Citations

TPS545 Background: Advanced cholangiocarcinoma (CC) is a life-threatening disease with limited effective chemotherapy options. Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in 13–15% of CC cases, and up to 25% of intrahepatic CC cases, leading to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite 2-hydroxyglutarate (2-HG). AG-120 (ivosidenib), a first-in-class oral mIDH1 inhibitor, displayed a favorable safety profile and clinical activity in a phase 1 study enrolling 73 mIDH1 CC patients who had received ≥1 prior systemic regimen. As of 10 Mar 2017, 4/73 (5%) had a partial response and 41/73 (56%) stable disease. Progression free survival (PFS) rates at 6 months and 12 months were 38.5% and 20.7%, respectively. The 500 mg once daily dose level of AG-120 was selected for further development in mIDH1 CC. Methods: ClarIDHy is a global, phase 3, multicenter, double-blind, randomized (2:1) study of AG-120 (500 mg once daily) vs. matched placebo in 186 mIDH1 CC patients (ClinicalTrials.gov NCT02989857). Key eligibility criteria: non-resectable or metastatic CC, documented mIDH1 by central laboratory testing, ECOG performance status 0–1, measurable disease (RECIST v1.1), documented disease progression after ≤2 prior systemic therapies in the advanced setting including at least 1 gemcitabine- or 5-fluorouracil-containing regimen, and no prior mIDH inhibitor therapy. Crossover from placebo to AG-120 will be allowed at time of radiographic disease progression. Primary endpoint: PFS assessed by independent radiologists. Secondary endpoints: safety, tolerability, overall response rate (RECIST 1.1), overall survival, pharmacokinetic/pharmacodynamic analyses, and quality of life (EORTC QLQ-C30 and QLQ-BIL21 scales). An independent data monitoring committee will monitor the data during study conduct. The ClarIDHy study is currently activated at participating sites in the US, UK, EU, and S. Korea. R eused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2017 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT02989857.

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.

TPS532 Background: Recent studies have shown that FGFR2 fusions may represent recurrent (prevalence ~10-15% in larger cohorts) driver events amenable to therapeutic targeting in patients with advanced, intrahepatic cholangiocarcinoma. Methods: This single arm pilot study (NCT02265341) is being conducted at 3 centers (Mayo Clinic Arizona, Mayo Clinic Florida and Mayo Clinic Rochester; enrollment initiated December 2014). Next-generation sequencing based assays and a FISH-break apart assay are used to identify tumors with FGFR2 fusions. Patients must additionally have histologically/cytologically confirmed cholangiocarcinoma, ECOG performance score 0-2, measurable disease, preserved hematologic/renal and hepatic function and absence of cardiac events/stroke in the preceding 6 months. Ponatinib is administered at 45 mg once daily. Patients will be treated until disease progression, intolerable toxicity or patient decision to not pursue further therapy. The primary objective of the study is to estimate the clinical benefit rate (defined as composite of partial response rate, complete response rate and stable disease rate ≥ 4 months; as defined by RECIST criteria v1.1). Secondary endpoints include estimation of progression-free survival, overall survival, CA19-9 response rate (defined as > 50% reduction from baseline) and evaluation of the overall adverse event profile of ponatinib in this patient population. Translational objectives include serial circulating DNA (ct-DNA) monitoring, target knockdown assessments in tumor tissue (p-FGFR2, p-FRS2, p-Akt and p-ERK) and evaluation of mechanisms of resistance through comparison of baseline and progression biopsy samples using multi-platform sequencing (exome, RNA-Seq and methyl-Seq). Additionally, quality of life assessments will be evaluated using EORTC-QLQ-C30 and BIL21 tools. A total of 30 patients will be enrolled into the study (12 of 30 patients have been enrolled). The trial is designed using an underlying assumption of clinical benefit rate (CBR) of 5% with significance level of 0.15 and 80% power to detect a 20% CBR. Clinical trial information: NCT02265341.

358 Background: Effective therapy for the treatment of PDAC remains one of the greatest unmet oncology clinical needs. The addition of C to G and AP has shown promising clinical data in a previously reported study [J Clin Oncol 35, 2017 (suppl 4S; abstract 341)]. In preclinical work, vitamin D (Vit D) analog therapy decreases myeloid derived suppressor cells and regulatory T cells, turning PDAC into a more immune-friendly microenvironment. This trial combines AP/C/G with Vit D analog P and the anti-PD-1 antibody N as a combination therapy for patients with previously untreated metastatic PDAC. This trial evaluates the efficacy and safety of NAPPCG in that patient population (NCT02754726). Methods: Eligibility criteria include Stage IV PDAC, no prior chemotherapy for systemic disease, KPS ≥ 70, and measurable disease. Doses are AP 125 mg/m2 undiluted, G 1000 mg/m2 in 250 ml of normal saline (NS), each infused over 30 minutes with C 25 mg/ m2 in 500 ml of NS infused over 60 minutes on days 1, 8, 22, and 29 of a 42-day cycle. N is given at a fixed dose of 240 mg as a 60 minute infusion on days 1, 15, and 29. P is given at a fixed dose of 25 µg IV twice weekly. Primary objective is to determine the efficacy of the combination for patients with previously untreated metastatic PDAC through determining CR, ORR, PFS, and OS. The secondary objective is to evaluate safety in patients with previously untreated metastatic PDAC. Results: Trial was initiated May 2016 and10 patients have been enrolled in the initial phase of the study and are evaluable (baseline and ≥1 follow up CT scan). Most common drug-related grade (Gr) 3-4 adverse events (AE’s), n = 10, are thrombocytopenia 100% (gr 3 = 50%, gr 4 = 50%) with no serious bleeding events, anemia 50% (gr 3 = 50%, gr 4 = 0%), and colitis 20% (gr 3 = 20%, gr 4 = 0%). By RECIST 1.1 criteria, the best response is 8 PR and 2 SD, yielding an 80% ORR. Median PFS is 8.2 months. Median OS has not been reached. Conclusions: Although a small study, the high response rate is encouraging. This regimen is being expanded to 25 patients with plans to include exploratory inflammatory biomarkers. Clinical trial information: NCT02754726.

355 Background: In this study, we sought to determine the prognostic factors impacting survival of patients with NELM who underwent LT at Mayo Clinic. Methods: We performed a three-site retrospective analysis of patients with unresectable NELM treated with LT from 1990 -2017. Cases were identified from clinical databases at Mayo Clinic. Data on demographics, timing of diagnosis and transplant, extent of liver involvement, and tumor grade, were extracted. Extent of liver involvement was calculated using previously validated standardized volumetry with high defined as > 25% increase in the weight of the extracted liver at the time of the transplant as compared to the standard liver volume. Survival was calculated using the Kaplan–Meier method. Results: We identified 37 patients. Median age at LT was 47 (range 17.0-64.0), male: female (73% vs. 27%, respectively). Primary tumor site was in the pancreas in 51.3% and in the small bowels in 43.2%; 78.4% had NELM at presentation. While primary tumor resection was done at the time of LT in 5 (13.9%) cases, most patients (80.6%) had ˃6-months interval between primary tumor resection and LT surgery. Prior to LT, 25 (74.3%) patients received somatostatin analogues and 18 (61.3%) had liver-directed therapy. Median time from diagnosis to transplant was 33.6 months (0-246). High extent of liver involvement was identified in 12 patients (33.3%). Disease-Free Survival (DFS) at 3, 5, and 10 years was 56.8%, 43.1%, and 22.4% respectively. Overall-survival (OS) at 3, 5, and 10 years was 86.9%, 79.6%, and 52.6% respectively. High extent of liver involvement at the time of transplantation was associated with inferior DFS and OS and patients˃45 years-old at the time of transplantation had worse DFS. Patients whose disease met the OPTN (Organ Procurement and Transplantation Network) criteria for NELM transplantation had significantly better DFS and OS with median 10-year OS of 80.7 % vs. 17%. Conclusions: LT is a reasonable therapeutic option for selected patients with unresectable NELM with 10-year OS of 52.6%. High extent of liver involvement was associated with worse long-term outcomes while meeting OPTN criteria resulted in best outcomes.

350 Background: BTCs are often diagnosed at an advanced stage and have a poor prognosis. The standard therapy for aBTCs is the combination of GC. However, the median overall survival (mOS) is dismal at 11.7 months (mos) with a median progression free survival (mPFS) of 8 mos. Methods: A single arm, phase II study was conducted at MD Anderson and Mayo Clinic Arizona. Patients (pts) with aBTC were treated at initial dose level of G/C/N (in mg/m2) at 1000/25/125 (n = 30) which was reduced to lower doses due to grade 3/4 hematological (heme) toxicity (tox) - G/C/N: 800/25/100 (n = 30). Cycles were q21 days with restaging q3 cycles until progression. PFS was the primary endpoint (endpt). Using a Bayesian hypothesis test-based design, we assumed mPFS of 8 mos under the null hypothesis (H0), 10 mos under the alternative (H1). Secondary endpts included mOS, RECIST v1.1 response rate (RR), safety and CA19-9 response. Results: 60 pts were enrolled with 51 being response-evaluable having received more than 1 cycle of therapy (age: median 60 yrs [range 31-77], ECOG PS 0/1 (22/38), M/F (33/27), intrahepatic cholangiocarcinoma/extrahepatic/gallbladder (38/9/13). Median follow-up was 14 mos and median number of treatment (trmt) cycles = 5.24. Pts at initial dose level had significant grade 3/4 heme tox: neutropenia, febrile neutropenia, anemia, and thrombocytopenia leading to trmt discontinuation in 6/30 pts. After dose reduction to G/C/N (in mg/m2) at 800/25/100, trmt was better tolerated with only 3 pts experiencing grade 4 heme tox. Non-heme tox were grade 3 in 19 pts: nausea/vomiting, diarrhea, thromboembolic event/CVA, hypokalemia, constipation, cystitis, LFT elevations. The mPFS = 11.4 mos (95% CI: 6.1, 16.1) and mOS = 19.2 (95%CI: 13.6, NA), 1-year survival rate 67.6%. 51 pts evaluable for response: disease control rate (PR+CR+SD)-84.3% and RR-39%. 12 unresectable cases were operated post trmt with 1 pathologic CR. Conclusions: The combination of GCN was well tolerated at adjusted doses and demonstrates encouraging efficacy having met its mPFS endpt and an impressive mOS higher than historical control. These results merit evaluating GC +/-N in a randomized controlled study. Clinical trial information: NCT02392637.

328 Background: Patients with a history of solid organ transplants have been excluded from PD-1/PD-L1 inhibitor clinical trials due to concern for graft rejection. Only 2 case reports of PD-1 inhibitor use in patients with liver transplantation (LT) have been reported thus far. Here, we report our experience with using checkpoint inhibitors in metastatic cancer patients with LT. Methods: A single center pilot evaluation was conducted to evaluate the safety and efficacy of PD-1/PD-L1 inhibitors in patients with LT. PD-L1 staining on both the tumor and allograft were assessed if there was available tissue. The primary endpoint was evaluation of the risk for allograft rejection. Secondary endpoints included RECIST v1.1 and Immune-Related Response criteria (iRC) response rates, progression free survival (PFS) and overall survival (OS). Translational objectives included the relationship of PD-L1/PD-1 staining of tumor/allograft with response and rejection. Results: Six metastatic cancer patients with a history of LT received PD-1 inhibitor therapy (hepatocellular n=5, melanoma n=1). 3 patients were on mTOR inhibitor as immunosuppressive regimen and 3 on calcineurin inhibitor. Overall, allograft rejection was observed in 1/6 patients (on mTOR inhibitor). One patient achieved a CR (melanoma), 3 patients had PD and 2 patients discontinued therapy prior to restaging assessments. A single response (by both RECIST v1.1 and iRC) and rejection were reported in patients who received mTOR inhibitors (1 of 3). Three patients were tested for PD-L1 staining in the allograft tissue and all of them were negative (0% staining) with no graft rejections observed. Four patients had tumor PD-L1 evaluated (2 patients tested positive with 1 patient obtained a CR). The median OS, PFS and duration of therapy were 1.2, 1.8 and 1.2 months respectively. Conclusions: In this pilot evaluation of PD-1/PD-L1 inhibitors in LT patients both preliminary efficacy (1 of 4) and allograft rejection (1 of 6) was exhibited. Larger, prospective trials are needed to elucidate optimal patient and immunosuppressive regimen selection in these patients.

293 Background: Cholangiocarcinoma (CCA) is a deadly cancer with ~20% five year survival. Obtaining tissue to confirm diagnosis of CCA is often challenging. This also limits the use of tumor genotyping that could guide potential molecularly targeted treatment (such as FGFR inhibitors for a subset of cases). We investigated whether circulating tumor DNA (ctDNA) analysis in plasma is feasible for noninvasive tumor genotyping in patients with advanced CCA. Methods: We collected and processed plasma samples for ctDNA analysis from 17 patients with CCA at presentation and from 11 healthy volunteers. Following cell-free DNA extraction and quality assessment using digital PCR, we performed low-pass, shallow whole genome sequencing (sWGS). We analyzed sequencing data to identify copy number aberrations and quantify tumor fraction in plasma using recently published computational approaches. Results: Median total cfDNA concentration in patients with CCA was 7,003 genome equivalents (GEs)/mL plasma (range: 1,512- 107,707 GEs/mL) and significantly higher than healthy volunteers (two tailed t-test p < 0.04, median: 1,658 GEs/mL, range: 661-4,938 GEs/mL). We successfully sequenced all tumor libraries, generating a median of 173 million paired-end reads. ctDNA was detectable in 10/17 samples using sWGS. In these 10 samples, median tumor fraction in plasma DNA was 7.1% (range: 3.9%-44.6%). We found recurrent copy number aberrations expected in CCA including 1q gain in 80%, 7p gain in 50%, 1p loss in 70% and 3p loss in 50% of cases. Conclusions: ctDNA analysis for noninvasive tumor genotyping is feasible in patients with advanced cholangiocarcinoma. On-going work is focused on expanding these results using targeted and whole-exome sequencing.

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.

263 Background: DNA repair genomic alterations (GAs) have been identified in 12% of Intrahepatic cholangiocarcinoma (IHCCA), 26% of extrahepatic CCA (EHCCA) and 8% of gallbladder cancer (GBC) patients (pts) ( Cancer 2016;122:3838–3847). Recently, the Cancer Genome Atlas (TCGA) has described more than 20 mutated DNA repair genes, many of which were not previously represented in prior reports. DNA repair GAs including MSI are associated with higher tumor mutational burden (TMB). Our study aim is to identify variations in the frequency of DNA repair GAs in IHCCA, EHCCA, and GBC. Methods: Hybrid capture-based next-generation sequencing of 422 fixed formalin paraffin embedded (FFPE) tissue blocks of BTC including; 270 IHCCA, 60 EHCCA, and 92 GBC was performed. We included 20 DNA repair genes and classified them as "direct" DNA repair genes ( ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, RAD50, SLX4) and "caretaker" genes that induce genomic instability ( BAP1, CDK12, MLL3, TP53, BLM). We calculated TMB on 1.1 Mb of sequenced DNA in 205 tissue specimens [138 IHCCA, 23 EHCCA, and 44 GBC] and classified into three groups; high (TMB-H; ≥ 20 mut/Mb), intermediate (TMB-I; 6-19mut/Mb) and low (TMB-L; < 6mut/Mb). Results: A distinct pattern of DNA repair GAs in each tumor type was detected. (Table 1). DNA repair GAs were more commonly noted in both EHCCA and GB (63%) as compared with IHCAA (45.2%) (p= .002). Direct DNA repair GAs were highest within EHCCA (25%), while indirect DNA GAs were predominant in GBC (59.8%) (p= 0.04 and 0.001, respectively). The frequency of TMB-H and TMB-I differed significantly between BTC subtypes. Pts with EHCCA and GBC had significantly higher TMB-H and TMB-I versus IHCCA. Conclusions: The frequency of DNA repair GA’s is higher in EHCCA and GBC as compared with IHCCA. These results may have implications for clinical trials with DNA repair inhibitors and immune checkpoint blockers. [Table: see text]