Citations

TPS594 Background: Effective treatment options are very limited for patients with advanced refractory biliary tract cancer (BTC). Fluoropyrimidine-based chemotherapy regimen such as 5-fluorouracil and irinotecan are frequently utilized for these patients after first-line therapy despite lack of FDA approval. Trifluridine/tipiracil (FTD/TPI) is a novel oral nucleoside with antitumor activity in both fluoropyrimidine sensitive and resistant tumors due to its unique mechanisms of action. Given early toxicity and efficacy data from our previous study on single-agent trifluridine/tipiracil (FTD/TPI) in advanced BTC, the clinical evaluation of its combination with irinotecan represents a rational approach for the treatment of advanced refractory BTC. Methods: This is a single-arm phase II trial with a two-stage design to assess the efficacy of trifluridine/tipiracil (FTD/TPI) and irinotecan in advanced refractory BTC. Key eligibility criteria include histologically confirmed advanced, unresectable BTC who have progressed on at least one line of systemic therapy and have measurable disease per RECIST v1.1. Target accrual is 25. Treatment includes trifluridine/tipiracil (FTD/TPI) 25 mg/m2 on days 1-5 and irinotecan 180 mg/m2 on day 1 in 14-day cycles. Patients will be evaluated for response every 4 cycles and in the absence of disease progression, therapy may be given up to 2 years. The primary end point is the progression-free survival rate at 16 weeks. Secondary endpoints include overall response rate, disease control rate, progression-free survival, overall survival, and incidence of adverse events. Correlative biomarker studies include evaluations of circulating tumor DNA and circulating tumor cells at baseline, after 4 cycles and at progression; and development of patient-derived tumor organoids from pre-treatment biopsies for parallel treatments. This study was approved and funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Taiho Oncology, Inc. Clinical trial information: NCT 04072445.

TPS592 Background: For advanced CCA, standard of care 1L systemic treatment is GEM + CIS. Genetic alterations in intrahepatic CCA provide potential therapeutic targets. Fibroblast growth factor receptor (FGFR) 2 gene rearrangements driving CCA tumorigenesis were identified almost exclusively in intrahepatic CCA patients (pts) (incidence, 10–16%). In phase 2, PEM (INCB054828), a selective, potent, oral FGFR1–3 inhibitor elicited an objective response rate (ORR) of 35.5% and median progression-free survival (PFS) of 6.9 months (mo) in previously treated, locally advanced or metastatic CCA with FGFR2 rearrangements (NCT02924376). FIGHT-302, a randomized, open-label, phase 3 study will evaluate efficacy and safety of 1L PEM vs GEM + CIS in unresectable/metastatic CCA with FGFR2 fusions or rearrangements (NCT03656536). Methods: Eligible pts are adults with confirmed unresectable/metastatic CCA; no prior systemic therapy for advanced disease < 6 mo before enrollment; radiographically measurable/evaluable disease (per RECIST v1.1); ECOG PS ≤1; documented FGFR2 fusions or rearrangements. Exclusions include clinically significant corneal or retinal disorder; history of calcium and phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification; untreated CNS metastases or history of uncontrolled seizures. Pts will be randomized (1:1; stratified by region and tumor burden) to PEM 13.5 mg QD on a 21-day (d) cycle or GEM (1000 mg/m2) + CIS (25 mg/m2) on D1 and D8 of 21-d cycles (max 8). Crossover to PEM allowed after confirmed progression. PEM titration to 18 mg from cycle 2 allowed for pts without hyperphosphatemia (serum phosphate > 5.5 mg/dL) and Grade ≥2 treatment-related adverse events during cycle 1. Hyperphosphatemia will be managed with diet modifications, phosphate binders, diuretics, or dose adjustments. Treatment will continue until progression or unacceptable toxicity. Primary endpoint is PFS (by independent review). Secondary endpoints are ORR, overall survival, duration of response, disease control rate, safety, and quality of life. Four pts (target N = 432) are enrolled as of Sep 25, 2019. Clinical trial information: NCT03656536.

583 Background: Hepatocellular cancer (HCC) continues to grow in incidence despite approval of many new therapies including immune checkpoint inhibitors (ICIs) and TKIs. Genomic landscape of HCC is becoming increasing apparent through WGS and WES. One major driver of HCC is the Wnt/b-catenin pathway. Mutations in CTNNB1, which encodes for b-catenin, are evident in 26-37% of all human HCCs. However, expression of mutant-b-catenin in liver in mice is insufficient for HCC development. Indeed, analysis of HCC cases has revealed CTNNB1 mutations to significantly co-exist with other aberrations including activation/overexpression of Met and Myc and mutations in TERT promoter or mutations in NFE2L2/KEAP1, APOB and ARID2. Methods: Using sleeping beauty transposon/transposase and hydrodynamic tail vein injection, we co-expressed mutant-CTNNB1 (S45Y, S33Y or T41A) and one other clinically relevant co-occurrence to study significance and biology of HCC. Any novel findings in the preclinical model were validated in HCC patient cohorts. Results: Co-expression of mutant-CTNNB1 and one relevant co-occurrence led to development of HCC in mice in 6-10 weeks. All HCC in these models showed a dramatic increase in glutamine synthetase (GS), encoded by Glul, a known target of the Wnt/b-catenin signaling pathway in the liver. This led to an increase in glutamine levels in the tumor-bearing livers. Increased glutamine in the tumors in turn led to increased levels of phospho-mTOR-S2448, a marker of mTORC1 activation. In fact, examination of ~400 patient HCCs showed a significant correlation between positive GS and p-mTOR-S2448 staining. Treatment of Met-b-catenin model with Rapamycin led to notable and significant decrease in HCC burden. Conclusions: Our studydemonstrates b-catenin-mutated HCC to be positive for both GS and in turn mTORC1 active. This provides a novel opportunity for personalized medicine in HCC and CTNNB1-mutated HCCs may be vulnerable to therapeutic targeting by mTOR and more specially, mTORC1 inhibitors.

580 Background: Though studies indicate that the genomic profiles of ICC and ECC are distinct, the clinical features that differentiate them still remain to be well characterized. The purpose of this study was to further analyze these differences and patient treatment patterns in a multi-center cohort. Methods: A retrospective chart review was performed at 8 institutions on patients (pts) with ICC or ECC diagnosed after June 2009. Data on demographics, risk factors, treatments, pathology and overall survival (OS) were collected. Tumor genotyping results from CLIA-certified tissue assays were analyzed. Fisher’s exact, Wilcoxon rank sum and log-rank tests were used to compare sub-groups. Results: In a database of 737 pts with cholangiocarcinoma, 538(73%) had ICC and 199(27%) had ECC. Pts with ICC more often presented in later stages, had tumors > 5cm at resection (p < 0.0001) and had metastases to the liver, lymph nodes, lung and/or bone (p < 0.01). Pts with ICC more often received liver directed therapy, targeted therapy and multiple lines of systemic therapy and they more often enrolled in a clinical trial (all p < 0.01). Pts with ECC were more likely to be male, undergo surgery, receive adjuvant chemotherapy and/or chemoradiation (all p < 0.05). Mutation profiling performed in 381 (52%) pts (ICC/ECC = 301/80) showed that pts with ICC were more likely to have IDH1 mutations and FGFR2 fusions, whereas pts with ECC were more likely to have KRAS, APC, SMAD4, WNT, TGFb and TP53 mutations (all < 0.05). Factors that did not differ significantly between pts with ICC and ECC include race, rates of primary sclerosing cholangitis, median diagnosis CA19-9 levels and R1 resection rate. Median OS from diagnosis was 18.9 months in ICC and 17.3 months in ECC (p = 0.8471). Conclusions: While pts with ICC and ECC have some similarities in their clinical features, differences in metastases patterns and molecular profiling significantly impact their management such that pts with ICC receive more liver-directed therapy, targeted therapy and more lines of systemic therapy. Further prospective studies are needed as referral patterns to tertiary care centers may have impacted these results.

494 Background: Our aim was to compare survival between patients receiving neoadjuvant chemoradiation and orthotopic liver transplantation (OLT group) versus definitive chemoradiation (CRT group) for extrahepatic or hilar cholangiocarcinoma. Methods: 49 patients (20 in OLT group vs. 29 in CRT group) with unresectable hilar/extrahepatic cholangiocarcinoma were treated at Mayo Clinic Arizona between Feb. 1998–Sep. 2019. Treatment included external beam radiation therapy (median 4500cGy) and boost (median 900cGy) with either continuous 5-flurouracil (dose range 180–225 mg/m2) or capecitabine (dose range 825–1000 mg/m2 BID) prior to or without OLT. Radiation boosts were delivered with EBRT or bile duct brachytherapy. Patients were between 27.9–84.3 years (median 64.3) at diagnosis. 18 patients had previous diagnosis of PSC. Results: Between Feb. 1998–Sep. 2019, 31(63%) of 49 patients died by the end of follow-up. Of patients treated with neoadjuvant therapy and OLT, 7(35%) of 20 patients died. 24(86%) of 28 patients treated with definitive therapy died. The OLT cohort were younger (mean age 56.5 vs. 69.0 years), more likely to have PSC and UC (65% vs. 17%), and had a lower CA 19-9 (median 43 vs. 535)(P < 0.003). From the end date of radiation, median overall survival was 76.8 months vs. 15.6 months for the OLT and CRT groups, respectively. Survival rates at 3 and 5 years were 78% and 69% in the OLT group compared to 19% and 6% in the CRT group (HR 7.73; 3.04-19.65:(P < 0.0001)). Progression-free survival (89% vs. 30% at 3 years), and distant metastasis-free survival (88% vs. 66% at 3 years) favored OLT versus CRT alone (HR 5.74;1.12-29.34:(P < 0.02)). Univariate analysis demonstrated that the method of treatment (OLT vs. CRT) was the only variable associated with better clinical outcomes. Conclusions: In patients with unresectable extrahepatic/hilar cholangiocarcinoma, survival was higher in those who underwent chemoradiation and OLT. Patients who received definitive chemoradiation in the absence of OLT were expected to have worse overall, progression-free, and metastasis-free survival.

375 Background: Combination FP with P CT have become the standard of care for advanced G/GEJ cancer. Clinical trials in conjunction with practice, have adopted induction FP and P CT for 3-4 months (mos). In other GI malignancies, induction CT followed by maintenance CT (MTC) has been shown to improve patient (pt) outcomes compared to observation, with a decrease in treatment (trmt) related toxicities with induction therapy. However a maintenance approach in G/GEJ cancer has not been investigated in clinical trials. We investigated pt outcomes with metastatic G/GEJ cancer who received continuous induction (CTX) versus induction followed by MTC. Methods: A retrospective analysis of pts with metastatic G/GEJ adenocarcinoma treated with (FP+ P)-based CT between 2007 to 2017 from three centers of a single institution was performed. Metastatic G/GEJ cancer pts who achieved at least stable disease after initial induction trmt were included. Pts were categorized into the CTX group if they received greater than 16 weeks or 8 cycles of combined CT and assigned to the MTC group if they received maintenance FP monotherapy after 8 or less cycles of combined induction CT. Data was extracted from the medical record to determine progression free survival (PFS), overall survival (OS), and toxicities. Results: Sixty-four pts that met criteria and were evaluated, thirty-four received CTX and thirty received MTC. No significant difference in PFS (12.1 vs 8.0 mos p = .72, HR=1.10 95%CI .66-1.83) was observed between the CTX and MTC groups, additionally there was no significant difference in OS. A significant decrease in trmt related toxicities were observed, with a higher proportion of thrombocytopenia (84.8% vs 50.0% p = .004), and grade 3 neuropathy (39.4% vs 13.8% p =.024) in CTX pts (Table). Conclusions: MTC following induction FP/P CT is associated with an improved toxicity profile and appears to be effective compared to CTX in metastatic G/GEJ cancer. Prospective randomized studies confirming its potential benefits compared with continuous induction CT are warranted. [Table: see text]

Purpose of review To review new treatment and advances in biliary tract cancer (BTC). Recent findings In the prespecified per-protocol analysis of the randomized phase III trial BILCAP, adjuvant capecitabine offers overall survival (OS) benefit when compared with observation with statistical significance. In the first-line setting in metastatic BTC, gemcitabine and S-1 had noninferior OS compared with gemcitabine and cisplatin. In a separate phase III study, the triplet of gemcitabine, cisplatin and S-1 (GCS) had superior OS compared with standard gemcitabine and cisplatin. The regimen of modified FOLFOX (fluorouracil, leucovorin and oxaliplatin) regimen can be considered a potential standard option in the second-line setting for patients who failed first-line therapy with gemcitabine-based regimens. Trials in genomically selected patients indicate activity of fibroblast growth factor receptor inhibitors, mutant isocitrate dehydrogenase inhibitors and immune checkpoint inhibitors. Summary Capecitabine is a new option for adjuvant treatment in resected BTC. In the metastatic setting, gemcitabine and S-1 or GCS are new options for first-line therapy and modified FOLFOX regimen should be considered as a potential new empirical standard of care in genomically agnostic patients requiring second-line therapy. Future randomized trials will evaluate the role of targeted agents and immunotherapy in advanced BTC, both in monotherapy and in combination.

AbstractTrial InformationClick here to access other published clinical trials.Lessons LearnedTrifluridine/tipiracil (FTD/TPI) shows promising antitumor activity in heavily pretreated patients with advanced biliary tract carcinoma, including patients with 5-fluorouracil refractory tumors. FTD/TPI has an acceptable safety profile and should be studied further in patients with advanced biliary tract carcinoma after progression on standard first-line therapy.BackgroundPatients with advanced biliary tract carcinoma (BTC) refractory to first-line therapy lack an established second-line option. Trifluridine/tipiracil (FTD/TPI) has activity in both fluoropyrimidine-sensitive and -resistant tumors, which led us to conduct a single arm phase II trial to evaluate the safety and efficacy of FTD/TPI for patients previously treated for advanced BTC.MethodsPatients with advanced BTC previously treated with at least one line of chemotherapy were enrolled and treated with FTD/TPI until disease progression or unacceptable toxicity. The primary endpoint target was to have at least 6 patients who were progression free and alive at 16 weeks among 25 evaluable patients. Secondary endpoints included overall survival (OS), overall response rate (ORR), progression-free survival (PFS), and toxicity.ResultsOf 27 evaluable patients, 59.3% received at least three prior lines of therapy, and 81.5% had previous exposure to fluoropyrimidine. Eight (32%, 95% confidence interval [CI], 14.9%–53.5%) patients were progression free at 16 weeks in the primary analysis population (n = 25), which met the predefined efficacy criteria. Median PFS and OS were 3.8 (95% CI, 2–5.8 months) and 6.1 (95% CI, 4.4–11.4 months) months, respectively. No objective responses were seen. There were no unexpected safety signals noted.ConclusionFTD/TPI demonstrated promising antitumor activity, with acceptable toxicity, in heavily pretreated patients with advanced BTC.

Abstract Abstract 4723 Introduction: Combination G/A has been shown to be apromising investigational therapy for patients with metastatic pancreatic cancer. A randomized phase II trial was initiated to determine if ODSH, a low anticoagulant heparin derivative that blocks several pancreatic cancer cell survival pathways, would enhance the efficacy of G/A. Preliminary data from the first 10 patients administered ODSH demonstrated an unexpected and profound preservation of peripheral blood counts, despite the highly myelosuppressive G/A regimen they also received. Methods: Patients with previously untreated, metastatic pancreatic cancer were treated with G (1000 mg/m2) and A (125 mg/m2) on days 1, 8, and 15 every 28 days until either disease progression or unacceptable toxicities ensued. ODSH (4 mg/kg bolus followed by a 48 hr. continuous IV infusion at a dose of 0.375 mg/kg/hr for 48 hrs) was administered with each treatment. The first 10 patients received A/G plusODSH with plans for a randomized comparison between A/G with and without ODSH involving 50 patients. Patients were required to have ECOG 0–1 as well as adequate hematological and bilirubin level <1.5 ULN. G-CSF administration was permitted per investigator discretion. Here we present hematological data on the 10 patients treated with A/G plus ODSH. Results: 10 patients were administered up to 5 cycles of G/A plus ODSH. The patients had a median age of 66 years (range, 59 to 75 years) and 50% were male. The median platelet and neutrophil counts prior to each cycle are listed in Table 1. No patients had grade 3/4 thrombocytopenia during any of the cycles. Forty percent of patients had grade 3 neutropenia, but none had grade 4 during any of the cycles. Only 1 patient received 1 dose of G-CSF after day 15 in cycle #1. Conclusions: A previous trial of G/A in patients with previously untreated, metastatic pancreatic cancer reported grade 3/4 thrombocytopenia and neutropenia in 28% (19% grade 3 and 9% grade 4) and 75% (26% grade 3 and 49% grade 4) of patients, respectively (Von Hoff, J Clin Oncol, 2011). With the addition of ODSH to an equivalent chemotherapy regimen in a similar patient cohort, the current trial reported grade 3 thrombocytopenia and neutropenia in 0% and 40% of patients, respectively, with no patients having grade 4 thrombocytopenia or neutropenia. With successive cycles, median platelet counts were stable to improved and a trend existed for reduced neutropenia with ODSH treatment. An explanation for the apparent salutary effects of ODSH on marrow function may involve its interaction with platelet factor 4 (PF4). PF4 is released from the alpha-granules of injured megakaryocytes after chemotherapy delivery. Increased PF4 levels promote thrombocytopenia by inhibiting thrombopoietin production and megakaryopoiesis (Lambert, Blood, 2007; Lambert, Int J Radiation Oncology Biol Phys, 2011). The high molecular weight and strong negative charge of ODSH may result in avid binding to platelet factor 4 (PF4), possibly leading to decreased PF4 levels and more rapid post-chemotherapy platelet recovery (Joglekar, Thromb Haemost, 2012). PF4 may also facilitate neutrophil adhesion to endothelial cells, and reduced PF4 levels from ODSH binding may demarginate and preserve neutrophil values (Kasper, Blood, 2006). Further study of ODSH as a marrow protective agent in myelosuppressivechemotherapy regimens is warranted. Disclosures: Off Label Use: The use of nab-paclitaxel and ODSH in pancreatic cancer. Marcus:Paringenix: Employment, Equity Ownership. Quintana Diez:Paringenix, Inc.: Employment.