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Background Fatigue interference with activities, mood, and cognition is one of the most prevalent and bothersome concerns of advanced gastrointestinal (GI) cancer patients. As fatigue interferes with patient functioning, family caregivers often report feeling burdened by increasing responsibilities. Evidence-based interventions jointly addressing cancer patient fatigue interference and caregiver burden are lacking. In pilot studies, acceptance and commitment therapy (ACT) has shown promise for addressing symptom-related suffering in cancer patients. The current pilot trial seeks to test a novel, dyadic ACT intervention for both advanced GI cancer patients with moderate-to-severe fatigue interference and their family caregivers with significant caregiving burden or distress. Methods A minimum of 40 patient-caregiver dyads will be randomly assigned to either the ACT intervention or an education/support control condition. Dyads in both conditions attend six weekly 50-min telephone sessions. Outcomes are assessed at baseline as well as 2 weeks and 3 months post-intervention. We will evaluate the feasibility, acceptability, and preliminary efficacy of ACT for improving patient fatigue interference and caregiver burden. Secondary outcomes include patient sleep interference and patient and caregiver engagement in daily activities, psychological flexibility, and quality of life. We will also explore the effects of ACT on patient and caregiver physical and mental health service use. Discussion Findings will inform a large-scale trial of intervention efficacy. Results will also lay the groundwork for further novel applications of ACT to symptom interference with functioning and caregiver burden in advanced cancer. Trial Registration ClinicalTrials.gov, NCT04010227. Registered 8 July 2019.

Individuals with breast and ovarian cancer susceptibility gene 1 (BRCA1) or BRCA2 germline mutations have a significantly increased lifetime risk for breast and ovarian cancers. BRCA-mutant cancer cells have abnormal homologous recombination (HR) repair of DNA. In these tumors, the base excision repair (BER) pathway is important for cell survival. The poly(adenosine diphosphate-ribose) polymerase (PARP) enzymes play a key role in BER, and PARP inhibitors are effective in causing cell death in BRCA-mutant cells while sparing normal cells-a concept called synthetic lethality. PARP inhibitors are the first cancer therapeutics designed to exploit synthetic lethality. Recent clinical trials in BRCA-mutant, metastatic breast cancer demonstrated improved outcomes with single-agent PARP inhibitors (olaparib and talazoparib) over chemotherapy. However, resistance to PARP inhibitors remains a challenge. Primarily due to myelosuppression, the combination of PARP inhibitors with chemotherapy has been difficult. Novel combinations with chemotherapy, immunotherapy, and other targeted therapies are being pursued. In this review, the authors discuss current knowledge of PARP inhibitors in BRCA-mutant breast cancer and potential future directions for these agents. Cancer 2018;124:2498-506. © 2018 American Cancer Society.

TPS446 Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Liposomal irinotecan injection (Nal-IRI) is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase II, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table below every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30 day postoperative complication rate. Clinical trial information: NCT03483038. [Table: see text]

TPS350 Background: Mutations in isocitrate dehydrogenase 1 (mIDH1) are found in approximately 20-30% of patients with intrahepatic cholangiocarcinoma (CCA), and less commonly in glioma, chondrosarcoma, and other gastrointestinal malignancies. Despite documented clinical activity of mIDH1 inhibition in solid tumors, there are no approved targeted therapies for this patient population. LY3410738 is a potent, selective, and covalent inhibitor of mIDH1 R132. LY3410738 is differentiated from prior mIDH1 inhibitors by 1) its unique covalent binding mode, 2) its increased potency, and 3) its unique binding site outside of the dimer interface, which enables activity in the setting of known common second-site IDH1 mutations. Methods: This is an open-label, multicenter, global phase 1 study with oral LY3410738 currently enrolling patients with advanced CCA and other solid tumor types (NCT04521686). A dose escalation cohort will be followed with 4 exploratory expansion cohorts. The primary objective for dose escalation is determination of the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary objective for dose expansion is to assess the preliminary anti-tumor activity by ORR of LY3410738 when administered alone or in combination with cisplatin plus gemcitabine. Secondary objectives include evaluating safety and tolerability, pharmacokinetics, pharmacodynamics, progression free survival, and overall survival. Key inclusion criteria include any solid tumor with the presence of mIDH1 R132, ECOG performance status ≤1, and adequate organ function. Any prior treatment including an IDH1 inhibitor is allowed in the dose escalation cohort. Exclusion criteria include presence of active central nervous system metastases, leptomeningeal disease, and active or uncontrolled infection. CCA patients must not have had locoregional therapy within 4 weeks prior to the initial study dose, history of hepatic encephalopathy or refractory ascites, ongoing cholangitis, or mixed hepatocellular-CCA histology. Dose escalation will follow a 3+3 design and will allow patient back-fill to dose levels previously cleared for safety. Each cycle will be 28 days (4 weeks). Once the RP2D is determined, LY3410738 will be evaluated as monotherapy in expansion cohorts 1-3, and in combination with cisplatin plus gemcitabine in expansion cohort 4. Cohort 1 will enroll CCA patients with measurable disease who have received prior chemotherapy. Cohort 2 will enroll patients with advanced solid tumors except CCA who have measurable disease and received standard therapies. Cohort 3 will enroll patients with advanced solid tumors who have non-measurable disease and received standard therapies. Cohort 4 will enroll CCA patients with measurable disease who are treatment naïve for advanced disease. Clinical trial information: NCT04521686.

Background: Gut microbiome composition affects response to PD-1 blockade; and recent proof of concept studies suggest that gut microbiome manipulation is effective in reversing resistance to PD-1 blockade. VE800 is an oral live biotherapeutic consisting of 11 distinct non-pathogenic, non-toxigenic, commensal bacterial strains manufactured in lyophilized form. VE800 induces CD8+ T cell infiltrate into tumors; and significantly enhances anti-tumor activity of PD-1 blockade preclinically in multiple tumor models in a CD103+ dendritic cell and major histocompatibility (MHC) class I dependent fashion (Tanoue et al., 2019). Retrospective analysis of cancer patient's (pt) samples also suggests that greater VE800 strain abundance is associated with improved response to PD-1 blockade. The objective of this phase I study is to evaluate the safety, tolerability, and clinical activity of VE800 administered orally in combination with nivolumab in pts with select cancers. Methods: CONSORTIUM-IO (NCT04208958) is an open-label, first-in-human study evaluating VE800 and nivolumab combination in pts with anti-PD-1/PD-L1 relapsed/refractory melanoma, anti-PD-1/PD-L1 naïve gastric/gastroesophageal junction (GEJ) adenocarcinoma and anti-PD-1/PD-L1 naïve microsatellite-stable (MSS) colorectal cancer. Following a 5-day course of oral vancomycin 125mg QID, VE800 will be administered daily along with nivolumab (480mg Q4W). A single dose level of VE800 will be evaluated. In the interests of maximizing safety, a Simon 2-stage design will be used for each disease cohort. Although no dose-limiting toxicities (DLT) are expected, the first 3 pts will be enrolled serially 1 week apart; and safety data of the first 6 pts will be reviewed prior to further accrual. Pts will continue to receive VE800/nivolumab combination until disease progression or unacceptable toxicity. Primary endpoints include safety, tolerability; and clinical activity by objective response rate (ORR) per RECIST v1.1. Secondary endpoints include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS); and metagenomic strain-level analysis of degree/duration of VE800 strain colonization. Exploratory endpoints include tumor and blood immunophenotyping, serum/stool metabolomics and global changes in fecal microbiome composition. CONSORTIUM-IO is currently actively enrolling pts. Citation Format: Diwakar Davar, Judy S. Wang, Michael Cecchini, Zev Wainberg, Martin Gutierrez, Anita Turk, Rose Szabady, Jason Norman, Bernat Olle, Bruce Roberts, Dmitri Bobilev. Consortium-IO: A safety and efficacy study of VE800 in combination with nivolumab in previously treated patients with select advanced metastatic cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT246.

e16764 Background: Both EGFR and the c-MET receptors are overexpressed in a majority of PDACs. Inhibition of both receptors simultaneously may be required for anti-tumor activity. Erlotinib, an EGFR inhibitor, has modest activity in metastatic PDAC and is approved by the FDA in combination with gemcitabine. Cabozantinib is a tyrosine kinase inhibitor targeting AXL, FLT-3, KIT, MER, MET, RET, ROS1, TIE-2, TRKB, TYRO3, and VEGFR-1, -2, and -3. Preclinical data suggests that the addition of cabozantinib to erlotinib leads to tumor shrinkage and improvement in survival in a KPC PDAC mouse model compared to gemcitabine alone. This phase II study tests this hypothesis in patients with metastatic PDAC that co-express c-MET and EGFR. Methods: Key eligibility includes patients (pts) with metastatic PDAC with EGFR and c-MET overexpression (as determined by centrally tested IHC of 2+ or greater) that have progression on one prior chemotherapy regimen. Patients were treated with cabozantinib (40mg daily) and erlotinib (100mg daily) continuously. This dosing is based on previous combination data in NSCLC. This is a single arm two-stage phase II study with a primary endpoint of overall response rate. Secondary endpoints include of PFS, DCR and OS. Results: From October 2017 to October 2019, 43 pts were screened with 7 pts (median age 62 [range 51-76)] enrolled and treated on study. Pts had a median of 1 line of prior systemic chemotherapy. Most common reason for screen failure was due to lack of co-expression of c-MET and EGFR. EGFR IHC expression was +2 in 4 pts, +3 in 3 pts; c-MET IHC expression was +2 in 5 pts and +3 in 2 pts. Most common any-grade adverse events attributable to cabozantinib and erlotinib include: diarrhea (71%), AST increase (43%), fatigue (43%), nausea (43%), and rash (43%). Only one grade 3 event of fatigue occurred. All pts had clinical and/or radiographic progression within 1-2 months after initiating study therapy. Conclusions: The combination of cabozantinib and erlotinib was well tolerated with manageable toxicity. Due to lack of clinical responses, this study has been terminated due to futility. Clinical trial information: NCT03213626 .

4046 Background: SBRT is used to treat liver metastatic CRC, causing an increase in immunogenic antigen release and influx of responding immune cells. We hypothesize that radiation enhances the immunogenicity of MSS CRC and potentiates the effectiveness of PD-1 blockade. This phase Ib study examines the safety and efficacy of the sequential combination of SBRT and Pem in patients (pts) undergoing resection of their disease. Methods: Eligibility criteria include MSS CRC with resectable liver-confined metastatic disease. Prior surgery and systemic chemotherapy are allowed. Subjects receive sequential SBRT and cycle 1 of Pem prior to operative management and adjuvant Pem. The primary objectives are to determine the safety/tolerability of this regimen and the recurrence free survival (RFS) at 1 year following clearance of metastatic disease. Correlative studies examined tumor infiltrating CD8+ T lymphocytes (TILs) and the accumulation and proteolysis of versican (VCAN), an immunoregulatory tumor matrix proteoglycan. Proteolysis of VCAN results in the release of an immunostimulatory fragment, versikine. Cancers with low VCAN and high versikine (VCAN proteolysis predominant (VPP)) are hypothesized to respond better to immunotherapies. Results: 15 pts (median age 58.2 [range 38-69]) have been enrolled. All pts had prior FOLFOX. SBRT median dose was 50 Gy (40-60 Gy) to a single lesion targeted in all pts. No DLTs were observed. AEs included one case of biliary tract injury and biloma, not related to immunotherapy. No grade 3/4 immunotherapy-related AEs have occurred. 10 pts have completed a minimum follow-up of 1 year post resection. In the intention to treat analysis, the 1 year RFS was 70% (historic control 50%). 2 of 3 pts with BRAF V600E mutations have had early recurrences. 2 pts had VCAN high tumors and both recurred prior to 1 year. 4 pts had VPP cancers and all were recurrence free at 1 year. TILs in the radiated lesions were > 2 times as abundant as in the pre-treatment (tx) tissue for 50% of pts. 3 of 4 pts who had non-radiated lesions available for analysis had TILs > 2 times pre-tx in the non-radiated lesions indicating a potential abscopal effect. Conclusions: The combination of SBRT with Pem and surgical resection is well tolerated with no signal of increased immunotherapy-related toxicity and preliminary evidence of potential enhanced efficacy. Clinical trial information: NCT02837263 .

272 Background: Expert knowledge is often shared among academic oncologists at tumor boards (TBs) at National Cancer Institute Designated Cancer Centers (NCI-CCs), but not documented or made accessible to community oncologists. Using an oncologist-only question and answer (Q&A) website, we sought to disseminate expert insights from TBs at NCI-CCs to provide educational benefit to the oncology community. Methods: A process was designed with faculty at 11 NCI-CCs to document and share discussions from TBs focused on areas of clinical complexity and practice variation on theMednet.org, an interactive Q&A website of over 8,700 US oncologists. One faculty member from each TB was selected as a site leader. She or he distilled discussions about patient management from the TB into a question that addressed the clinical situation being discussed. After the question was posted, faculty at the participating NCI-CCs were asked to answer the question on theMednet. Answers were peer reviewed, indexed, stored and disseminated via email newsletters to registered oncologists. Community engagement was measured by Q&A page views, upvotes of Q&A, and poll participation. Results: A total of 15 Breast, Thoracic, and Gastrointestinal programs from 11 NCI-CCs participated. Between 12/2016 and 5/2019, faculty highlighted 146 questions from their TBs. Q&A were viewed 43,291 times by 3,585 oncologists including 2,264 community oncologists. One hundred and eighty-four answers are posted by 56 academic physicians and peer reviewed by 76 academic physicians. One hundred and eighty-five publications were cited. Community oncologists upvoted Q&A 808 times and voted in 45 polls related to the questions 1,667 times. Viewership of NCI-CC Q&A increased by 419% over time. Q&A were repeatedly searched and viewed, with 90% of all TB Q&A viewed every month. Conclusions: Via the online Q&A theMednet platform, NCI-CC providers effectively made expert knowledge easily accessible to community oncologists across the US. Timely access to evidence based recommendations from expert faculty can inform future practice choices in the community. [Table: see text]

e15047 Background: Adjunctive therapies are essential to enhance the effect of anti-PD1 therapies for the treatment of microsatellite stable (MSS) colorectal cancer. SBRT is utilized to treat liver metastatic CRC, causing an increase in immunogenic intra-tumoral and intra-lymphatic antigen release and a rapid influx of responding immune cells. We hypothesize that radiation enhances the immunogenicity of MSS CRC and potentiates the effectiveness of PD-1 blockade. This phase Ib study examines the safety and efficacy of the sequential combination of SBRT and Pem in patients for whom the goal is to resect all sites of known disease. Methods: Key eligibility criteria include MSS CRC with liver-confined metastatic disease with the therapeutic goal of resection of all radiographic disease with one operation. Subjects must be a candidate for SBRT to 1-3 liver metastases. Prior surgery and systemic chemotherapy are allowed. Subjects receive sequential SBRT and cycle 1 of Pem prior to operative management. Postoperatively, patients complete cycles 2-9 of Pem followed by scheduled surveillance with imaging every 12 weeks. The primary objectives are to determine the safety/tolerability of this regimen and the recurrence rate at 1 year following clearance of metastatic disease. Secondary objectives include time to recurrence, DFS, and OS. Results: 10 patients (median age 61.5 [range 39-69]) have been enrolled and completed the intended neoadjuvant therapy, operative management and at least 4 adjuvant cycles of Pem. All patients had received prior FOLFOX. SBRT median dose was 50 Gy (40-60 Gy) to a single lesion targeted in all patients. Mean gross tumor size targeted was 19.1cc (2.3-80.4). Any-grade post-operative AEs (>20%) attributable to Pem include diarrhea (30%), hyperbilirubinemia (20%%), and leukopenia (20%). Post-operative AEs included one case of biliary tract injury and biloma, not related to immunotherapy. No grade 3/4 immunotherapy AEs have occurred. Conclusions: The combination of SBRT with Pem and surgical resection is well tolerated with no signal of increased immunotherapy-related toxicity in the post-operative setting. Clinical trial information: NCT02837263.

4041 Background: Neoadjuvant CRT followed by surgery is the standard of care (SOC) for patients (pts) with stage II/III E/GEJ cancer. However, recurrence rates are high. Immunotherapy has demonstrated promising activity in advanced E/GEJ cancer. This trial evaluates safety and efficacy of perioperative A with CRT in resectable E/GEJ cancer. Methods: This is a 2-part phase I/II trial. Part 1 is a run-in phase with 6 pts for safety evaluation. Part 2 will enroll additional 18 pts in the expansion cohort. Pts with E/GEJ cancer of any histology receive CRT (41.4 Gy in 23 fractions) with carboplatin and paclitaxel as per SOC. Three doses of A (10 mg/kg, q14 days) are administered starting on day 29 of treatment, to coincide with the last chemotherapy dose. Surgery is performed ~8 weeks after CRT completion. Pts receive 6 doses of A after resection. Dose-limiting toxicity (DLT) evaluations are completed on the first post-operative clinic visit, 2-4 weeks post resection. Results: Between 6/2018 and 2/2019, 6 pts (all male, median age 62) enrolled in part 1: 6 adenocarcinoma (100%); 1 E, 3 Siewert 1, 2 Siewert 2; 1 cT2N0, 2 cT3N0, 3 cT3N1. All pts underwent successful resection with negative surgical margins. 1/6 pts had R1 resection due to tumor extension to inked adventitial surface without invasion of surrounding structures. There were no unexpected surgical complications. At resection, 2 pts had ypT0N0, 2 ypT1N0, 1 ypT2N0, and 1 ypT3N1 disease. Combination of CRT and A had an acceptable toxicity profile. No DLTs were seen in the first 5 pts, so expansion cohort is open to enrollment. No grade ≥3 immune-related AEs were observed. Immune-related hypothyroidism was seen in 1 patient (grade 2). 6/6 pts had reversible grade 3 or 4 lymphopenia; 1/6 had grade 3 neutropenia. Correlative studies are ongoing and will be presented at the meeting. Conclusions: Perioperative CRT with A is well tolerated with no unexpected toxicities. Additional safety and correlative data will be presented at the meeting. This study is actively enrolling pts to an expansion cohort at University of Wisconsin. Clinical trial information: NCT03490292.

e15104 Background: ASCO defined clinically meaningful trial endpoints in colorectal cancer (CRC) as absolute overall survival (OS) of 3-5 months and OS hazard ratio (HR) ≤0.67. Few tools predict clinically distinct subgroups from heterogeneous populations. Effect size (Glass’s delta) calculates the absolute difference in clinical outcomes relative to the standard deviation of control group. We hypothesized that effect sizes ≥1 would be useful in predicting subgroup populations of clinical significance for trials with an indeterminate HR. Methods: Prospective phase II-III trials in metastatic CRC were queried from clinicaltrials.gov and cataloged by clinical outcomes of PFS and OS. Effect size was back-calculated from trials reporting 95% confidence intervals and compared with absolute difference in clinical outcome and hazard ratio. Results: 46 prospective trials were evaluable including 49% with biomarker selection, 57% in the first-line setting, and more commonly studied with targeted therapy over chemotherapy (70 v. 30%; p < 0.001). EGFR inhibitors were studied in 34% and VEGF inhibitors in 23%. Both effect size and HR correlated similarly with PFS (correlation coefficients, R = 0.65 vs. 0.76) and OS (R = 0.83 vs. 0.84) across these studies. Of studies with an indeterminate HR (0.69-0.86; n = 24), 10 studies had a significant effect size (Glass’s delta > 1), indicating the potential for sub-populations with improved clinical benefit within the experimental treatment group. These included 4 trials with planned biomarker analyses. Remaining trials were enriched for studies investigating anti-angiogenic therapies (83% vs. 23%, p = 0.001), including bevacizumab, aflibercept, regorafenib, and ramucirumab. Conclusions: Effect size holds potential as a measure to indicate the presence of subpopulations of patients benefiting in clinical trials. Those trials with a significant effect size despite an indeterminate HR should be examined closely for such populations. In CRC, effect size indicates the potential of a subgroup of patients who benefit significantly from anti-angiogenic agents. Further investigations are needed to validate effect size as a tool to delineate improved clinical outcomes from heterogeneous populations.

680 Background: Adjunctive therapies are essential to enhance the effect of anti-PD1 therapies for the treatment of microsatellite stable (MSS) colorectal cancer. SBRT is utilized to treat liver metastatic CRC, causing an increase in immunogenic intratumoral and a rapid influx of responding immune cells. We hypothesize that radiation enhances immunogenicity of MSS CRC and potentiates effectiveness of PD-1 blockade. This phase Ib study examines the safety and efficacy of the sequential combination of SBRT and Pem in patients for whom the goal is to resect all sites of known disease. Methods: Key eligibility criteria include MSS CRC with liver-confined metastatic disease with the therapeutic goal of resection of all radiographic disease with one operation. Subjects must be a candidate for SBRT to 1-3 liver metastases. Prior surgery and systemic chemotherapy are allowed. Subjects receive sequential SBRT and cycle 1 of Pem prior to operative management. Postoperatively, patients complete cycles 2-9 of Pem followed by scheduled surveillance with imaging every 12 weeks. The primary objectives are to determine the safety of this regimen and the recurrence rate at one year following clearance of metastatic disease. Secondary objectives include time to recurrence, DFS, and OS. Results: Nine patients (median age 61.5 [range 39-69]) have completed the intended neoadjuvant therapy, operative management and at least one adjuvant cycle of Pem. All patients received prior FOLFOX. Any-grade AEs (> 20%) through cycle 2 of Pem attributable to SBRT include fatigue (44%) and nausea (22%). Any-grade AEs related to Pem include lymphopenia (25%). Postoperative AEs included one case of biliary tract injury and biloma, not related to immunotherapy. One patient developed a rash following SBRT and Pem which may be an immunotherapy-related toxicity. No grade 3/4 immunotherapy AEs have occurred. Conclusions: The combination of SBRT, Pem, and surgical resection is well tolerated with no signal of increased immunotherapy-related toxicity. Clinical trial information: NCT02837263.

TPS181 Background: Neoadjuvant chemoradiation (CRT) followed by resection is the standard treatment for patients with stage II and III esophageal cancer. However, about 50% of patients develop recurrent disease after treatment completion. Patients with residual disease at the time of resection (~ 75%) and especially those with persistent lymph node involvement have the worst prognosis. Hence, novel strategies are needed to improve outcomes. A number of preclinical and clinical studies demonstrated synergism between radiation and immunotherapy. In esophageal cancers, CRT has been shown to alter tumor microenvironment with upregulation of PD-L1 expression and increase in CD8+ T lymphocyte infiltration. Immune checkpoint inhibitors have demonstrated promising activity in metastatic gastroesophageal cancer. Utilizing these agents in earlier disease stages and combining with chemoradiation may increase their efficacy by taking advantage of potential synergism with radiation. This trial will evaluate safety and efficacy of avelumab in combination with CRT in resectable esophageal cancer. Methods: This is a two-part phase I/II clinical trial evaluating safety and efficacy of perioperative avelumab plus CRT in patients with resectable esophageal cancer. This trial will enroll a total of 24 subjects with untreated resectable esophageal cancer (including gastroesophageal junction). Part 1 will be a run-in phase that enrolls 6 patients for safety evaluation. Part 2 will enroll 18 additional patients for efficacy and additional safety evaluation. The primary endpoint for the phase II component is the pathological complete response rate. Subjects will receive neoadjuvant radiation (41.4 Gy in 23 fractions) with weekly carboplatin (AUC 2) and paclitaxel (50 mg/mg2). Three doses of avelumab (10 mg/kg, every 14 days) will be administered starting on day 29 of treatment, to coincide with the last chemotherapy dose. Esophagectomy will be performed ~ 8 weeks after CRT completion. Subjects will receive 8 doses of avelumab after resection. This study is actively enrolling patients at University of Wisconsin. Clinical trial information: NCT03490292.

e14640 Background: Poly(ADP-ribose) polymerase (PARP) enzymes are involved in DNA repair and activated by DNA strand breaks. DNA damage from carboplatin is associated with activation of PARP. Preclinical data indicate that PARP inhibition and trapping potentiates the anti-tumor effect of platinum chemotherapy. Talazoparib (T) is an oral, selective PARP inhibitor. This phase I study combines T with carboplatin (C) and paclitaxel (P). Methods: Two dosing schedules are being investigated. C is administered on day 1 and P on days 1, 8, and 15 of a 21-day cycle. T (100-1000mcg) is dosed once daily for days 1-7 (schedule A) or days 1-3 (schedule B). Dose escalation is by 3+3 design. Patients (pts) must have tumor type that is expected to respond to C + P or have BRCA germline or somatic mutation and adequate organ function. After 4-6 cycles of combination therapy, pts may continue the combination, change to C and intermittent T without P or change to T alone. Each schedule will have a 6 pt dose expansion at the MTD. The dose level (DL) 1 for schedule B is the previously reported MTD from schedule A (T 250mcg with C AUC 6 + P 80mg/m2). Results: Schedule B results are reported: 15 pts (median age 56 yrs [range 43-76]) have been enrolled. Primary malignancies include colorectal (4), pancreas (4), prostate (2), urothelial (2), and other (3). Dose was initiated at Schedule A MTD. DL2 (T 350mcg with C AUC 6 + P 80mg/m2) exceeded the MTD with 2 of 6 pts experiencing hematologic dose limiting toxicities (DLTs). DL1 is the confirmed schedule B MTD. Dose expansion to 6 pts is ongoing. Of the 11 pts with measurable disease, 3 (27%) had PR and 5 (45%) had SD. Pts were on study a median of 10 weeks (range 5-36+). Most common grade 3/4 AEs include leukopenia (53%), neutropenia (47%), and anemia (47%). One grade 5 AE of intracranial hemorrhage occurred, possibly related to therapy in the setting of grade 3 thrombocytopenia and concern for CNS disease. Conclusions: The schedule B MTD and RP2D is T 250 mcg with C AUC 6 and P 80mg/m2. Data from the full dose expansion will be presented. This combination was tolerated with prolonged responses seen at lower dose T in combination with C+P. Clinical trial information: NCT02317874.

314 Background: Poly(ADP-ribose) polymerases (PARP) are activated by DNA strand breaks and important for DNA repair in response to platinum-based chemotherapy. PARP inhibition with Vel might enhance anti-tumor effects of Cap with Ox. This phase I study (NCI 8604) examines the tolerability, safety and preliminary efficacy of the combination of Vel with Cap and Ox. Methods: This is a phase I dose escalation protocol testing escalating doses of Vel with Cap and Ox every 28 days (Table 1). Pts were treated in cohorts of 3-6 pts until cycle 1 DLTs were defined. Key eligibility criteria included age ≥ 18 with histologically confirmed malignancy meeting at least one of the following: documented BRCA1/2 mutation and a BRCA related malignancy; a 20% probability of harboring a BRCA mutation; metastatic colorectal cancer; mucinous ovarian cancer; other GI malignancy in which Ox has demonstrated activity. Results: 17 pts (median age 52 [range 19-71]; 14 female, 3 male) were treated at 4 dose levels (DL) (Table 1). Pts had cholangiocarcinoma (6), breast (4), ovarian (4), neuroendocrine (1), pancreas (1), and colon (1) cancers. 7 pts (4 breast, 3 ovarian) are BRCA1+. Dose escalation was initiated at DL1. One DLT (mucositis) occurred at this dose level. At DL2, two DLTs (mucositis with neutropenic fever and thrombocytopenia) were noted. The protocol was amended for escalation to begin at DL1A. At DL2A, a grade 2 DLT of fatigue requiring dose delay occurred in one pt. Pts were on study for median 10 weeks (range 1 – 88). 24% of pts remained on study ≥ 6 months. Of the 14 pts with measurable disease, 5 had PR (2 ovarian, 2 breast, 1 colon) and 4 had SD (3 cholangiocarcinoma, 1 pancreas). Common AEs include nausea/vomiting (94%), diarrhea (47%), mucositis (41%), anemia (35%), neutropenia (24%), and thrombocytopenia (18%). Conclusions: Vel in combination with Cap and Ox is safe and well tolerated in pts with advanced solid malignancies. The recommended phase II dose is DL2A Vel 40mg BID (D 1-7, 15-21), Cap 1000mg/m2 BID (D 1-7, 15-21), and Ox 85mg/m2 (D 1 and 15). Clinical trial information: NCT01233505. [Table: see text]

Inferior vena cava (IVC) filters, first introduced in 1998, have been utilized to reduce risk of pulmonary embolism (PE) in the setting of an inability to anticoagulate patients. The use of IVC filters has increased and continues to rise, especially with the introduction of retrievable IVC filters. Since their initial introduction, guidelines have been developed on the appropriate use of IVC filters. According to the American College of Chest Physicians (ACCP), the use of an IVC filter is limited to patients with an absolute contraindication to therapeutic anticoagulation or failure or complication of anticoagulation in the setting an acute proximal venous thrombus. Relative indications for IVC filter placement include high clot burden in setting of low cardiopulmonary reserve, high risk patients, or severe trauma without documented thrombosis. In 2010, the FDA announced a safety communication recommending removal of retrievable IVC filters due to reports of several adverse clinical outcomes associated with retained filters including thrombus formation, recurrent PE, filter migration, erosion or perforation through the IVC wall, and filter fracture with fragment embolization. In 2014, the FDA recommended removal of the IVC filter within 2 months after filter placement if the patient's risk of thrombosis had passed. In this retrospective analysis of IVC filter management, we reviewed indications for placement according to current guidelines as set by the ACCP, initiation of appropriate anticoagulation, complication rates, and retrieval rates. In addition, we compared the data prior to the FDA recommendations in late 2014 and data after the recommendations to determine if there was a change in practice. After reviewing 179 patients, 89 patients in 2014 and 90 patients in 2015, who underwent IVC filter placement, only 81% (N=145) of patients had appropriate indications for IVC filter placement and 30% (N=54) of patients had inappropriate anticoagulation after IVC filter placement, given as prophylactic dosing of low molecular weight heparin. A comparison of retrieval rates prior to and after the FDA warning, showed a 19% (60% in 2014 vs 79% in 2015) improvement in IVC filter removals. There was an 11% complication rate, mainly related to IVC filter related acute DVT or IVC occlusion. A root cause analysis specifically for inappropriate IVC filter placement and appropriate anticoagulation and determined that familiarity of the guidelines and non-evidence based recommendations from consultants were major factors. Based on the analysis, we next plan to utilize the electronic health record system to help clinicians understand indications and when to initiate appropriate anticoagulation, with the opportunity for hematology consultants to be involved in situations that do not clearly fit within published guidelines. Disclosures No relevant conflicts of interest to declare.