Both EUS and PC guided CPN were effective at reducing post-procedural pain in pancreatic cancer patients but their effectiveness waned by 1 month. Percutaneous patients had significantly lower pain scores immediately following the procedure. However, EUS patients seemed to have more durable pain relief with lower pain scores at 1 month and improved QOL.
Metastatic pancreatic cancer (MPC): Contrast of short- (STS) and long-term (LTS) survivor characteristics.
Authors: Kowalczyk Mark , Mandelson Margaret T. , Lin Bruce Shih-Li , Picozzi Vincent J.
Published: January 2019

415

Background: MPC is associated with 6-12 month (mo) median overall survival (OS) in published clinical series. However, there is wide variability in OS using standard chemotherapy (CTX) regimens (e.g. gemcitabine/nab-paclitaxel, FOLFIRINOX). 10-20% of patients (pts) live ≤ 3 mo (STS); conversely 5-10% pts live ≥ 24 mo (LTS). We examined pretreatment characteristics of our institutional MPC population for their association with STS/LTS. Methods: From our institutional database, we identified over 400 pts with MPC who received CTX between the years 2003 and 2015. Pts who 1) received all of their CTX at our institution 2) had complete longitudinal follow- up available and 3) lived either ≤ 3 or ≥ 24 mo were further analyzed. A number of pretreatment characteristics were considered, including A) patient and B) disease-related factors. Results: To date,37 pts (median OS 2.0 mo)/ 41 pts (median 28.2 mo) have been identified as STS/LTS respectively. In univariate analysis factors significantly associated with STS/LTS ( p < 0.0001) were ECOG ≥2 and neutrophil /lymphocyte ratio (NLR) > 5. Age at dx, pain at dx, BMI > 30, albumin < 4.0 g/dL, Ca19.9 > 500U/mL, ascites at dx and liver involvement also were statistically significant (all p≤ 0.05 or greater). Among factors not statistically different between STS/LTS were sex, race, yr of dx, presence of diabetes or biliary obstruction at dx. A multivariate model that included ECOG ≥2 and NLR ≥5 along with other of the above factors correctly discriminated between STS and LTS with 90% accuracy (95% CI 83-97%) . Conclusions: 1) Examination of pretreatment characteristics in MPC can aid in identification of pts more likely to be STS / LTS. 2) For STS and LTS these data may aid in identifying candidates for new initial and new consolidation treatment strategies, respectively. 3) Prognostics models for STS/LTS require additional validation in independent data sets. 4) Integrating additional pretreatment information (e.g. molecular, clinical, therapeutic) may further improve OS prognostication in MPC.
A multicenter phase ib-IIR trial assessing activity of regorafenib in combination with modified gemcitabine-oxaliplatin (mGEMOX) in patients with advanced biliary tract cancer (aBTC).
Authors: Assenat Eric , Portales Fabienne , Ychou Marc
Published: January 2019

427

Background: News therapeutic options are needed in aBTC systemic treatment. Regorafenib (a multi target tyrosine kinase inhibitor) showed efficacy in several digestive tumors and could be associated with conventional chemotherapy in BTC. The Phase Ib primary objective was to determine the recommended Regorafenib dose combined with mGEMOX. The randomized phase II will assess efficacy of the combination compared to mGEMOX alone. We present here the results of the analysis planned at the end of phase Ib. Methods: Three dose levels (80, 120 and 160mg) of Regorafenib combined with mGEMOX, 3 to 6 patients each, were planned, and up to 12 patients to confirm the recommended dose-level. Patients received Regorafenib from day 1 to 14, and mGEMOX on days 1 and 8 (IV Gemcitabine 900mg/m2 followed with Oxaliplatin 80mg/m2 IV). Results: From 10.2014 to 11.2016, 22 patients were included in two French centers: 6, 3 and 13 patients in levels 1, 2 and 3, respectively. 2 patients (level 3) were not evaluable for recommended dose identification or tolerance and excluded from analysis. Patients were 70% men, of median age 62.5 years (20-74), ECOG PS 0 (60%) or 1 (40%). Primary tumor was localized within (60%) or outside (30%) the liver, or in the gall-bladder (10%). Eight (30%) patients underwent surgery. The Regorafenib relative dose-intensity was 101.8 [89.3-107.1], 100 [96.4-100] and 100% [51.8-103.6] for dose levels 1, 2 and 3, respectively. Regorafenib dose modifications during treatment occurred for 0 (level 1), 0 (level 2), and 3 patients (27%) (level 3). Toxicities were (level 1, 2, 3): grade 3 diarrhea (1, 0, 0), grade 3 asthenia (0, 0, 1), grade 2 hand-foot syndrome (1, 0, 0), grade 3 hypertension (2, 1, 2), grade 3/4 neutropenia (1/0, 1/0, 0/2), grade 3 thrombopenia (1, 0, 1), grade 3 anemia (0, 0, 1). Four DLTs were reported: 1 in level 1 (grade 3 diarrhea) and 3 in level 3 (2 grade 4 neutropenia, 1 grade 3 anemia). Conclusions: Regorafenib shows acceptable toxicity combined with mGEMOX; the DLTs reported were mainly related to conventional chemotherapy. Dose level 3, 160mg/day Regorafenib will be used in ongoing phase IIR assessing efficacy of this combination. Clinical trial information: NCT02386397.
Gemcitabine, nab-paclitaxel, cisplatin, and anakinra (AGAP) treatment in patients with localized pancreatic ductal adenocarcinoma (PDAC).
Authors: Becerra Carlos , Paulson Andrew Scott , Cavaness Keith M , Celinski Scott A.
Published: January 2019

449

Background: Treatment options for localized PDAC include surgery, chemo- and radio-therapy. Inflammatory stimuli cause IL-1 release and mediate inflammatory and immunological responses. PDAC cells can induce secretion of IL-1β which facilitates tumor development and progression. We showed that anakinra, a recombinant, non-glycosylated form of the human interleukin-1 receptor antagonist, when given with FOLFIRINOX, was safe for use in metastatic PDAC. Herein we report the preliminary results of AGAP in patients with non-metastatic PDAC. Methods: 16 patients with non-metastatic PDAC were treated with AGAP on Day 1 and 8 of a 21 day cycle for up to 6 cycles. Patients self-administered anakinra a day after their first dose of chemotherapy (100 mg every other day; SC). Restaging scans evaluation was performed after every 2 cycles. Patients filled a QOL questionnaire once a month and serum was collected at baseline and at defined time points for biomarker analysis. Results: Grade 3/4 toxicities: neutropenia (50%), alopecia (13%), anemia (25%), thrombocytopenia (19%), diarrhea (19%), hypomagnesemia (13%), vomiting (13%), and 6% of patients, respectively had febrile neutropenia, nausea, hypocalcemia, and erythema at the injection sites. Twelve patients had surgery and all had negative margins in the pathology specimen. Ten patients had normal CA19-9 prior to resection and 3 had disease recurrence. Two patients had elevated CA19-9 prior to surgery and 1 patient had disease recurrence. Four patients did not have surgery; 3 received XRT and had disease progression and 1 patient declined further therapy and expired on hospice. No patients had systemic progression while on AGAP chemotherapy. Eight patients are alive without recurrence at a median follow up of 13 months. Conclusions: AGAP was tolerable with expected toxicities from the combination regimen. Biomarker analysis, disease recurrence and survival will be updated at the meeting. The study has been expanded to include additional patients. Clinical trial information: NCT02550327.
Circulating tumor DNA (ctDNA) landscape and prognostic implications in advanced gastroesophageal adenocarcinoma (GEC).
Authors: Maron Steven Brad , Joshi Smita Suhas , Lomnicki S , Oliwa Tomasz , Landron Stacie , Johnson Julie , Kiedrowski Lesli Ann , Nagy Rebecca J , Lanman Richard B. , Janjigian Yelena Yuriy , Kelly Kaitlyn J. , Kim Seung Tae , Lee Jeeyun , Catenacci Daniel V.T.
Published: January 2019

45

Background: Esophagogastric junction (EGJ) and gastric (GC) cancer, together GEA, have a poor prognosis, high molecular heterogeneity, and few targeted therapeutic options. Guardant360 is a clinical gene panel test for next generation sequencing (NGS) of plasma circulating tumor (ct) DNA. Methods: We evaluated a large cohort of ctDNA-derived genomic results (Guardant Health, Inc.), including a subset of pts from the University of Chicago (UC) with clinical data. GEA pts in these 2 cohorts were assessed for genomic alteration (GA) distribution: mutations (mt), indels, amplifications (amp) and fusions. UC survival analyses were performed using log-rank test and select gene-by-gene alteration frequency by pt with chi-square comparisons. Results: The overall ctDNA cohort comprised 1128 pts with median age 64 yrs (range 19-98) and 73% males. At least 1 detectable GA (median 4, range 0-102) was observed in 870 pts (77%). The UC subset of pts (n=171), median age 63 yrs (range 19-87), included 2/10/27/61% stage I/II/III/IV, 77/13/5/5% Caucasian/African American/Asian/Hispanic, 74% male and 63% EGJ. At least 1 detectable GA (median 4, range 1-102) was observed in 157 pts; median GAs per test by stage I vs II/III vs IV was 1.5/3.5/4.5. GA distributions were similar to the larger cohort (Table 1). Stage IV pts tested within 6 weeks of diagnosis/recurrence (n=34) had a median survival of 8.7 months. In these pts, BRAF/ FGFR2 amps and ARAF mts were each prognostic for worse survival ( p<0.05), and MET and KRAS amps trended towards significance. Mt allele frequency (MAF) ctDNA burden inversely correlated with survival ( p=0.01) . In 138 pts with ≥2 serial tests, non-synonymous GAs in MET, PIK3CA, and FGFR1 were more commonly late events (all p<0.05 ). Conclusions: GAs in plasma ctDNA were detected in 77% of GEA pts including numerous actionable targets. ctDNA analysis merits further evaluation as a prognostic biomarker assessing specific genes, overall ctDNA burden, and molecular heterogeneity at baseline and serially. [Table: see text]
Efficacy and tolerability of tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma.
Authors: Sharma Padmanee , Dirix Luc , De Vos Filip Yves Francine Leon , Allison James Patrick , Decoster Lore , Zaucha Renata , Park Joon Oh , Vanderwalde Ari M. , Kataria Ritesh S. , Ferro Salvatore , Patel Gargi , Ben Yong (Ben) , Oh Do-Youn
Published: January 2019

470

Background: Clinical activity and tolerability of the anti-CTLA-4 antibody, tremelimumab, has yet to be established in metastatic pancreatic ductal adenocarcinoma (mPDAC). In a Phase 2, multicenter, open label study (NCT02527434), tremelimumab was evaluated in pts with advanced solid tumors. We report a planned analysis of the safety and efficacy of tremelimumab monotherapy in a cohort of pts with mPDAC. Methods: Eligible pts were adults with histologically or cytologically confirmed mPDAC with tumor progression following prior standard first-line 5-FU- or gemcitabine-containing chemotherapy. Pts received tremelimumab 750 mg IV Q4W for 7 doses, followed by 750 mg Q12W for 2 doses, for up to a total of 12 mo (total 9 doses in 12 mo) or until disease progression or unacceptable toxicity. Pts were radiographically assessed Q6 wks relative to first dose. The primary endpoints were safety (evaluated by CTCAE v4.0) and objective response rate (ORR) by investigator assessments (evaluated by RECIST v1.1). Results: As of April 5, 2017, 20 mPDAC pts had received treatment and were evaluable for efficacy analysis. Median treatment duration was 1.8 mo. There were no observed objective responses (ORR 0%; 95% CI, 0.0, 16.8%). Of 20 pts, 2 were not evaluable and 18 had progressive disease (PD). Based on the full analysis set (N = 20), progression occurred in target lesions in 14 (70%), non-target lesions in 7 (35%), and new lesions in 13 (65%) pts (not mutually exclusive categories). At the time of progression, 11 (61%) pts were on treatment and 7 (39%) had discontinued treatment. Median overall survival was 4 mo (95% CI 2.83 - 5.42). Two (10%) pts were still in follow up at 12 mo after treatment initiation. Treatment-related AEs (trAEs) occurred in 14 pts (70%); grade ≥3 trAEs occurred in 6 pts (30%). Three pts (15%) discontinued therapy due to trAEs. There were no treatment-related deaths. Conclusions: Tremelimumab monotherapy did not appear to be active in mPDAC pts who had tumor progression following prior standard first-line 5-FU- or gemcitabine-containing chemotherapy. Clinical trial information: NCT02527434.
Retrospective study of postoperative chemoradiation of cholangiocarcinoma in South Korea: Efficacy, side effect, and prognostic factors.
Authors: Lee Guk Jin , Lee Jong Hoon , Kim Sung Hwan , Shim Byoung Yong
Published: January 2019

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Background: There is no estabilished consensus about chemoradiation therapy for resected cholangiocarcinoma, and many studies are ongoing. We tried to cofirm the effectiveness and side effects of chemoradiation after operation of cholangiocarcinoma and find the prognostic factors. Methods: We found the patients with cholangiocarcinoma who receieved chemoradiation after surgery between 2002 and 2015 from two hospitals in South Korea. We checked the baseline chareacteristics, efficacy and toxicities. And we tried to identify the prognostic factors for recurrence by statistical anaylsis. Results: We retrospectivally studied 51 cholangiocarcinoma patients. Median age was 64 (range 48-83), and Men was 30 patients (58.8%) of them. By location, there were 10 (19,6%) intrahepatic cholangiocarcinomas, 13 (25.5%) hilar cholangiocarcinoma, and 28 (54.9%) extrahepatic cholangiocarcinomas. All patient received 5-FU chemoradiation after surgery. R0 resections were 31 (60.8%), R1 resections were 20 (39.2%) There was recurrence with 35 (68.6%) patients. Median relapse free survival was 292 (range 86-1769) days. Locoregional recurrence were 16 (31.4%), and distant recurrences were 26 (51.0%). For hematological toxicity, the patients showed grade 3 toxicities, as leukopenia 5 (9.8%), anemia 1 (2.0%) , thrombocytopenia 1 (2.0%). For non-hematological toxicities, there were G3 toxicities as Infection 2 (4.0%), nausea/vomiting 1 (2.0%), Adhesive ileus 1 (2.0%), bleeding 1 (2.0%). For multivariate analysis, Tumor site (HR 1.88 (95% CI 1.09-3.23). P = 0.022) and modality of radiation therapy (HR 13.27 (95% CI, 3.56-49.50)), P < 0.001) were statistically meaningful factors. Conclusions: Although this is a retrospective study, we found that the result of chemoradiation therapy for some patients showed good efficacy and tolerable toxicity. We could consider chemoradiation for adjuvant therapy in cholangiocarcinoma, especially for extrahepatic cholangiocarcinoma. And intensity-modulated radiation therapy should be performed than three-dimensional radiation therapy in cholangiocarcinoma.
Efficacy of oral chemotherapy with capecitabine and temozolomide (CapTem) in metastatic neuroendocrine tumors (NETs): A single-institution experience.
Authors: Smiroldo Valeria , Carnaghi Carlo , Rimassa Lorenza , Personeni Nicola , Pressiani Tiziana , Bozzarelli Silvia
Published: January 2019

487

Background: CapTem chemotherapy regimen represents one of the standard of treatment for NETs, an interesting option of care due to its feasibility and efficacy although not enough prospective data support this evidence. Methods: This retrospective analysis included all patients (pts) with metastatic NETs treated with CapTem regimen at our institution from April 2013 to April 2017. This oral chemotherapy included capecitabine 600 mg/m2/BID (capped at 1,000 mg BID total dose) on days 1–14 and temozolomide 75 mg/m2/BID on days 10–14 every 28 days according to the schedule published by Fine RL et al. (Cancer Chemother Pharmacol, 2013). Overall survival (OS), progression free survival (PFS), overall response rate (ORR) and toxicities were retrospectively evaluated. Results: Twenty-seven pts (15 males) were included. Median age was 61 yrs (range 46-85). Primary tumor included pancreas in 8 pts (29.6%), midgut 8 pts (29.6%), lung 8 pts (29.6%), other NETs 3 pts (11.1%). Most of pts had well-differentiated tumors (88.8%) and Ki67 was less than <20% in 59% of pts. Median number of cycles was 6 (range 2-25). Ten pts (37.0%) received CapTem as 1st line treatment, 7 pts (25.9%) as 2nd line and 10 (37.0%) pts as > 3rd line. ORR was 33.3%; 31.2% for Ki67 < 20% group and 40.0% in Ki67 >20%. DCR (partial response + stable disease) for the entire cohort was 59.2%. Median PFS was 4 mos, without any differences between pancreatic, midgut and lung groups, but mPFS was 8.0 mos for pts who received CapTem as 1st line treatment. At present mOS was not reached. In term of toxicity CapTem regimen was very well tolerated and only 1 pt reported a G3 reversible toxicity (neutropenia). No G3/4 toxicity were observed. Conclusions: Our experience confirms that CapTem regimen is effective and well tolerated. Efficacy does not seem to be related to the primary tumor or Ki67. DCR and ORR are superior to the response produced by tyrosine kinase inhibitors, suggesting a strategy when tumour shrinkage and symptom control are needed.