Pancreatic Cancer Pts Research Articles

FOLFIRINOX in pancreatic cancer patients age 75 years or older.

362 Background: Although FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS) (11.1 vs 6.8 months [m] with gemcitabine, P < 0.001), pts > 75 yrs old were excluded from this study. As per SEER 2011-2015 data, 38% of new PC cases are diagnosed in pts age > 75. The purpose of this study was to assess the safety and efficacy of FOLFIRINOX in this group of pts. Methods: We retrospectively analyzed unresectable PC pts, age ≥ 75, treated with FOLFIRINOX at MD Anderson since 2011. Data obtained include demographics, line of treatment (tx), starting dose, progression free survival (PFS), OS and toxicities. Response was determined by chart documentation. Primary outcomes were mOS and rates of grade 3/4 hematologic toxicity (HT). Results: A total of 24 pts (19 male) were included with median age of 76 (range 75 to 84). 18 had metastatic disease, and FOLFIRINOX was the 1st line of tx for 18 of the 24 pts. The median number of cycles administered was 4 (range 1 to 12). The most frequent starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Bolus 5-FU and leucovorin were omitted in all but 3 pts. Median PFS was 3.7 m (95% CI: 3.0-5.7) with mOS of 11.6 m (95% CI: 6.14-15.7). 16 pts (67%) experienced disease control (response to tx or stable disease). Grade 3 or 4 HT occurred in 11 pts (46%), and 9 (38%) were supported with granulocyte colony-stimulating factor at some point during tx. 6 pts (25%) required hospital admission for any toxicity, most commonly infection (3 pts), and 10 (42%) stopped FOLFIRINOX due to toxicity, most commonly fatigue (6 pts). Conclusions: In this single-center retrospective analysis of 24 unresectable PC pts age 75 or older given FOLFIRINOX, OS outcomes were similar to those reported by Conroy et al in the original trial which excluded pts older than 75. In our review, toxicities including incidences of grade 3 or 4 HT were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar efficacy and toxicity when compared to younger pts.

Impact of new chemotherapy regimens on the treatment landscape and survival of advanced pancreatic cancer (PAC) patients (pts).

403 Background: The clinical phase III first-line trials MPACT and PRODIGE4/ACCORD11 in metastatic PAC pts have changed the treatment paradigm. We aimed to analyse the impact of these regimens on the treatment landscape and survival of advanced PAC pts. Methods: In this single institutional retrospective cohort analysis patient characteristics and overall survival (OS) from all pts with advanced PAC treated between 01/2011-12/2017 were analysed. Survival analyses were performed by Kaplan-Meier method. Results: A total of 301 pts started a systemic treatment in the observation period. Concerning the first-line treatment, there was a clear shift from four different main regimens (gemcitabine/nab-paclitaxel (G+nab-P), FOLFIRINOX, gemcitabine/oxaliplatin +/- erlotinib, gemcitabine mono) to only two (G+Nab-P, FOLFIRINOX), that made up more than 80% of the administered first-line treatments in each of the groups (2011-2013 vs. 2014-2017). The rate for first-line FOLFIRINOX treatment was balanced between the two groups (19% and 15%). G+nab-P treated pts had a median age of 66 years, 41.3% had an ECOG 1-2, the FOLFIRINOX treated pts were younger and fitter (57 years and 24.5 % ECOG 1, 0% ECOG 2). 60.7% of pts treated with G+nab-P received a second-line and 30.7% pts received a third-line treatment, while for the FOLFIRINOX pts these rates were 69.8% and 41.5%. Median OS of pts that started first-line treatment between 2011 and 2013 was 8.77 months (95% CI 6.98-10.57) and for those that started first-line treatment between 2014 and 2017 median OS was 11.07 months (95% CI 8.94 13.20) (p = 0.038, Log-Rank-Test). Conclusions: There is a clear impact of new chemotherapy regimens on the treatment landscape. Furthermore, we provide real-world evidence that since the introduction of these new treatment options, the survival of pts with advanced PAC has significantly improved.

Impact of glycemic control on treatment efficacy and safety during nabpaclitaxel plus gemcitabine therapy in unresectable pancreatic cancer.

337 Background: Diabetes mellitus (DM) and hyperglycemia have been widely considered to be associated with the risk of pancreatic cancer. However, the aim of this study was to evaluate the relationship between glycemic control and the efficacy or safety in pancreatic cancer pts receiving treatment with nab-Paclitaxel (nab-PTX) plus Gemcitabine (GEM). Methods: We retrospectively reviewed 285 pts with unresectable pancreatic cancer with nab-PTX plus GEM as the first-line chemotherapy from December 2014 to March 2017 at the National Cancer Center Hospital East, Kashiwa, Japan. The pts were divided into two groups, average blood glucose level during the period of chemotherapy was less than 160 mg/dL (Group GC: Good glycemic control group) and more than 160 mg/dL (Group PC: Poor glycemic control group). Results: A total of 285 pts were enrolled. Median age was 66 years (range: 26-84) and males/females: 180/105, PS (0-1/2-3): 272/13, stage (III/IV): 77/208. There were 226 pts in GC group and 59 pts in PC group. No significant differences were seen in the overall survival between Group GC and PC (median: 16.1 months vs. 13.8 months, p = 0.344) and in the progression free survival between the two groups (median: 7.5 months vs. 8.2 months, p = 0.862). The incidence rate of grade 2-3 chemotherapy-induced peripheral neuropathy (CIPN) was significantly higher in Group PC compared with Group GC (Group GC 28.3%, Group PC 45.8%, p = 0.010). Univariate and multivariate analyses identified glycemic control as significant independent factors associated with the incidence of grade 2-3 of CIPN (Odds ratio 2.182, 95% CI 1.20-3.96, p = 0.010). There was no significant difference in the relative dose intensity of nab-PTX between two groups (median, 56.6% in group GC, 56.5% in group PC, p = 0.952). Conclusions: Glycemic control during the chemotherapy with nab-PTX plus GEM in unresectable pancreatic cancer was not associated with OS. The incidence of severe CIPN was higher in pts with poor glycemic control compared with good glycemic control.

Implementing universal genetic counseling (GC) and multigene germline testing (MGT) for pancreatic cancer (PC) patients (pts).

1512Background: MGT will identify cancer susceptibility gene variants in 4-10% of unselected PC pts. Such data have prompted calls for universal GC and MGT of all PC pts, but the real-world benefit...

Clinical assessment of pancreatic cancer cases with thromboembolism complications.

495 Background: Cancer patients, particularly those with pancreatic cancer (PC), have an increased risk of developing thromboembolism, such as venous thromboembolism (VTE) and cerebral infarction (CI). Moreover, thromboembolisms in cancer are associated with poor prognosis. The purpose of this study was to investigate the clinical characteristics, clinical courses, and prognosis of PC patients (pts) with VTE and/or CI. Methods: We retrospectively reviewed the medical records of PC pts who were radiologically diagnosed with VTE and/or CI at our institution. We investigated the patients’ clinical information and evaluated overall survival (OS), which was defined as the date from diagnosis of VTE and/or CI to the date of death by any causes or censored. Results: Between January 2012 and December 2015, 100 pts were diagnosed with PC. A total of 14 pts developed VTE and/or CI at our institution. All 14 pts had unresectable advanced or metastatic PC, 10 pts (71%) were men, and the median age at the time of VTE and/or CI diagnosis was 68.8 (range, 29–84) years. Complications of VTE and CI developed in 6 (43%) and 8 pts (57%), respectively (3 pts with development of both VTE and CI were included as CI). The median OS in pts who developed VTE and CI was 7.59 and 1.48 months (p = 0.007), respectively. After the development of VTE and/or CI, 5 pts (36%) (3 with VTE and 2 with CI) received chemotherapy (CTx), while the remaining 9 pts (64%) received best supportive care (BSC). In pts with VTE, the median OS of those who received CTx and BSC was 7.59 and 3.15 months (p = 0.221), respectively. Meanwhile, in pts with CI, the median OS of those who received CTx and BSC was 3.84 and 1.48 months (p = 0.113), respectively. Conclusions: The prognosis of PC pts who developed CI as complications was significantly poorer than those who developed VTE. However, in both cases, treatment with CTx prolonged the OS of these patients.

Molecular and clinical characterization of BRAF mutations in pancreatic ductal adenocarcinomas (PDACs).

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.

Nab-paclitaxel plus gemcitabine in the treatment of metastatic pancreatic cancer: our experience

Background: Pancreatic cancer (PA) is the fourth most fatal cancer for both man and women. Many of patients(pts) with metastatic disease are often not included in clinical trials due to comorbidity such as diabetes, jaundice, etc.and poor performance status at diagnosis. These patients are the most treat in our clinical practice and they have few opportunities for cure. Von Hoff D. et all. (2013) published the data of the phase III MPACT study showing a statistically significant benefit of the nab-paclitaxel plus gemcitabine vs gemcitabine alone in terms of OS (8,5 vs 6,7 months) and PFS(5,5 vs 3,7months) as first line treatment for metastatic disease with acceptable toxicity. Materials and methods: From September 2015 to May 2017 we collected the data of 26 unselected metastatic pancreatic cancer pts treated with nab-paclitaxel 125mg/mq and gemcitabine 1g/mq on days 1,8,15 q 28 days cycle, as first line treatment. Median age was 64 year (range 46-78); 9pts (34%) were over 70 years old. 9pts(34%) were male and 17(65%) female. PS 0: 10pts(38%), PS1:10pts(38%), PS2:6pts(23%). NLR was > 5 in 6pts(23%). They received a median of 15 drug administrations (range 1-32). Results: The treatment was well tolerated. No toxic death or grade 4toxicity were recordedHematologic G3 toxicity included: Neutropenia 4pts (15%), Thrombocytopenia 4pts(15%). Non Hematologic G3 toxicity included: Neuropathy 1pts (3%), Asthenia 2pts (7%). ORR was 38%(10/26), DCR(PR+SD) was 53%(14/26), median PFS was 6 months (range 1-12), median OS was 9 months (range 2-18). 38%(10/26) of pts received a second line treatment. Conclusion: We believe that nab–paclitaxel plus gemcitabine is an active and discreetly tolerated schedule and that the literature data can be reproduced in clinical practice in unselected pts with metastatic disease.

TAS-118 (S-1 plus leucovorin) versus S-1 in gemcitabine-refractory advanced pancreatic cancer: A randomized, open-label, phase III trial (GRAPE trial).

4099 Background: Addition of oral leucovorin (LV) to S-1 significantly improved progression-free survival (PFS) in a previous randomized phase II trial in Japanese patients (pts) with gemcitabine (GEM)-refractory advanced pancreatic cancer (PC). TAS-118 is an oral drug containing S-1 and LV. This phase III trial conducted in Japan and Korea compared overall survival (OS) between GEM-refractory advanced PC pts treated with TAS-118 and S-1. Methods: GEM-refractory PC pts were randomized in a 1:1 ratio to receive TAS-118 (S-1; 40-60 mg and LV; 25 mg bid for 1w, q2w) or S-1 (S-1; 40-60 mg bid for 4w, q6w). The primary endpoint was OS. The secondary endpoints included PFS, overall response rate, disease control rate, duration of response, and safety. Results: Five hundred and eighty-six pts were eligible for efficacy assessment (TAS-118: n=296 and S-1: n=290). Baseline characteristics were well balanced between the treatment arms. TAS-118 did not result in a statistically significant improvement in OS compared with that achieved with S-1 (median OS, 7.6 months vs. 7.9 months; hazard ratio [HR], 0.98; 95% CI, 0.82 to 1.16; P=0.756). However, it significantly improved PFS compared to that achieved with S-1 (median PFS, 3.9 months vs. 2.8 months; HR, 0.80; 95% CI, 0.67 to 0.95; P=0.009). Pre-planned subgroup analysis of OS showed significant interactions between the treatment effects and pancreatic resection (P=0.025), and between the treatment effects and country (P=0.004). Grade 3/4 drug-related adverse events (≥5% incidences) in TAS-118 and S-1 arms included diarrhea (7.0% vs. 7.3%), anorexia (6.7% vs. 5.0%), stomatitis (6.7% vs. 0.7%), and anemia (3.3% vs. 5.0%). Conclusions: The primary endpoint was not met. Further, the interactions between the treatment effects and pancreatic resection, and between the treatment effects and country, might affect the results. Clinical trial information: 132172. [Table: see text]

Prevalence of homologous recombination deficiency among all tumor types.

1502 Background: Triple negative breast and ovarian cancer are known to have a high frequency of homologous recombination deficiencies (HRDef). The prevalence of HRDef among all tumors is unknown. Methods: Molecular profiles of 48,733 tumors obtained from pts with bladder, breast, ovarian, pancreas, prostate, thyroid, cervical, hepatobiliary, colorectal (CRC), endometrial, gastric/esophageal (GE), head/neck, renal, non-small cell lung (NSCLC), small cell lung (SCLC), GIST, glioma, melanoma, sarcoma and unknown 1° cancers were reviewed to identify somatic pathogenic mutations (mut) in HR genes ATM, ATRX, BARD1, BLM, BRCA1/2, BRIP1, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51, RAD51B, or WRN. Molecular profiles were generated from tumors submitted to Caris Life Sciences using multiple technologies including next generation sequencing (average read depth 500X). Results: Overall frequency of HR mut among all tumors is 11.61% (5658/48733). Cancer lineages with highest frequency of HR mut are endometrial (38.08%, 1956/5137), glioma (15.90%, 265/1667), ovarian (12.99%, 1151/8862), prostate (11.21%, 77/687), cervix (10.06%, 79/785) & breast (9.66%, 562/5818). Least commonly mutated lineages include GIST (1.50%, 3/200), sarcoma (3.12%, 55/1763), head/neck (3.70%, 24/648), hepatobiliary (4.72%, 39/827) & pancreas (5.05%, 102/2022). Frequencies of HR gene mutations are depicted in Table 1. Conclusions: HR mutations were seen in 11.61% of tumors. While the percentage of HRDef in pancreatic cancer pts is lower than what has been seen in other datasets, the percentage in breast and ovarian cancer, as well as the percentage of other tumors with HRDef, provide a path to employ HRDef-directed therapies such as platinums, but especially PARP inhibitors and newer agents such as ATRX inhibitors. [Table: see text]

Modified IPCW model: A method for adjusting for bias in the estimation of overall survival due to the use of second and third line therapies in locally advanced or metastatic pancreatic cancer patients.

e15787 Background: Nimotuzumab, a unique and affinity differentiated anti-EGFR antibody had been used in combination with gemcitabine on the treatment of pancreatic cancer patients. The aim of the study was to evaluate overall survival. Methods: Patients with newly diagnosed, locally advanced or metastatic pancreatic cancer, KPS ≥ 70 %, 18-72 years old, with adequate renal and liver function were included. Pts received gemcitabine 1000 mg/m2and nimotuzumab or placebo fixed dose of 400 mg once a wk, for 3 wks, followed by a 1-wk rest (d1, 8, 15, q28) until disease progression or unacceptable toxicity. The primary endpoint was OS and secondary PFS, ORR, CBR, safety and QoL. For OS determination, a KM log-rank test was used and a modified IPCW with a cox regression as a secondary analysis. On this evaluation using a modified IPCW model, 41.7% of pts from treatment arm and 42.7% from control arm who received 2nd and 3rd line treatment were censored after progression, while pts that did not receive 2nd and 3rd line treatment were weighted to compensate for the bias created by censoring switchers to 2nd and 3rd line treatment. Results: 192 pancreatic cancer pts were recruited. Ninety-six pts (62 male and 34 female) with a median age of 67 years, range (31, 83) were randomized to treatment arm and 96 pts (57 male and 39 female) with a median age of 64 years, range (41, 82) were randomized to control arm. In the primary analysis, median OS [95% CI] in the treatment arm was 8.57 mo [5.93, 10.90] vs 6.03 mo [4.97, 7.60] in the control arm. The HR [95% CI], 0.83 [0.62, 1.12] and p = 0.23 and when a modified IPCW model as a secondary analysis was used to remove the effect of 2nd and 3rd line therapies, the median OS was statistically significant with a HR [95% CI], 0.81 [0.67, 0.98] and a p = 0.030. The median PFS [95% CI] was 4.43 mo [3.67, 6.00] in the treatment arm vs 3.47 mo [2.60, 4.03] in the control arm with a HR [95% CI] 0.68 [0.51, 0.92] and p = 0.012. Conclusions: A modified IPCW model had proven that addition of nimotuzumab to gemcitabine increases median overall survival of newly diagnosed chemotherapy-naïve locally advanced or metastatic pancreatic cancer patients. Clinical trial information: NCT00561990.

A phase 1b study of ruxolitinib (Rux) + gemcitabine (G) ± nab-paclitaxel (N) in patients (pts) with advanced solid tumors.

439 Background: Aberrant activation of the JAK-STAT pathway has been associated with increased malignant cell proliferation and survival. Rux, a potent JAK1/2 inhibitor, was evaluated in combination with G±N in advanced solid tumors. Methods: This was an open-label study of Rux + G, without N (regimen A) or with N (regimen B) in advanced solid tumors. The objective of the dose-finding phase (reported here) was to identify MTDs of Rux + G and Rux + G/N. See Table for evaluated cohorts. Results: Among 42 pts enrolled, median age was 62.5 years, 81% had pancreatic cancer (PC), 50% had 1 prior regimen and 12% had 2 prior regimens. Discontinuations were mainly due to radiological or clinical disease progression (86% of pts). Median treatment durations: 55.5 d (A) and 97.5 d (B). 4 pts in B had DLTs: Grade (Gr) 3 pneumonia (n = 1, SAE), Gr 3 neutropenia (n = 1) and Gr 4 thrombocytopenia (n = 2). Table summarizes AEs. The most common Gr 3/4 hem AEs (lab) were anemia (88% A, 85% B) and thrombocytopenia (81% A, 89% B). SAEs occurring in ≥ 2 pts were abdominal pain (n = 4, A), sepsis (n = 2, A), dehydration, anemia and asthenia (n = 2 each, B). Rux + G was tolerated with standard doses of G. Rux + G/N was tolerated with reduced doses of G/N or concomitant GCSF. These combinations were not pursued further, therefore MTDs were not defined. ORRs were 2/16 (13%) in A and 10/26 (39%) in B. ORRs in PC pts: 8/34 (24%); 2/14 (14%) in A and 6/20 (30%) in B. Conclusions: Rux + G or Rux + G/N at the doses investigated were generally safe and well tolerated in pts with advanced PC and other solid tumors. ORRs were noted in multiple tumor types including PC. Clinical trial information: NCT01822756. [Table: see text]

Clinical and molecular determinants of treatment benefit with phase I trials in patients (pts) with advanced pancreatic cancer (PC).

409 Background: PC is the 4th leading cause of cancer-related death, with limited efficacy of systemic treatment (tx) beyond first-line chemotherapy (chemo). We aimed to assess the potential benefit of phase 1 trials in this setting. Methods: From 2011 to 2016, 49 pts were enrolled in 54 phase 1 trials at our institution. Clinical and molecular data were retrospectively extracted from medical records. Time to progression (TTP) was calculated from time of tx start to discontinuation due to progressive disease, and clinical benefit rate (CBr) was defined as partial response or stable disease > 4 months. Results: Median age was 58 (41-75), 69% were male, 60% had metastases in liver. Most pts received gemcitabine-based regimens (47%) or Folforinox (32%) as first-line tx (median TTP of 5.63 months [CI 95% 4.0-8.1]). Median tx line of Phase 1 trial was 3 (range 2-5). Regimens included chemo or immunotherapies (chemo-imm group) in 16 cases (12 and 4, respectively), small molecule inhibitor (SMI) as single-agent in 19 cases (SMI.1 group), and SMI in combinations in 19 cases (SMI.2 group). In 17 cases, tx was matched to genomic profile; most frequent matches were PI3K + MEK SMI or RAF SMI ( KRAS mut in 7 pts), PI3K SMI ( PTEN loss/ PIK3CA mut in 3 pts) and PD1 blockade (PDL1 high in 4 pts). There were 3 (6%) partial responses (PI3K SMI unmatched, RAF SMI matched and anti-PD1 agent matched) and 12 (24%) disease stabilizations. Median TTP in phase 1 trial was 1.9 months [CI 95% 1.6-2.5], without significant differences if matched/unmatched agent (p = 0.5) or tx given as second-line/later regimen (p = 0.5). Median TTP was 2.7 months [CI95% 1.6-10.7] with chemo-imm (control arm), 2.0 months [CI95% 1.8-5.6] with SMI.2 (HR = 1.8, p = 0.13) and 1.4 months [CI95% 1.3-2.8] with SMI.1 (HR = 3.0, p = 0.004). This difference was maintained in a multivariable model (HR = 2.9, p = 0.005). CBr with chemo-imm (38%) or SMI.2 (21%) was higher as compared with SMI.1 (5%; p = 0.06). Conclusions: Selected PC pts are eligible to phase 1 trials and up to one-third derive substantial benefit from the intervention. In our experience, chemo-imm agents or targeted SMI given as combination regimens associate with longer TTP and CBr when compared with single-agent SMI.

A UGT1A1 genotype-guided dosing study of modified FOLFIRINOX (mFOLFIRINOX) in previously untreated patients (pts) with advanced gastrointestinal malignancies.

427 Background: FOLFIRINOX improves survival compared with gemcitabine in advanced pancreatic cancer (PC), but with significant toxicity (Conroy, NEJM 2011). UGT1A1 clears SN-38, the active metabolite of irinotecan (IRI); UGT1A1*28 polymorphism reduces enzymatic activity and predisposes to severe IRI toxicity. We hypothesized that dosing mFOLFIRINOX based on UGT1A1 genotype would improve tolerability. The primary objective of this study (NCT01643499) was to determine whether genotype-guided dosing of IRI in mFOLFIRINOX is tolerable. A secondary objective was to describe objective response rates (ORR) in PC and biliary tract cancers (BTC). Methods: mFOLFIRINOX was given every 14 days. CT scans were obtained every 8 weeks. UGT1A1 *1/*1, *1/*28, and *28/*28 pts received initial IRI doses of 180, 135, and 90 mg/m2, respectively. 5-FU dose was 2400 mg/m2 over 46 hours (no bolus); leucovorin 400 mg/m2; oxaliplatin 85 mg/m2. In cohort 1 (tolerability cohort by genotype), prophylactic pegfilgrastim was not allowed in cycle 1 (28 days) unless clinically indicated. In cohort 2 (expansion tolerability cohort in PC and BTC), prophylactic pegfilgrastim was given. DLT during cycle 1 was defined as Grade (Gr) 3/4 neutropenia with fever; Gr 4 neutropenia lasting ≥ 5 days; Gr 4 thrombocytopenia, or Gr 3/4 non-hematologic toxicity despite optimal medical management. Doses were tolerable if the DLT rate during cycle 1 was ≤ 33% with 70-80% statistical confidence. Results: In cohort 1, DLTs were observed in 2/15 (13%) *1/*1 pts; 2/16 (13%) *1/*28 pts; 3/9 (33%) *28/*28 pts. In cohort 2, DLTs were observed in 6/19 (32%) PC pts and 4/19 (21%) BTC pts. DLTs in cohort 1 (some pts with multiple): neutropenic fever (5); Gr 3 fatigue (4); Gr 3 diarrhea (2). DLTs in cohort 2: Gr 3 fatigue (3); Gr 3 diarrhea (3); Gr 3 nausea/vomiting (2); Gr 5 sepsis without neutropenia (1); Gr 5 multi-organ failure (1); neutropenic fever (1); Gr 3 anorexia (1). To date, ORR is 13/39 (33%) in PC and 6/28 (21%) in BTC. Conclusions: mFOLFIRINOX is not tolerable in PC and BTC, even with UGT1A1 genotype-guided dosing of IRI and prophylactic pegfilgrastim. More needs to be done to improve the tolerability of this regimen. Clinical trial information: NCT01643499.

Early tumor shrinkage as a predictor of favorable outcomes in patients (pts) with advanced pancreatic cancer treated with FOLFIRINOX.

237 Background: Results from the phase III PRODIGE 4/ACCORD 11 trial provided one of current standard regimens for advanced pancreatic cancer (PC), consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX), which has superior response rate (RR) and survival benefit even with severe toxicity (Thierry C, et al. N Engl J Med 2011;364:1817-1825). There are several reports on the correlation between early tumor shrinkage (ETS) or depth of response (DpR) and survival in chemotherapies for colorectal cancer; however, few studies have investigated it in PC. We therefore analyzed retrospectively whether the ETS will predict outcomes in pts with PC treated with FOLFIRINOX therapy. Methods: Advanced PC pts with ECOG PS of 0 or 1, who received FOLFIRINOX as 1st- or 2nd-line treatment between November 2012 and July 2015 in 3 institutes of Showa University were included in this analysis. ETS was defined as a reduction ≥ 20% of target lesions’ diameters measured at 8 weeks from treatment start. We evaluated the association of ETS with progression-free survival (PFS) and overall survival (OS) but also addressed the correlation between outcomes and DpR, which was percentage of maximal tumor shrinkage observed at the nadir diameter compared with baseline. Results: Fifty-nine PC pts with median age of 63 (range 34-76) years and males of 68% were enrolled: 80% of pts had metastatic disease. In the population, RR, median PFS, and OS were 28%, 5.4 months, and 10.7 months, respectively. Among 46 (78%) evaluable pts for the ETS, 12 (26%) pts experienced ETS. The PFS was significantly longer in pts with ETS compared to pts with no ETS (9.0 vs. 4.2 months, HR 0.43, 95%CI 0.17-0.96, log-rank P= 0.045). Moreover, pts with ETS had a better OS although no statistical significance (HR 0.53, log-rank P= 0.25). Median DpR was 11.1% (from -75.7 to 100), and the correlation of DpR with clinical outcome was observed (P= 0.024 for PFS, P= 0.22 for OS). Conclusions: This retrospective analysis suggests that the early response to FOLFIRINOX treatment may predict better outcomes in pts with advanced PC. The ETS may serve as a novel predictor of prolonged survival time in PC pts treated with FOLFIRINOX.

Molecular prescreening (MP) to treat patients (pts) with advanced pancreatic cancer (PC) in early clinical trials.

272 Molecular prescreening (MP) to treat advanced pancreatic cancer (PC) patients (pts) in early clinical trials Background: Advanced PC has a dismal prognosis, with conventional therapies having poor impact on disease course. The aim of this study was to investigate the impact of a MP program to identify potentially targetable alterations (PTa) in PC pts eligible for clinical trials with matched targeted therapies. Methods: From Jan 2011 to June 2015, a total of 86 chemorefractory PC pts were referred to MP at the VHIO Phase I Unit. Archived tumor samples were analyzed for selected gene mutations (mut) in using mass spectrometry (MassARRAY, Sequenom) until June 2014 or next-generation sequencing (Amplicon, MiSeq) thereafter. PTEN and PDL1 expression levels were measured with immunohistochemistry. All demographic, treatment and survival data were extracted retrospectively from electronic medical records. Results: Median age was 61 years (range 29-78) and 64% were male. Median treatment lines before MP was 2 (range 1-5). Tissue used for MP was primary tumor in 74% and metastatic lesion in 26%. In total, 29% of the samples did not have enough material for mut analysis. The most common PTa were KRAS mut (20/35 with Sequenom, 57%; 22/26 with Amplicon, 85%; p = 0.02), PTEN low (9/22, 41%), PTEN null (4/22, 18%) and CDKN2A mut (2/26, 8%). RNF43 mut, STK11 mut, BRAF V600E and BRAF G469A were found in one sample each. A total of 30 pts were enrolled in Phase I trials following MP, 10 of them with a direct matched therapy (5 with PI3K pathway inh - PTEN low/null, 3 with PI3K + MEK inhibitor - KRAS mut, 1 anti-PDL1 therapy - PDL1 high, 1 HDM2 inh - TP53 wild-type). Partial response was observed in 1 case (PI3K inh + chemotherapy, PTEN null) and stable disease in additional 4 pts (3 with PI3K inh +/- chemotherapy, PTEN low/null; 1 PI3K + MEK inh, KRASmut). Median time on treatment with matched therapy was 2.5 months (CI95% 1.8 – not reached). Conclusions: Genomic/proteomic characterization of PC is able to identify a subpopulation eligible for matched therapy in early clinical trials, with rare cases presenting a clear treatment benefit. Low recruitment can be linked to lack of enough material for MP, low prevalence of PTa and patient characteristics

Outcomes of neoadjuvant chemotherapy versus chemoradiation among patients with resected pancreatic head adenocarcinoma.

398 Background: Increasing use of neoadjuvant therapy in pancreatic cancer has been reported. We compared patterns of practice and outcomes of neoadjuvant chemotherapy (nCHT) versus chemoradiation (nCRT) among pancreatic cancer pts receiving pancreaticoduodenectomy. Methods: National Cancer Data Base pancreatic head adenocarcinoma patients (pts) diagnosed between 2003 and 2011 treated by nCHT or nCRT followed by pancreaticoduodenectomy. Backward elimination logistic and Cox regression models were used. Primary outcome measures were 30-day and 90-day postsurgical mortality and overall survival; adjusted odds (aOR) & hazard ratios (aHR) and 95% confidence intervals (CI) are reported. Results: In all 1,432 pts received neoadjuvant treatment with nCHT (n = 523) or nCRT (n = 909). Odds of 30-day mortality were influenced by age (aOR 1.03, CI 0.99-1.06,p = 0.077), average annual resection volume of facility (aOR 0.98, CI 0.97-1.00, p = 0.135), and household income quartile (aOR 1.94, CI 0.97-3.90, p = 0.060), but not by delivery of RT, comorbidities, gender, insurance status or facility type. Odds of 90-day mortality were influenced by age (aOR 1.03, 1.01-1.05,p = 0.004), household income quartile (aOR 1.37, CI 0.87-2.16, p = 0.171), and delivery of nCRT (aOR 1.69, CI 1.04-2.74, p = 0.032), but not by average annual resection volume of facility, comorbidity, gender, insurance status or facility type. Survival odds were influenced by age (aHR 1.01, CI 1.00-1.02, p = 0.001), margin status (aOR 1.50, CI 1.27-1.77, p < 0.001), ypN status (aHR 1.45, CI 1.26-1.68), p < 0.001), adjuvant CHT (aHR 0.81, CI 0.69-0.94, p = 0.006), and nCRT (aHR 1.21, CI 1.04-1.40, p = 0.012). On average pts with nCHT as compared to nCRT lived longer (median OS 26.4 vs. 24.2 months, p = 0.001; actuarial 3 yr 58% vs 49%, and 5 year survival 30% vs 14%). Conclusions: There is no detectable difference in early outcome (30-day postsurgical mortality) among pancreaticoduodenectomy pts treated with nCHT or nCRT. Trend toward a more favorable long-term outcome (30-day postsurgical mortality and overall survival) among those with nCHT without radiation is noted. Further studies with more detailed data sources are needed.

Resected pancreatic cancer (PC): Impact of adjuvant therapy (Rx) at a high-volume center (HVC) on overall survival (OS).

191 Background: Surgical outcomes for resected PC are known to be superior at HVCs. However, the impact of adjuvant (Rx) performed at HVCs is less studied. We examined the impact of site of adjuvant Rx administration on our resected patients (pts). Methods: Eligible pts were diagnosed 2003-2014 and resected at HVC. Pts were excluded for neoadjuvant Rx, synchronous cancer, death/lost to follow-up within 3 months or contraindications (e.g. morbidity) to adjuvant Rx.. Pts were also excluded if they refused adjuvant treatment or if a community oncologist (CC) was not identified in the medical record or in the western Washington population-based cancer registry. Pt and tumor characteristics were compared in univariate analysis and survival was calculated from date of diagnosis to death or last follow-up. Five year OS was estimated by the Kaplan Meier method and compared using Cox proportional hazards modeling to evaluate the impact of HVC adjuvant Rx on OS while adjusting for potential confounding factors. Results: 245 pts were eligible for study: 139 (57%) treated at HVC, 106 (43%) treated at CC. HVC and CC pts were similar with respect to stage and tumor size, nodal status, resection margins and average distance travelled to HVC. They differed by age (HVC: 63.1, CC: 68.2 p < 0.01). Median and 5-yr OS was 36 mos and 33%. Median OS for HVC vs CC was 44 mos vs. 28 mos (p < 0.01), and 5yr OS was 38.6% vs. 24.8% (p < 0.01), adjustment for age did not alter our findings. Conclusions: 1) With respect to adjuvant Rx for resected PC, HVC and CC pts differed with respect to age only. 2) Both median and 5- yr OS was statistically superior at HVC vs CC. 3) Our study supports the use of HVCs for all Rx components for PC treated with curative intent. 4) Ongoing investigation of patterns of care and their impact on OS in PC is warranted.

Abstract 556: The detection of viable human circulating tumor cells (v-hCTCs) in resectable pancreatic cancer induced by neoadjuvant chemoradiotherapy (NACRT) using gemcitabine, S-1 and intensity-modulated radiotherapy (IMRT)

Abstract Circulating tumor cells (CTCs) are thought to be “metastatic intermediates”. Recently, we reported encouraging survival rates following neoadjuvant therapy using gemcitabine (Gem) and S-1 concurrently with radiotherapy (NACRT) in patients (pts) with resectable pancreatic cancer (PC). However, NACRT may have disadvantages. We hypothesized that NACRT in PC may induce epithelial to mesenchymal transition (EMT), which is associated with metastasis followed by the increase of CTCs. To extend our assessment of EMT during NACRT, we investigate the results of the v-hCTC detection in the pts treated with NACRT. This study was a single institution trial, approved by the Kure Medical Center IRB. Pts with resectable cytologically or histologically proven ductal adenocarcinoma of the pancreas were enrolled. Treatment consisted of an intervenous infusion of Gem 800 mg/m2 on day 1, 8, 22, and 29; and S-1 80 mg/m2 orally on day 1-5, 8-12, 22-26, and 29-33 given concurrently with IMRT to 60 Gy (2 Gy/day, 5 times per week, 30 fractions). Surgical exploration was scheduled 4-7 weeks after the final radiation fraction. To detect v-hCTCs, we employed a telomerase-specific replication-selective adenovirous expressing GFP (TelomeScan F35). 7.5 ml of blood samples were obtained from the pts included in this clinical study before NACRT, after 1 month of NACRT, and after 2 months of surgical resection. To distinguish between leucocyte and cells with epithelial origin, cells were stained with anti-CD45 and anti-Cytokeratin Abs. To distinguish cells with mesenchymal origin, cells were labeled with anti-Vimentin Ab. GFP-positive and CD45-negative cells were counted as v-hCTC. 12 pts aged 44-77 years (2 males and 10 females) were enrolled. No treatment-related deaths occurred. CA19-9 was reduced to <50% of baseline values in 7 of 9 measureable pts. 11 of 12 enrolled pts successfully underwent surgical resection. Only 4 out of 12 pts had one or two v-hCTCs detected before NACRT. After NACRT, 6 of 12 pts without tumor progression had v-hCTCs detected, which expressed Vimentin (1-56 CTCs). Among them, 3 pts had v-hCTCs detected at baseline. These 3 CTC-positive pts still had two or more Vimentin-positive CTCs detected (2-27 CTCs) after surgery, whereas remaining 9 pts had no detectable v-hCTCs. 1 of these 3 CTC-positive pts early developed liver metastasis and died, despite R0 resection. For the remaining 2 CTC-positive pts after surgery, one pt with postoperative therapy had no detectable CTCs at 1 year after surgery, however another pt without postoperative therapy still had 7 v-hCTCs detected (Vimentin[+]). We believe that our NACRT is feasible. However, we may consider “surgery first” for CTC-positive PC pts at baseline. In conclusion, v-hCTCs may become useful for prognosis assessment or stratification, especially when radiotherapy is considered. Citation Format: Masahiro Tanemura, Toshimitsu Irei, Masashi Inoue, Shinya Yamashita, Kenta Furukawa, Masaki Wakasugi, Kentaro Kishi, Hiroaki Nagano, Hiroki Akamatsu, Yasuo Urata, Nobuyoshi Hatanaka, Masaki Mori, Yuichiro Doki. The detection of viable human circulating tumor cells (v-hCTCs) in resectable pancreatic cancer induced by neoadjuvant chemoradiotherapy (NACRT) using gemcitabine, S-1 and intensity-modulated radiotherapy (IMRT). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 556. doi:10.1158/1538-7445.AM2015-556

Abstract B102: A phase 2, open-label study of the PARP inhibitor rucaparib in patients with pancreatic cancer and a known deleterious BRCA mutation

Abstract Background: Despite the recent progress made with front-line treatment for advanced pancreatic cancer (PC), most patients (pts) will either relapse or be refractory to treatment. Others may not even be eligible due to the toxicity profile of the available options or due to clinical deterioration. Once the disease progresses following front-line treatment, there is no accepted standard of care. Treatment options are clearly needed for patients with refractory disease. Approximately 5% of unselected PC pts, 10% of PC patients of Ashkenazi Jewish descent, and up to 19% of familial PC cases, harbor a germline BRCA mutation. Though less well characterized to date, somatic BRCA mutations also appear to play a significant role in PC. Clinical data have shown that pts with BRCA-mutant (BRCAmut) tumors, including those with PC, respond to treatment with a PARP inhibitor (PARPi). Early data suggest that other genomic characteristics may be surrogate biomarkers of homologous recombination deficiency (HRD) and define a larger group of responders than just BRCA mutation(s) alone. Rucaparib, an oral PARPi, is being developed for treatment of cancers associated with HRD due to a BRCA mutation or other homologous recombination pathway defect. Rucaparib has a desirable PK profile, is well tolerated, and has demonstrated clinical activity (RECIST and/or CA-125 responses) in patients with BRCAmut pancreatic, ovarian, or breast cancer in an ongoing Phase 1/2 study (NCT01482715). Three studies are currently ongoing in ovarian cancer and a trial in BRCAmut pancreatic cancer is now planned. The clinical activity of PARPi, including rucaparib, in BRCAmut PC, combined with the paucity of active 2nd-line therapies, support evaluation of rucaparib in PC pts with a BRCA mutation. Methods: Study CO-338-023 (NCT02042378) is a single-arm, open-label Phase 2 trial of continuous monotherapy rucaparib in up to 100 pts with pancreatic ductal adenocarcinoma (or related subtype) who are known to harbor a deleterious BRCA mutation (germline or somatic). Pts must have received at least 1, but no more than 2, prior regimens for locally advanced or metastatic disease and have relapsed / progressive disease confirmed by radiologic assessment, or are no longer able to tolerate chemotherapy due to toxicity, and radiologic assessment confirms stable or progressive disease. Other key inclusion criteria include measurable disease, ECOG Performance Status 0 or 1, and adequate organ function. Pts with endocrine tumors or who received prior PARPi treatment are excluded. Pts will take 600 mg BID rucaparib continuously and be evaluated for safety every 2–4 wks, disease status (CT scans, CA19–9) every 4–8 wks until disease progression, and then for survival every 4 wks. Blood and archival tumor tissue (if available) will be collected from all pts. The primary endpoint is ORR by RECIST v1.1. Key secondary endpoints include duration of response, PFS, OS, and safety. Exploratory analyses include gene sequence and structural rearrangements of tumor DNA and evaluation of circulating tumor DNA. A group sequential interim monitoring plan will be implemented to stop the study early for either superior efficacy or futility. Interim analyses will occur after every 10th patient enrolled has sufficient disease assessment data available. If robust activity is observed in the BRCAmut PC population, the trial may be broadened to include PC pts with HRD due to other than a BRCA mutation. The trial will be open to enrollment at clinical sites in the US and Israel in 2Q 2014. Citation Format: Susan M. Domchek, Robert McWilliams, Andrew Hendifar, Rachna T. Shroff, Lawrence Leichman, Ron Epelbaum, Ravit Geva, George Kim, Steven R. Alberts, Robert A. Wolff, Andrew Allen, Heidi Giordano, Mitch Raponi, Jeff Isaacson, Lindsey Rolfe, Andrew Biankin, Robert H. Vonderheide. A phase 2, open-label study of the PARP inhibitor rucaparib in patients with pancreatic cancer and a known deleterious BRCA mutation. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B102.

Gemcitabine (Gem) and nab-paclitaxel (nab-P) in patients (pts) with refractory advanced pancreatic cancer.

413 Background: The combination of nab-P and Gem improves survival compared to Gem alone in first-line therapy of metastatic pancreatic cancer. Efficacy data with this doublet in previously treated pts are scant. Our group presented preliminary results on 10 pts treated with this two-drug combination in the second and third line setting and herein present updated data on 59 pts. Methods: This IRB approved analysis identified all pts diagnosed with advanced refractory pancreatic cancer, treated with second-line Gem and nab-P at University of Miami and Sylvester Comprehensive Cancer Center between September 2010 and June 2014. Response by RECIST, CA19-9, and symptomatic improvement were assessed. Progression-free survival (PFS) and overall survival (OS) were calculated from the start of Gem + nab-P and were analyzed using the Kaplan-Meier method. Clinical benefit was defined as the percentage of patients with a partial response (PR) or stable disease (SD). Results: Data from59 pts were analyzed. The median age was 60; 55% were male; 54% received Gem + nab-P as second line therapy and 46% received it as third-line or beyond. Five (10%) pts had confirmed PR, 23 (47%) SD and 21 (43%) progressed. Among the 31 (52%) pts who received prior Gem, 18 (58%) had clinical benefit, 3 PR and 15 SD. The median OS was 3.9 months. The median PFS was 3 months. Toxicity appears similar to what has been reported on the MPACT trial with the combination. Conclusions: The clinical benefit seen withGem and nab-P in this group of pretreated pancreatic cancer pts suggests that it can be considered as an option. Additionally, prior Gem treatment appears not to decrease Gem and nab-P benefit in this population. Since nab-P monotherapy has modest activity in pre-treated pancreatic cancer pts, our data suggests a positive interaction between Gem and nab-P that may overcome resistance to Gem. [Table: see text]