bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of fluzoparib, a PARP1 Inhibitor in combination with apatinib and paclitaxel in patients (pts) with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Xu Jian-Ming , Liu Rongrui , Ba Yi , Jiang Da , Wang Mingxia , Zheng Yulong , Wei Jia , Bai Yu-Xian , Lin Lizhu , Xiong Jianping , Zhu Xixi , Zhao Chuanhua , Jia Ru , Zhang Yun , Liu Jianzhi , Zhang Gairong , Li Guangze , Wang Quanren 
Published: May 2019

4060 Background: Fluzoparib (SHR3162) is an oral, selective PARP1 inhibitor. In our gastric cancer PDX model, fluzoparib + apatinib + paclitaxel demonstrated significant tumor growth inhibition as compared to apatinib alone, and fluzoparib + paclitaxel. In this phase I study, we hypothesized that the combination of fluzoparib+apatinib+paclitaxel should be safe and active in pts with advanced gastric and GEJ cancer. Methods: Dose-escalation phase (P1) explored 4 dose levels of fluzoparib with a 3+3 design to identify a recommended phase II dose (RP2D) for further study. Pts received fluzoparib (20, 30, 40, 60 mg/twice daily)+apatinib (250mg/day)+paclitaxel (60mg/m2, Day1, 8, 15). Dose-expansion phase (P2) was to assess safety and efficacy. Pts received RP2D of fluzoparib+apatinib+paclitaxel until progression or intolerant toxicity. Treatment was repeated every 4 weeks. Pts had to have progressive disease after standard platinum-based regimen treatment. Adverse events (AE), PK, and response per RECIST 1.1 (every 8 wks in pts with measurable disease) were assessed. Results: 39 pts (median age 58) have been treated in P1 and P2, including fluzoparib 20mg (n=4), 30mg (n=27; 6 pts in P1, 21 pts in P2), 40mg (n=6), and 60mg (n=2). The median treatment duration for this study was 2.8 months. No DLTs were reported in 20mg cohort. One DLT occurred in 30 mg cohort (grade 3 [G3] hypophosphatemia), 1 DLTs (1 grade 4 [G4] febrile neutropenia) occurred and 1 G4 neutropenia occurred and recovered in 3 days in 40mg cohort, 2 DLTs (1 G4 neutropenia, 1 G4 febrile neutropenia) in 60mg cohort. Therefore, 40 mg dose was deemed the MTD. There were no treatment-related deaths on study. The most common AEs≥G3 were neutropenia, febrile neutropenia, and hypertension. 1 treatment-related discontinuation was observed. Of 36 evaluable pts, 12 (30.0%) had confirmed partial response and 13 had stable disease (36.1%). Median progression-free survival was 4.9 months. PK analysis will be presented. Conclusions: The RP2D of combination of fluzoparib + apatinib + paclitaxel is well tolerated and has activity in pts with advanced gastric and EGJ cancer who have failed to platinum-based regimen. Clinical trial information: NCT 03026881.
A phase II study of anti–PD-1 antibody camrelizumab plus FOLFOX4 or GEMOX systemic chemotherapy as first-line therapy for advanced hepatocellular carcinoma or biliary tract cancer.
Authors: Qin Shukui , Chen Zhendong , Liu Ying , Xiong Jianping , Ren Zhenggang , Meng Zhiqiang , Gu ShanZhi , Wang Linna , Zou Jianjun 
Published: May 2019

4074 Background: Advanced hepatocellular carcinoma (HCC) and biliary tract cancer (BTC) patients (pts) have very limited treatment options. Considering the immunogenic effects of oxaliplatin, combination of camrelizumab with oxaliplatin-based chemotherapy might bring a better clinical benefit. Methods: That was an ongoing single-arm, multicenter phase 2 trial. Advanced HCC or BTC pts naive to systemic treatment were given camrelizumab (3 mg/kg i.v., every 2 weeks) plus typical FOLFOX4 (infusional fluorouracil, leucovorin and oxaliplatin) or GEMOX (gemcitabine and oxaliplatin) regimen. Primary endpoints were confirmed objective response rate (ORR) per RECIST v1.1 and safety per CTC AE 4.03. Results: From Apr 27, 2017 to Oct 31, 2018, 34 Chinese HCC and 47 BTC pts were treated, in which 27 (79.4%) HCC and 17 (36.2%) BTC pts were HBV-infected. In the 34 evaluable HCC pts, confirmed ORR was 26.5% and disease control rate (DCR) was 79.4%. Median time to response (TTR) was 2.0 mo (range 1.5–5.7). Six of the 9 responses were still ongoing, and median duration of response (DoR) was not reached (range 3.3–11.5+ mo). Median progression-free survival (PFS) was 5.5 mo. At data cutoff, 61.7% BTC pts were still receiving study drug. In the 43 evaluable BTC pts, with a median duration of exposure of 2.9 mo, confirmed ORR was 7.0% and DCR was 67.4%. Median TTR was 1.9 mo (range 1.8–2.1). Median DoR was 5.3 mo (range 3.7–7.0). Median PFS was not reached yet. Median estimates for overall survival in both HCC and BTC were also not reached. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 85.3% of HCC and 57.4% of BTC pts, most commonly neutrophil count decreased (HCC: 55.9%; BTC: 29.8%), white blood cell decreased (HCC: 38.2%; BTC: 21.3%), platelet count decreased (HCC: 17.6%; BTC: 12.8%), and anaphylaxis (BTC: 19.1%). Only one BTC pt stopped treatment due to a TRAE (recurrent Grade 2 anemia related to FOLFOX4). Grade ≥3 immune-related AEs occurred only in 5.9% of HCC (lipase increased) and 3.8% of BTC pts (anaphylaxis). Conclusions: Camrelizumab plus FOLFOX4 or GEMOX chemotherapy was tolerable and might offer a new promising choice for advanced HCC and BTC pts. Clinical trial information: NCT03092895.
Comprehensive genomic profiling in FIGHT-202 reveals the landscape of actionable alterations in advanced cholangiocarcinoma.
Authors: Silverman Ian M. , Murugesan Karthikeyan , Lihou Christine F. , Féliz Luis , Frampton Garrett M. , Newton Robert C , Tada Hiroomi , Albacker Lee A. , Burn Timothy C. 
Published: May 2019

4080 Background: Genomic studies of cholangiocarcinoma (CCA) have identified actionable alterations in multiple genes including IDH1, IDH2, FGFR2 and BRAF, but no targeted therapies have been approved for this indication. Pemigatinib (formerly INCB054828) is a selective FGFR1-3 inhibitor currently being evaluated in multiple tumor types, including advanced CCA harboring FGFR2 rearrangements. Comprehensive genomic profiling (CGP) was used to identify and enroll advanced CCA patients with FGFR2 rearrangements into FIGHT-202 (NCT02924376). Here we provide an overview of the genomic landscape of advanced CCA and identify actionable alterations. Methods: CGP was performed on tumor samples from 1104 patients with advanced CCA using FoundationOne, a broad-based genomic panel which identifies mutations, rearrangements, and amplifications in 315 cancer genes. Results: The most frequently altered genes in advanced CCA were TP53 (38.1%), CDKN2A/B (28.8%), KRAS (21.9%), ARID1A (15.7%), SMAD4 (11.3%), BAP1 (10.6%), IDH1 (10.5%), PBRM1 (10.0%), FGFR2 (9.4%), ERBB2 (7.6%), PIK3CA (7.0%), MDM2/ FRS2 (5.8%), and BRAF (4.7%). FGFR2: BAP1 was the most significantly co-occurring alteration pair (odds ratio = 8.5; q-value = 1.08 x 10-13, Fisher’s exact test). 42.9% of patients had at least one alteration for which a targeted agent has been either approved or is under investigation. 91 (8.2%) patients had FGFR2 rearrangements, involving 44 unique partner genes, 37 (84.1%) of which were observed only once. The most prevalent FGFR2 rearrangement partner, BICC1, occurred in only 28 (30.7%) FGFR2 rearrangement positive patients. FGFR2 activating point mutations were found in 13 (1.2%) patients. Of 1,091 evaluable patients for microsatellite instability (MSI) or tumor mutational burden (TMB), only 10 (0.9%) were MSI-H and 13 (1.2%) had high TMB (≥ 20 mutations/megabase). None of the MSI-H or TMB-High patients had FGFR2, IDH1 or IDH2 activating alterations. Conclusions: The high frequency (42.9%) of patients with actionable alterations and myriad FGFR2 rearrangement partners strongly support the use of fusion partner-agnostic CGP in advanced CCA.
Frequency of BRCA mutation in biliary tract cancer and its correlation with tumor mutational burden (TMB) and microsatellite instability (MSI).
Authors: Spizzo Gilbert , Puccini Alberto , Xiu Joanne , Goldberg Richard M. , Grothey Axel , Shields Anthony Frank , Arora Sukeshi Patel , Khushman Moh'd M. , Salem Mohamed E. , Battaglin Francesca , El-Deiry Wafik S. , Tokunaga Ryuma , Philip Philip Agop , Hall Michael J. , Marshall John , Kocher Florian , Korn Wolfgang Michael , Lenz Heinz-Josef , Seeber Andreas 
Published: May 2019

4085 Background: Biliary tract cancers constitute ~3% of cancers worldwide with incidence increasing, especially for intrahepatic cholangiocarcinoma (IHC). The prognosis of these tumors remains dismal and novel treatment strategies are needed to improve overall survival. BRCA mutations occur in biliary tract cancers but their frequency in distinct sites of biliary tract cancer is unknown. Moreover, no data are available correlating BRCA mutation with immunogenic markers such as TMB, MSI, or PD-L1 expression. Methods: Tumor samples from 1288 primary biliary tract cancers, comprising IHC (n = 746), extrahepatic cholangiocarcinoma (EHC) (n = 189), gallbladder (GBC) (n=353) were profiled at Caris Life Sciences, Phoenix, AZ. Testing included NextGen SEQ (MiSeq on 47 genes, NextSeq on 592 genes) and PD-L1 IHC (SP142). TMB was calculated based on somatic nonsynonymous missense mutations, and MSI was evaluated by NGS of known MSI loci. Results: BRCA mutations were detected in 3.6% (N = 46) of samples ( BRCA1 0.6%, BRCA2 3%), no differences were seen based on the site of the tumor. In GBC and IHC BRCA2 mutations (4.0% and 2.7%) were more frequent than BRCA1 (0.3% and 0.4, p < 0.05) while in EHC, similar frequency was observed ( BRCA1: 2.1%; BRCA2: 2.6%). There was no significant association with gender or age. In BRCA-mutant biliary tract cancer the most frequently mutated genes were TP53 (55.6%), ARID1A (52.2%) and KRAS (26.1%), KMT2D/C (20%, 13%) and CDKN2A(13%). Overall, BRCA mutations were associated with a higher rate of MSI-H (19.5% vs 1.7%, p = 0.001) and higher TMB in both MSI-H and MSS tumors (p<0.05). When investigated separately, BRCA association with elevated TMB was seen in IHC and EHC, but not in GBC. No correlation was seen with PD-L1 expression. TP53, KMT2D/C, RB1, PTEN, KDM6A mutations and FGFR1 amplifications were significantly higher in BRCA mutated tumors (p < 0.05). Conclusions: BRCA mutations are found in a significant subgroup of biliary tract tumors and are associated with an immunogenic tumor profile. These data provide rationale for trials testing PARP inhibitors in combination with immunotherapy and targeted therapies in patients with BRCA-mutant biliary tract cancers that are MSS.
Cell-free junctional DNA fragment from hepatitis B virus integration in HCC for monitoring postresection recurrence and clonality.
Authors: Wang Ya-Chun , Li Chiao-Ling , Ho Ming-Chih , Lin You-Yu , Tzeng Sheng-Tai , Chen Yun-Ju , Pai Hsin-Yung , Yeh Shiou-Hwei , Chen Pei-Jer 
Published: May 2019

4090 Background: About one-third of patients suffer tumor recurrence within the first year after surgical resection of HCC. Early recurrence compromised their overall survival. Timing detection of HCC recurrence and its clonality is required to implement therapeutic trials appropriately. This study examined the virus-host chimera DNA (vh-chimera DNA), generated from junctions of HBV integration in HCC chromosome and released into blood, as a potential circulating biomarker for this clinical setting. Methods: We established a capture-next generation sequencing (NGS) platform to identify the HBV integrations in 50 resected HBV-related HCC. For individual HCC, the major clonal HBV integration sites were chosen to design specific primers for droplet digital PCR (ddPCR) to detect and quantify the vh-chimera DNA in plasma samples, collected either just before surgery or two months after surgery. Levels of vh-chimera DNA were then correlated with baseline HCC size or recurrence in one-year follow up. Results: We succeeded in detecting HBV integrations in the HCC from 44 out of 50 HBV-related HCC patients (88%). The copy number of vh-chimera DNA in plasma at surgery from 42 patients correlated with tumor sizes, with the detection limit at 1.5-2 cm. Among the plasma collected 2 months after surgery, 26.2% of samples contained the same HCC signature vh-chimera DNA as baseline plasma, indicating a possible residual tumor. Consistently, 81.8% of them suffered HCC recurrence within one year. The signature vh-DNA in the plasma suggested the majority of recurrences coming from the original HCC clones, whereas 2 from de novo ones. Conclusions: This study supported vh-chimera DNA as a new circulation marker for detecting the existence of most HBV-related HCC. This new biomarker may complement AFP to help detect residual or recurrent HCC and their clonality after curative therapies.
Impact of tumor shrinkage pattern by biweekly triplet gemcitabine/cisplatin/s-1 for biliary tract cancers: Implication for neoadjuvant therapy (KHBO1401-1A study).
Authors: Kobayashi Shogo , Eguchi Hidetoshi , Kanai Masashi , Wada Hiroshi , Sakai Daisuke , Baba Hideo , Seo Satoru , Taketomi Akinobu , Yoshimura Kenichi , Hatano Etsuro , Nagano Hiroaki , Ioka Tatsuya ,   Kansai Hepatobiliary Oncology Group (KHBO)
Published: May 2019

4093 Background: There have not been any new evidenced regimen for biliary tract cancers (BTC) after ABC-02 study, we conducted biweekly triplet gemcitabine/cisplatin/s-1 regimen (GCS) and compared with conventional doublet gemcitabine/cisplatin regimen (GC) as phase III (KHBO1401) study. Biweekly GCS was proved not only to prolong patients’ survival (HR 0.791 (90% C.I. 0.628-0.996), one-sided P = 0.046) but also to achieve high response rate (42% versus 15%, P < 0.001) and good conversion rate (2.5% versus 0.0%), and would be good for neoadjuvant therapy. Herein, we investigated tumor shrinkage pattern to explore possibilities of neoadjuvant therapy. Methods: Totally 246 patients were enrolled in multi-center phase III KHBO1401 study between 2014 and 2016. Tumor shrinkage pattern (best response, timing, response at 100 days (14 weeks, approx. 6 cycles in GCS and 4 cycles in GC), etc.) and survival were investigated in the patients with measurable BTC (n = 183, 74%, 91 in GCS and 92 in GC) as sub-analysis. P < 0.05 was considered statistically significant. Results: Tumor shrinkage pattern could be divided to 4 categories by the response at 100 days after enrollment; category A ( < -30% in size), B (-30% to 0%), C (0% to +20%), and D ( > +20%). GCS arm contained more category A & B (61 (67%) vs. 33 (36%), P < 0.0001). Each category predicted best response and overall survival (p < 0.0001). Timing for maximum tumor response were different among categories, category A achieved maximum tumor shrinkage at 165 +/- 76 days in GCS and 225 +/- 190 days in GC, category B at 139 +/- 78 versus 154 +/- 82 days, and category C and D did not achieve tumor shrinkage. Maximum tumor shrinkage in category A was -53% in GCS versus -65% in GC (P = 0.0892), and 20% patients in GCS underwent tumor regrowth 154 +/- 143 days later. Conclusions: GCS provided faster and more tumor shrinkage with better survival in the comparison of GC, although it had 20% risk of re-growth after 6 cycles.
The prognostic role of soluble transforming growth factor-β related with soluble programmed death-ligand 1 in biliary tract cancer.
Authors: Kim Jin Won , Ha Hyerim , Lee Kyung-Hun , Nam Ah-Rong , Bang Ju-Hee , Jin Mei Hua , Oh Kyoung Seok , Bang Yung-Jue , Oh Do-Youn 
Published: May 2019

4094 Background: We previously reported that soluble programmed death-Ligand 1 (sPD-L1) at pre-chemotherapy indicated the prognostic value for overall survival (OS) and the dynamics of sPD-L1 during palliative chemotherapy correlated with disease burden in biliary tract cancer (BTC). Transforming growth factor (TGF) -β attenuates tumor response to PD1/PD-L1 inhibitors. Strategy of dual targeting of PD1/PD-L1 and TGF-β is now under investigation. This study aimed to evaluate the association between soluble TGF-β (sTGF-β) and sPD-L1, dynamics during chemotherapy and its prognostic role in BTC. Methods: Study population consisted of 90 BTC patients treated with first line chemotherapy. Blood samples at pre-and post-chemotherapy and at disease progression (PD) were prospectively collected. Plasma sTGF-β and sPD-L1 levels were measured by using an enzyme-linked immunosorbent assay. Results: The median progression free survival (PFS) and OS of all patients was 6.9 months (m) (95% CI, 5.2-8.6) and 11.5 m (95% CI, 9.4-13.6). The best response was CR in 7 (7.8%), PR in 20 (22.2%), SD in 52 (57.8%), and PD in 11 patients (12.2%). The mean baseline sTGF-β and sPD-L1 were 16.4 ng/ml and 1.3 ng/ml. There was a positive association between sTGF-β and sPD-L1 in terms of baseline levels and changes after chemotherapy (at pre-chemo, Pearson correlation = 0.578, p < 0.001; change after chemotherapy, Pearson correlation = 0.542, p < 0.001). Patients with higher pre-chemotherapy sPD-L1 ( > 1.3 ng/ml) showed worse OS (9.2 vs 16.2 m, p < 0.001). Both sPD-L1 (1.8 vs 1.0 ng/ml, p < 0.001) and sTGF-β (20.5 vs 11.6 ng/ml, p < 0.001) were increased significantly at the time of PD compared with pre-chemotherapy. Regarding changes after chemotherapy, increased sTGF-β after chemotherapy (Δ > 3.2 ng/ml) had worse prognosis (PFS: 5.1 vs 7.3 m, p = 0.024; OS: 9.2 vs 12.3 m, p = 0.028). This prognostic value of change of sTGF-β after chemotherapy was also significant in multivariable analysis with other clinical factors (PFS: HR = 1.78, p = 0.022; OS: HR = 1.86, p = 0.018). Conclusions: In BTC, there is a positive association between sTGF-β and sPD-L1 value in terms of baseline levels and changes after chemotherapy. sTGF-β could be associated with the survival, particularly, increased value after chemotherapy indicates worse prognosis.
Non-invasive detection of acquired resistance to FGFR inhibition in patients with cholangiocarcinoma harboring FGFR2 alterations.
Authors: Varghese Anna M. , Patel Juber Ahamad A , Janjigian Yelena Yuriy , Meng Fanli , Selcuklu S Duygu , Zimel Catherine , Hyman David Michael , Iyer Gopa , Houck-Loomis Brian , Abou-Alfa Ghassan K. , Berger Michael F. , Lowery Maeve Aine 
Published: May 2019

4096 Background: FGFR2 alterations are present in 14% of cholangiocarcinomas (CCA) and are promising targets of investigational FGFR-directed therapies. Cell-free DNA profiling has emerged as a non-invasive approach to monitor disease and longitudinally characterize tumor evolution. We describe the use of circulating tumor DNA (ctDNA) among patients (pts) with FGFR2-altered CCA receiving FGFR-targeted therapy in the identification of acquired FGFR2 mutations (mut) at resistance. Methods: Serial blood samples were collected from 8 pts with FGFR-altered CCA for ctDNA isolation and next generation sequencing. Plasma ctDNA collected at baseline and resistance to FGFR-targeted therapy were sequenced using a custom ultra-deep coverage cfDNA panel, MSK-ACCESS, incorporating dual index primers and unique molecular barcodes to enable background error suppression and high-sensitivity mut detection. The assay was enhanced to include all protein-coding exons and relevant introns of FGFR2. In 5/8 pts, genomic profiling of an initial tumor biopsy was performed. Results: 8 pts with FGFR2-altered CCA (7 gene fusions, 1 amplification) were treated with FGFR-targeted therapies. 7/8 pts exhibited stable disease or partial response. 19 total acquired mut in FGFR2 were detected at resistance in 5/8 pts (between 1-9 unique mut identified in each sample). All mut were located in the kinase domain. Conclusions: Acquired mut in FGFR2 are seen in pts who have developed resistance to targeted therapy. CtDNA can be used to identify these mut at the time of acquired resistance. The multitude of FGFR2 mut observed within individual pts suggest heterogeneity and evolutionary convergence of resistance mechanisms. Our results illustrate the utility of ctDNA as a less invasive way to monitor for signs of resistance and to identify other potential targetable alterations. [Table: see text]
A phase II study of nivolumab in patients with advanced refractory biliary tract cancers (BTC).
Authors: Kim Richard D. , Kim Dae Won , Alese Olatunji B. , Li Daneng , Shah Neal , Schell Michael J. , Zhou Jun Min , Chung Vincent 
Published: May 2019

4097 Background: Biliary tract cancers (BTC) are often typically diagnosed at an advanced stage. There is no established second line option for patients with advanced BTC who have failed one prior systemic therapy. The phase II study evaluated safety and efficacy of nivolumab, anti PD-1 antibody in refractory BTC patients. Methods: Pts with histologically proven BTC who progressed on at least one line but no more than three lines of systemic therapy received nivolumab 240mg IV q2weeks for 16 weeks and then 480 mg IV every 4 weeks until disease progression or unacceptable toxicity. The primary endpoint of the study was objective response rate (ORR) by RECIST 1.1 every 8 weeks. The Simon two staged design was used to assess ORR.18 patients were accrued and if one response was seen, the plan was to accrue additional 34 patients. Secondary endpoints were PFS, OS and safety profile. Results: At data cutoff (Jan 14, 2018), 54 patients with BTC (female: 50%, Median age: 65 years) were enrolled. The primary sites of tumor were intrahepatic cholangiocarcinoma (63%) extrahepatic (11%), and gallbladder (26%). 30 pts (56%) failed 1 line of therapy and 24 (44%) failed more than one line of therapy. 45 pts (1 pt withdrew consent, 1pt just enrolled prior to data cutoff and 7 pts came off the study due to clinical progression) were evaluable for response rate. Out of 45 pts, 10 pts (22%) achieved PR (1 unconfirmed PR) and 17 pts (37.8%) achieved SD. DCR was 60%. All patients who responded were microsatellite stable. For evaluable 45 pts with median follow up of 13.34 months, median PFS was 3.98 months (95% CI: 2.33-5.98) and the median OS was 14.22 months (95% CI: 6.64-NA). 6 and 12month OS was 71.4 and 52.3% and 6 and 12 month PFS was 35.2% and 24.1% respectively. Most common treatment related AEs (TRAE) was alkaline phosphatase increased (24.5%). Grade III/IV TRAEs were seen in 11 pts (20.4%); most common were hyponatremia (3 pts) and elevated alkaline phosphatase (2 pts). No treatment related AEs led to discontinuation of the study drug. Tissue samples were collected in all pts with planned correlative studies underway including the PDL 1 status. Conclusions: Nivolumab was well tolerated and has shown promising efficacy in refractory BTC including durable responses lasting 2 years. Further randomized trial is warranted in refractory BTC. Clinical trial information: NCT02829918.