Hubbard, Joleen M.

420 Background: Advanced biliary cancers respond poorly to chemotherapy and have a dismal survival. Currently gemcitabine-cisplatin (GC) is the standard of care for patients with advanced disease. The efficacy of second line treatment options is not well-defined. We retrospectively evaluated outcomes of patients undergoing second line treatment for advanced biliary cancers at Mayo Clinic. Methods: After obtaining approval from the institutional board review (IRB), we identified 42 patients with advanced and metastatic biliary cancers that progressed after first line (GC) and received second line treatment from 2007-2014. All patients had adequate follow up data. JMP software was used for statistical analysis. Kaplan-Meier method and log-rank tests were used for survival analysis, and multivariate cox proportional hazards model was used to evaluate the prognostic effect of pertinent clinical variables. All tests were two sided and a P value of < 0.05 was considered significant. Results: The median age at diagnosis was 61.5 (range 26-87). The most common regimens used for second line settings were 5-FU-based (69%) followed by gemcitabine-based regimens (19%). The overall response rate (ORR) was 9.1%, while the disease control rate (DCR; stable disease and partial response) was 33%. The median overall survival (mOS) for the entire cohort from first line was 16.8 months (95% CI 12.7-21.7) and the progression-free survival (PFS) was 9.16 months (95% CI 7.3-14.7). From second line start the mOS was 10.4 months (95%; CI 7.3-23.7), and PFS was 2.8 months (95% CI 2.3-4.0). 73% of patients who received second line therapy were alive at 6 months and 50% at 12 months. 25 patients received third line treatment after progression. An univariate and multivariate analysis were performed including age, sex, stage at diagnosis, regimen used, CA19-9 and total body weight loss > 5%, but no significant prognostic factors were identified. Conclusions: Patients with biliary cancers who progress after first line treatment have poor prognosis, but may benefit from second line regimens. 5-FU based regimens were the most commonly used in the second line setting, and 73% of patients who received second line therapy were alive at 6 months.

294 Background: CX-4945 is a first-in-class casein kinase-2 (CK2) threonine kinase small molecule inhibitor. CK2 is pleiotropic and regulates key cellular processes such as proliferation and DNA damage repair, and has been shown to enhance efficacy of gemcitabine (G) and cisplatin (C) in cell line and xenograft CCA model systems. A Phase IB study of G+C with CX-4945 was conducted in advanced cholangiocarcinoma (CCA) patients. Methods: A multi-center “3+3” dose escalation study was conducted in advanced CCA patients. Eligible patients had ECOG PS 0-1 and adequate hematologic, hepatic, and renal function. Primary endpoints were maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary endpoints included pharmacokinetic (PK) analyses, overall toxicity evaluation and preliminary assessment of efficacy. Routine clinical dosing for G (1000 mg/m2) and C (25 mg/m2), both on days 1 and 8 every 21 days, was used. Dose escalation cohort were CX-4945 given twice daily on days 0,1,2 and 7,8,9 at 200 mg (DL1), 400mg (DL2), 600 mg (DL3), 800 mg (DL4) and 1000 (DL5) mg. NCI CTCAE v4.03 was used for toxicity assessment and RECIST v1.1 for efficacy evaluation. Results: Nineteen patients were enrolled (DL1:n = 3; DL2:n = 4 DL3:n = 3; DL4:n = 4; DL5:n = 5). No dose limiting toxicities were encountered. MTD and RP2D were ascertained to be DL5. No grade 3 or 4 toxicities at prevalence > 10% were encountered and the overall toxicity profile of the combination was reflective of standard G+C toxicity profile. At data cut-off, preliminary efficacy evaluation demonstrated disease control rate (CR+PR+SD) of 64% (PR:32%, SD:32% and CR:0%), along with median progression-free survival (PFS) of 5 months (range 0-14 months). PK analyses showed no evidence of drug-drug interactions between G, C and CX-4945. Conclusions: RP2D for G+C with CX-4945 is DL5 (CX-4945 dosed on days 0,1,2 and 7,8,9 at 1000 mg PO bid with standard G and C dosing). Preliminary clinical efficacy and tolerability of the regimen support planned controlled, randomized Phase 2 evaluation. Clinical trial information: NCT02128282.

551 Background: Sorafenib inhibits various pro-angiogenesis pathways including PDGFR-B, a factor associated with resistance to anti-VEGF therapy. A previous phase II trial in patients with chemorefractory metastatic CRC demonstrated a 63% disease control rate with a combination of bevacizumab (BEV) and sorafenib. This phase I trial sought to determine the MTD of BEV and sorafenib combined with standard cytotoxic therapy for advanced gastrointestinal (GI) cancers. Methods: Patients with advanced GI malignancies appropriate for irinotecan-based therapy were enrolled (14 with CRC, 3 gastroesophageal). A standard 3 + 3 design was used with 3 escalating sorafenib dose levels (DL): (1) 200 mg po daily, days 3-7, 10-14; (2) 200 mg po twice daily, days 3-6, 10-13; and (3) 200 mg po twice daily, days 3-7, 10-14. FOLFIRI: irinotecan 180 mg/m2 d1, leucovorin 400 mg/m2 d1, 5-fluorouracil (FU) bolus 400 mg/m2 d1, 5-FU infusion 2400 mg/m2d1-2 and BEV 5 mg/kg d1. 1 cycle = 14 days. Results: Seventeen pts were enrolled, median age of 56 (range 32 and 81). Two pts were replaced, as they did not complete DLT evaluation, leaving 15 evaluable pts. Four evaluable pts at DL1 and 6 pts at DL2 had no DLTs. At DL 3, the first cohort of 3 pts did not experience any DLTs. In the second cohort of 3 pts, 2 pts experienced DLTs (asymptomatic G3 hypophosphatemia, G3 dehydration and diarrhea). MTD was determined to be DL2: sorafenib 200 mg PO twice daily, days 3-6, 10-13 combined with FOLFIRI and BEV at standard doses. Of the 15 evaluable pts, 4 pts had PR, 8 pts had SD as best response, 1 pt had PD, and 2 pts discontinued treatment prior to first tumor assessment. The median number of cycles was 10 (range 1-37). Three pts with CRC had disease control > 12 months. Conclusions: The MTD of this regimen is sorafenib 200 mg PO twice daily, days 3-6,10-13 combined with standard doses of FOLFIRI and BEV. Dual VEGF inhibition combined with cytotoxic therapy may provide prolonged disease stabilization for select patients with advanced GI malignancies. Supported by CA69912 and CA15083. Clinical trial information: NCT01383343.

678 Background: Improvements in outcome of medical therapy for mCRC are closely linked to availability of active agents. Based on phase III clinical data, regorafenib, a multikinase inhibitor, received FDA approval September 2012 for patients with mCRC previously treated with all approved therapies. Post regorafenib therapy (PRTx) has not been established. Based on clinical observations, we established a multi-institution collaboration to assess chemotherapy response in mCRC after regorafenib therapy. Methods: After IRB approval, patient records at Mayo Clinic (MC), MD Anderson (MDA) and the University of Southern California (USC) from April 2010 to February 2014 were reviewed for regorafenib use and outcomes for mCRC. Therapies, patient and tumor characteristics were reviewed. Response and progression were determined by investigator review. Kaplan-Meier method was used to calculate survival. Results: Regorafenib was given to 173 patients with mCRC (MC:59 MDA:95 and USC:19). Of these, 11 (6%) continued on regorafenib at time of analysis and 98 (57%) received no additional therapy. PRTx was given to 64 (37%) patients, 31 of which went on a clinic trial. 33 patients were treated with standard approved therapy of which 11 (33%) progressed, 20 (61%) showed response or SD, and 2 (6%) were not evaluable. Out of the 33 treated with standard agents, 8 (24%) had stable disease or response to a treatment previously discontinued without definitive PD, whereas 4 (12%) responded to rechallenge with chemotherapy previously discontinued due to PD. Response was noted in 8 (24%) patients that received an agent not given prior to regorafenib. After discontinuation of regorafenib, mOS was 6.5 mo (CI 4.9 – 9.4), and the probability of survival at 6 and 12 months was 52% and 27% respectively. Conclusions: With the caveat of a small sample size and a potential selection bias, our multi-institution study shows that re-utilizing standard treatment options after regorafenib may be beneficial in select patients with mCRC including in patients with progression on identical therapy before regorafenib. Further retrospective and prospective studies could be warranted to define the role of regorafenib as a chemotherapy re-sensitizing agent.

711 Background: For patients with stage IVA rectal cancer with liver metastases treated with curative-intent chemotherapy and surgery, the role of adjuvant pelvic radiotherapy (RT) is unclear. The purpose of this study was to evaluate the impact of pelvic RT on oncologic outcomes in this patient population. Methods: We retrospectively reviewed medical records of all patients with stage IVA rectal adenocarcinoma with liver metastases treated with curative-intent resection of the primary tumor and all liver metastases at our institution between 1991 and 2010. Patient and treatment characteristics were compared between patients who did or did not receive pelvic RT using chi-square and unpaired ttests. Survival and recurrence estimates were calculated from date of initial diagnosis using the Kaplan-Meier method. Local recurrence (LR) was defined as recurrence in the pelvis occurring at or before distant recurrence (DR). Cox regression was used to compare rates of freedom from LR (FFLR), freedom from DR (FFDR), and overall survival (OS) between patients who did or did not receive pelvic RT. Results: The analysis included 65 patients. Median patient age at diagnosis was 59 years (range, 27-87). Tumor stage was T2 (n = 4), T3 (n = 53), or T4 (n = 8). The median number of liver metastases was 2 (range, 1-14). Surgery was low anterior resection (n = 54) or abdominoperineal resection (n = 11). All patients received perioperative fluoropyrimidine based chemotherapy. Pelvic RT was administered to 35 patients (54%), either preoperatively (n = 22) or postoperatively (n = 13). Median RT dose was 50.4 Gy (range 25-58). Patient characteristics were similar for those who did or did not receive pelvic RT. Median follow-up was 3.7 years. The 3-year estimates of FFLR, FFDR and OS were 81% vs 58% (p =.056), 35% vs 29% (p =.75), and 66% vs 71% (p =.81) for RT vs no RT, respectively. Conclusions: In this analysis of patients with stage IVA rectal cancer with liver metastases undergoing curative intent therapy, pelvic RT (vs. no pelvic RT) was associated with a trend to lower rates of LR and similar rates of DR and OS.

569 Background: BBI-608 is an oral first-in-class cancer stemness inhibitor that blocks STAT3-mediated transcription of cancer stemness genes. Potent anti-CSC activity was observed in vitro and in vivo,in mono and combination therapy. In phase I studies, BBI-608 was generally well tolerated with encouraging signs of anti-tumor activity. Methods: A phase Ib open label, multi-center study in pts with advanced CRC was undertaken to confirm the RP2D of BBI-608 in combination with FOLFIRI with or without BEV. BBI-608 was administered at 240 mg BID in combination with FOLFIRI (5-FU 400 mg/m2 bolus with 2400 mg/m2, irinotecan 180 mg/m2, and leucovorin 400 mg/m2infusion) with or without BEV 5 mg/kg, administered bi-weekly until progression of disease, unacceptable toxicity, or other discontinuation criterion was met. Results: 18 heavily pretreated pts with an average of > 3 prior lines of therapy of which 10 pts (56%) previously progressed on FOLFIRI were enrolled. Of the 17 pts evaluable for response, 8 pts received FOLFIRI and 9 pts received FOLFIRI with BEV in combination with BBI-608. Most common adverse events included grade 1 and 2 diarrhea, abdominal pain, nausea, vomiting and anorexia. No dose limiting toxicity or new adverse events were seen, and the safety profile was similar to that of each regimen as monotherapy. Grade 3 events related to protocol therapy included diarrhea occurring in 3 pts, fatigue in 2 pts and dehydration in 1 pt. All events resolved after dose reduction and/or start of anti-diarrheal medications. No significant pharmacokinetic interactions were observed. Disease control (PR+SD) was observed in 16 of 17 evaluable pts (94%) with 2 PR (per RECIST 1.1 criteria: 44% and 33% regression) and 14 SD (of which 13 (93%) had tumor regression < 25%). In the evaluable pts, median progression free survival was 5.54 months. Of 17 pts, 7 (41%) had prolonged SD of > 6 months. Conclusions: This phase Ib study confirmed that BBI-608 at 240 mg bid can be safely combined with FOLFIRI with and without BEV, and shows encouraging anti-tumor activity in heavily pretreated CRC pts, even in pts with prior progression on FOLFIRI-based therapy. Clinical trial information: NCT02024607.

291 Background: Cholangiocarcinoma (CCA) is a rare malignancy with poor survival. The only curative therapy is resection and the role of adjuvant therapy is not well defined. Despite the unproven benefit, adjuvant therapy is used in resected CCA. The aim of this study is to analyze our institution’s outcomes for peri-operative treatment of resected intrahepatic and extrahepatic CCA. Methods: We retrospectively analyzed 145 intrahepatic (iCCA) and 109 extrahepatic (eCCA) CCA patients who underwent resection at the Mayo Clinic, Rochester. The majority of treated patients received adjuvant chemotherapy; however neo-adjuvant and radiation were also included. Results: In stage 1-2 iCCA patients, the HR indicated worse outcomes for time to recurrence and death. For stage 3-4 or node positive disease, outcomes were not significantly different. Those with node unknown/negative disease had significantly worse time to recurrence but not OS. There was a significant difference in stage and treatment modality between these groups (see table). Among eCCA, for any stage and node positive disease, outcomes were not different. In the node unknown/negative group, neither time to recurrence nor OS differed significantly. In controlling for different features in multi-variable analyses, no significant differences were observed (see table). Conclusions: This retrospective study does not show a significant difference in recurrence free or OS for treated patients. The apparent lack of benefit most likely reflects selection bias among treatment groups. Prospective, randomized trials are needed to make sound recommendations in adjuvant treatment for CCA. [Table: see text] [Table: see text]

225 Background: Recent guidelines promote simultaneous palliative care with active treatment for advanced/metastatic cancers, including interventions addressing all quality of life (QOL) domains. Dignity Therapy (DT) is an intervention demonstrating promising outcomes at end of life. It has not been offered earlier to cancer patients nor paired with a Life Plan (LP) intervention. The purpose of this phase I/II feasibility study was to determine the feasibility, acceptability and selected patient-reported outcomes (PROs) of the Dignity Therapy/Life Plan intervention and pilot study methods in advanced pancreatic cancer patients pursuing chemotherapy. Methods: DT is a brief psychotherapeutic intervention consisting a focused life review/values clarification delivered during 3 outpatient oncology clinic visits. Interviews were audiotaped, transcribed, and edited to produce a Generativity Document, which the patient can later share with family. Life Plan is a type of “bucket list”, where patients document future hopes/dreams. Feasibility was evaluated, distress measured with the Distress Thermometer (0-10 scale) and QOL measured with the Linear Analogue Self Assessment (LASA, 0-10 scale). Baseline scores of distress and QOL were compared with scores after the intervention, 4-6 weeks later (Time 2 [T2]). Results: Ten pancreatic adenocarcinoma patients enrolled, mean age 63. Two-thirds of those recruited enrolled; 90% completed all study procedures. Two-thirds were satisfied/very satisfied with DT/LP, and 78% found study participation worthwhile, DT/LP timing to be just right and would recommend DT/LP to others. QOL improved (baseline mean = 7.0; T2 = 7.25). Distress scores improved (Baseline mean = 6.13; T2 = 5.63). Conclusions: Distress and QOL modestly improved from baseline to T2. Baseline scores were collected before patients had begun any chemotherapy, therefore any improvements while undertaking aggressive chemotherapy are noteworthy. Participants felt the intervention was acceptable and better than they had expected. Conducting DT/LP in an outpatient oncology setting for newly diagnosed pancreatic cancer patients is both feasible and acceptable. Outcomes are encouraging for future larger scale trials. Clinical trial information: NCT02132325.

229 Background: Modern clinical practice places time restrictions on the amount of information and processing that can be done in a typical office visit. Meeting patient needs within the healthcare system is often inefficient and ineffective, contributing to patient and clinician dissatisfaction and suboptimal outcomes. We developed a point-of-care case management system for oncology clinical practices adapted from an algorithm initially designed for patients with diabetes. The system’s goal is to obtain patient-reported quality of life (QOL) outcomes and provide clinicians with information regarding QOL issues to address. Methods: Literature review and focus groups of oncology patients were used to identify key patient concerns. The program was adapted for cancer patients to collect the identified patient concern including QOL, fatigue, pain and other cancer-specific issues scored on a scale of 0-10. Suggested actions and available resources were identified for the patient/clinician based on the issue selected. We performed a pilot study involving 20 cancer patients to assess feasibility, and administered a “was it worth it survey” (WIWI). Results: The resultant hematology/oncology electronic system includes a set of eight primary “buttons”: Personal Relationships, Emotional health, Physical healthy, Cancer diagnosis and treatment, Health behaviors, Money, Care planning and Something else. Every “button” was selected, most commonly Cancer diagnosis and treatment 6/20 (30%). The median (range) reported QOL, fatigue and pain were 7 (1-10), 4 (0-8), 2 (0-8), respectively. The average completion of the tool took 4 minutes. One hundred percent of patients who took the survey thought it was worth it, would participate again and recommend it to others. Conclusions: The system was quick and easy to utilize in a small pilot of patients. All of the identified categories were chosen and relevant to our patient population. This tool has the potential to improve patient well-being and clinical outcomes, reduce the burden on clinicians and distribute case management activities to the most appropriate providers. Next steps include initiating a larger prospective protocol to assess if this tool improves QOL over time.

446 Background: MutKRAS and mutBRAF are important predictive and prognostic markers, respectively, in colorectal cancer (CRC). However, little is known about why some tumors harbor these mutations. N0147 is a phase III adjuvant trial for stage III CRC patients (N=3397) in which patients completed questionnaires and tumor variables and KRAS/BRAF mutation status was assessed. Methods: 2,323/3,397 patients who were enrolled prior to a 2008 amendment requiring KRAS testing completed a Patient Questionnaire. Primary tumors were assessed for mutKRAS and mutBRAF using standard methods; MMR status was determined using IHC. Multivariate analysis was performed to identify predictors of mutation status. Results: 60% and 86% of mutKRAS and mutBRAF tumors were right-sided, respectively. MutKRAS was less likely if there was a family history of CRC and in ever-smokers, and was nearly mutually exclusive with mutBRAF. MutBRAF was associated with deficient MMR (dMMR), high grade histology, and 4+ positive lymph nodes at surgery. MutBRAF was more likely in patients age > 70, retired persons, ever-smokers, but was less likely in non-whites and men. Conclusions: Smoking, family history of CRC, and dMMR status are associated with lower frequency of mutKRAS , but higher mutBRAF. Both mutations tend to be right sided, and mutBRAF is more common in the elderly, females, and non-Hispanic whites. [Table: see text]