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Objective Preclinical studies with muscadine grape extract (MGE) show antitumor activity and decreased systemic inflammation. This phase I study (NCT02583269) assessed safety and tolerability of a proprietary MGE preparation in patients with advanced solid tumors. Methods Patients with metastatic or unresectable cancers who were progressing on standard therapies were assigned to MGE in a standard 3+3 design. Five dose levels were tested (320 to 1600 mg total phenolics/d). Safety and maximum-tolerated dose were assessed after 4 weeks. Patients were evaluated for response at 8 weeks and continued on MGE if clinically stable. Secondary outcomes were response, survival, adherence, fatigue, and quality of life (QOL). Results In total, 23 patients (lung, n=7; gastrointestinal, n=7; genitourinary, n=6; other, n=3) received MGE capsules by mouth twice daily. The cohort [median age 72 years, 48% Eastern Cooperative Oncology Group (ECOG) 2] was heavily pretreated. After 4 weeks on MGE, possibly attributable adverse events grade 2 or higher were fatigue (n=1), decreased lymphocyte count (n=1), and constipation (n=2), including 1 dose-limiting toxicity for grade 3 constipation. Maximum-tolerated dose was not reached. No partial responses were observed. Median time on therapy was 8 weeks, with 29% of patients treated beyond 16 weeks and a median overall survival of 7.2 months. QOL and fatigue levels were stable from baseline to 8 weeks. Higher MGE dose was correlated with improvement in self-reported physical well-being QOL at 8 weeks (r=0.6; P=0.04). Conclusions MGE is safe and well-tolerated in heavily pretreated and older cancer patients. The potential anticancer properties and the effects of MGE on physical well-being and QOL metrics will be evaluated in future studies.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC. Patients and Methods: Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1–5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability. Results: A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen. Conclusions: Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.

4023 Background: Metastatic pancreatic cancer (mPC) remains a deadly disease with very limited treatment options. FFX is a standard first-line therapy for mPC with a median overall survival (mOS) of 11.1 months. CPI-613 is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic cycle preferentially within the mitochondria of cancer cells. In a phase I study, CPI-613+mFFX was safe and exhibited promising signal of efficacy. Methods: A global, randomized phase 3 trial was conducted across 73 sites to investigate the efficacy and safety of CPI-613 in combination with mFFX compared to standard dose FFX in treatment-naïve patients with mPC. Treatment was administered in 2-weekly cycles until progression or intolerable toxicity. In the experimental arm, CPI-613 at 500 mg/m2 was given intravenously on days 1 and 3. The doses of irinotecan, oxaliplatin, and 5-fluorouracil in the experimental arm were 65 mg/m2, 140 mg/m2, and 2,400 mg/2, respectively. Primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics, patient reported outcomes and safety. Results: 528 patients were randomly assigned (266 in test and 262 in control arm). There were 362 deaths, with a mOS of 11.1 months for CPI-613+mFFX vs. 11.7 months for FFX [hazard ratio (HR), 0.95; 95% CI, 0.77 to 1.18; P = 0.655]; mPFS was 7.8 months vs. 8.0 months respectively [HR, 0.99; 95% CI, 0.76 to 1.29; P = 0.94]; ORR was 39% in the test arm vs. 34% in the control arm [ORR ratio, 1.23 (95% CI, 0.86 to 1.75)]. Grade ≥ 3 treatment-emergent adverse events with ≥ 10% frequency in CPI-613 plus mFFX vs. FFX arm were diarrhea (11.2% vs. 19.6%), hypokalemia (13.1% vs. 14.9%), anemia (13.9% vs. 13.6%), neutropenia (11.2% vs. 14.0%), thrombocytopenia (11.6% vs. 13.6%) and fatigue (10.8% vs. 11.5%). Conclusions: The addition of CPI-613 to mFFX failed to show significant improvements of ORR, PFS or OS. The mFFX in the test arm that had the lowest prospectively tested doses of FFX was without compromise on PFS or OS and may be considered as a reference for future FFX administration. Clinical trial information: NCT03504423.

Developing effective strategies to prevent or treat coronavirus disease 2019 (COVID-19) requires understanding the natural immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We used an unbiased, genome-wide screening technology to determine the precise peptide sequences in SARS-CoV-2 that are recognized by the memory CD8+ T cells of COVID-19 patients. In total, we identified 3-8 epitopes for each of the 6 most prevalent human leukocyte antigen (HLA) types. These epitopes were broadly shared across patients and located in regions of the virus that are not subject to mutational variation. Notably, only 3 of the 29 shared epitopes were located in the spike protein, whereas most epitopes were located in ORF1ab or the nucleocapsid protein. We also found that CD8+ T cells generally do not cross-react with epitopes in the four seasonal coronaviruses that cause the common cold. Overall, these findings can inform development of next-generation vaccines that better recapitulate natural CD8+ T cell immunity to SARS-CoV-2.

Development of effective strategies to detect, treat, or prevent COVID-19 requires a robust understanding of the natural immune response to SARS-CoV-2, including the cellular response mediated by T cells. We used an unbiased, genome-wide screening technology, termed T-Scan, to identify specific epitopes in SARS-CoV-2 that are recognized by the memory CD8+ T cells of 25 COVID-19 convalescent patients, focusing on epitopes presented by the six most prevalent HLA types: A*02:01, A*01:01, A*03:01, A*11:01, A*24:02, and B*07:02. For each HLA type, the patients’ T cells recognized 3–8 immunodominant epitopes that are broadly shared among patients. Remarkably, 94% of screened patients had T cells that recognized at least one of the three most dominant epitopes for a given HLA, and 53% of patients had T cells that recognized all three. Subsequent validation studies in 18 additional A*02:01 patients confirmed the presence of memory CD8+ T cells specific for the top six A*02:01 epitopes, and single-cell sequencing revealed that patients often have many different T cell clones targeting each epitope, but that the same T cell receptor Vα regions are predominantly used to recognize these epitopes, even across patients. In total, we identified 29 shared epitopes across the six HLA types studied. T cells that target most of these epitopes (27 of 29) do not cross-react with the endemic coronaviruses that cause the common cold, and the epitopes do not occur in regions with high mutational variation. Notably, only 3 of the 29 epitopes reside in the spike protein, highlighting the need to design new classes of vaccines that recapitulate natural CD8+ T cell responses to SARS-CoV-2.

Summary Background Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Interpretation Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding Merck & Co, Inc.

TPS637 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by stromal fibrosis, hypoxia, and nutritional deprivation. PDAC tumors grow aggressively, diagnosis is typically made after metastasis and the disease remains associated with poor outcomes. The triplet chemotherapy regimen of gemcitabine, nab-paclitaxel with cisplatin was associated with a median overall survival of 16.4 months in patients with metastatic pancreatic cancer in the first-line setting (Jameson et al., 2020). Nutritional, metabolic interventions offer an opportunity to fundamentally change the tumor microenvironment and improve outcomes for patients. A ketogenic diet defined as lower carbohydrate, lower protein, and higher fat can significantly reduce glucose and insulin and increase metabolically active ketone bodies and has been evaluated in patients with a variety of solid tumors (Weber et al, 2020). Recently, a ketogenic diet combined with triplet chemotherapy was shown to inhibit murine pancreatic KPC tumor growth and significantly prolong animal survival over chemotherapy alone. Tumor growth inhibition was associated with glucose depletion, altered TCA substrate usage, and NADH elevation. Methods: In this Phase II randomized clinical trial (NCT04631445), we are evaluating a medically supervised ketogenic diet (MSKD) versus a standard diet when combined with the triplet therapy in patients with treatment-naive advanced pancreatic cancer. The primary endpoint is progression free survival for triplet therapy while on MSKD or non-MSKD. Secondary endpoints include disease control rate (PR+ CR+ SD for at least 9 weeks), change in CA 19-9 (or CA125, or CEA if not expressers of CA 19-9), average insulin levels, HbA1c, body weight, a comparison of gut microbial diversity, changes in serum metabolites and quality of life via the EORTC QLQ-C30 assessment. Unlike prior ketogenic intervention studies, the MSKD is being supported by a continuous care nutrition intervention through Virta Health Corp, that offers tracking of daily ketone and glucose levels, a web-based software application, education, and communication with a remote care team to ensure sustained nutritional ketosis. A total of 40 patients with untreated metastatic PDAC are planned for enrollment, 20 randomized to each arm. The trial opened for accrual November 2020. Clinical trial information: NCT04631445.

Summary Background Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. Methods In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0–1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m 2 , leucovorin at 400 mg/m 2 , irinotecan at 140 mg/m 2 , and fluorouracil 400 mg/m 2 bolus followed by 2400 mg/m 2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m 2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Findings Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m 2 . The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4–19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250–602). Two patients enrolled at a higher dose of 1000 mg/m 2 , and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3–4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3–4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1–3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. Interpretation A maximum tolerated dose of CPI-613 was established at 500 mg/m 2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Funding Comprehensive Cancer Center of Wake Forest Baptist Medical Center.

Background Solid tumors residing in tissues and organs leave footprints in circulation through circulating tumor cells (CTCs) and circulating tumor DNAs (ctDNA). Characterization of the ctDNA portraits and comparison with tumor DNA mutational portraits may reveal clinically actionable information on solid tumors that is traditionally achieved through more invasive approaches. Methods We isolated ctDNAs from plasma of patients of 103 lung cancer and 74 other solid tumors of different tissue origins. Deep sequencing using the Guardant360 test was performed to identify mutations in 73 clinically actionable genes, and the results were associated with clinical characteristics of the patient. The mutation profiles of 37 lung cancer cases with paired ctDNA and tumor genomic DNA sequencing were used to evaluate clonal representation of tumor in circulation. Five lung cancer cases with longitudinal ctDNA sampling were monitored for cancer progression or response to treatments. Results Mutations in TP53, EGFR, and KRAS genes are most prevalent in our cohort. Mutation rates of ctDNA are similar in early (I and II) and late stage (III and IV) cancers. Mutation in DNA repair genes BRCA1, BRCA2, and ATM are found in 18.1% (32/177) of cases. Patients with higher mutation rates had significantly higher mortality rates. Lung cancer of never smokers exhibited significantly higher ctDNA mutation rates as well as higher EGFR and ERBB2 mutations than ever smokers. Comparative analysis of ctDNA and tumor DNA mutation data from the same patients showed that key driver mutations could be detected in plasma even when they were present at a minor clonal population in the tumor. Mutations of key genes found in the tumor tissue could remain in circulation even after frontline radiotherapy and chemotherapy suggesting these mutations represented resistance mechanisms. Longitudinal sampling of five lung cancer cases showed distinct changes in ctDNA mutation portraits that are consistent with cancer progression or response to EGFR drug treatment. Conclusions This study demonstrates that ctDNA mutation rates in the key tumor-associated genes are clinical parameters relevant to smoking status and mortality. Mutations in ctDNA may serve as an early detection tool for cancer. This study quantitatively confirms the hypothesis that ctDNAs in circulation is the result of dissemination of aggressive tumor clones and survival of resistant clones. This study supports the use of ctDNA profiling as a less-invasive approach to monitor cancer progression and selection of appropriate drugs during cancer evolution. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0468-1) contains supplementary material, which is available to authorized users.

Background: Improving outcomes of PDAC with checkpoint inhibitors (CPIs) have been ineffective, underscoring the need to co-target alternative pathways. Preclinical data showed that CXCR4-SDF1 axis modulates the tumor microenvironment (TME) in PDAC and that CXCR4 inhibition enhances T cell access to the TME, increasing tumor sensitivity to CPIs. This was confirmed in the COMBAT Cohort 1 (CC1) study showing that the dual combination M+P increases activated CD8+ T cells and decreases myeloid derived suppressor cells (MDSCs) within the TME. Moreover, our pre-clinical studies showed that adding C to M+P resulted in improved efficacy vs C alone. The COMBAT Cohort 2 (CC2) aims to test the safety and efficacy of the triple combination of M+P+C in 2L mPDAC. Methods: Single arm phase 2a study in mPDAC. In cohort 2, patients with stage IV PDAC at diagnose who had progressed to 1L gemcitabine-based C received 5 days M priming, followed by M BIW + P Q3W plus C [Irinotecan liposomal injection/5-FU/LV (OFL)] Q2W. The primary endpoint was RR. Results: A total of 43 patients with stage 4 PDAC, 98% of whom were diagnosed with stage 4 disease, were enrolled. Median age was 68 (40-85) and 74.4% had liver disease. The safety profile was consistent with the individual profiles of each treatment alone. Of note, the incidence of ≥G3 neutropenia (G3Neu) was 7% and ≥G3 infection was 7%, which is lower than expected for C (OFL) alone (20% and 17%, respectively). The levels of T-cells increased during M priming and returned to normal values, which remained stable across the study despite the OFL treatment. For the evaluable patients (N=38) the ORR was 21.1% with a 13.2% confirmed ORR (defined as two consecutive assessments showing PR) and a 63.2% DCR (PR+SD). Median duration of clinical benefit was 5.6 months. Median OS and PFS were 6.5 months and 4.0 months, respectively (6.6 months and 3.8 months, respectively, for the ITT population). Conclusions: The triple combination of M+P+C is tolerable and shows encouraging results with cORR 13.2%, mPFS 4.0 months and mOS 6.5 months (compared to 7.7%, ~3 months and 4.7 months, respectively, on a historical basis for OFL alone in the stage 4 diagnosis subpopulation). SD of 42.1% and DCR of 63.2% were also higher than historical data on SoC chemotherapy used in 2L patients. The incidence of severe neutropenia and infections is lower than the historical data on C. The results from the CC2 suggest that M+P may expand the efficacy and safety benefit of OFL in PDAC, and warrants further investigation in a randomized study. Citation Format: Manuel Hidalgo, Teresa Macarulla, Valerya Semenisty, Erkut Borazanci, Jaime Feliu, Mariano Ponz-Sarvise, David Gutierrez Abad, Paul Oberstein, Angela Alistar, Andres Muñoz, Ravit Geva, Carmen Guillén-Ponce, Mercedes Salgado Fernandez, Amnon Peled, Marya Chaney, Irit Glicko-Kabir, Liron Shemesh-Darvish, Debby Ickowicz, Ella Sorani, Shaul E. Kadosh, Abi Vainstein-Haras, Bruno Bockorny. A multi-center phase 2a trial of the CXCR4 inhibitor motixafortide (BL-8040) (M) in combination with pembrolizumab (P) and chemotherapy (C), in patients with metastatic pancreatic adenocarcinoma (mPDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT177.

2512 Background: BDB001 is an intravenously administered TLR 7/8 dual agonist immune modulator capable of reprogramming dendritic cells to produce antitumor activities. BDB001 monotherapy has demonstrated favorable tolerability and robust systemic immune activation leading to durable clinical responses in a phase I dose escalation trial. Here, we report on the safety and efficacy of BDB001 in combination with pembrolizumab in a phase I dose escalation trial in advanced solid tumors (NCT03486301). Methods: BDB001-101 is a phase 1, open label, dose escalation/expansion trial of BDB001 (IV, Q1W) in combination with pembrolizumab (IV, Q3W) in patients with advanced solid tumors. The primary endpoint was safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics and pharmacodynamic profiling of immune activation. Results: Twenty-three subjects with 13 different tumor types were enrolled across 4 dose levels. Sixty one percent were female, median age was 63 years (range, 33-86), median number of prior therapies was 3 (range, 1-8), and 48% of tumors had progressed on prior anti-PD-(L)1 therapy. Overall, BDB001 in combination with pembrolizumab was well tolerated and dose-limiting toxicities were not observed. The most common treatment related adverse events (TRAEs) were fever (39.1%), fatigue (39.1%), chills/rigor (34.8%), pruritus/rash (21.7%), and nausea (13.0%). Most of these TRAEs were grade 1 or 2 and transient. Only 3 (13.0%) subjects experienced grade 3 TRAEs of fatigue, rash, stomatitis, and alkaline phosphatase elevation. There were no grade 4 or 5 TRAEs. Pharmacodynamic evaluation of plasma cytokine levels showed robust increases in interferon gamma and interferon inducible protein-10 (IP-10) at BDB001 Dose Level 3 and 4. Preliminary efficacy evaluation of the 14 subjects treated at Dose Level 3 and 4 showed durable and deep clinical responses in 4 (29%) subjects with anti-PD-(L)1 mAb refractory melanoma, hepatocellular carcinoma, cholangiocarcinoma, and platinum-resistant ovarian carcinoma. The responses were observed by the initial efficacy assessment at 9-weeks, with some seen as early as 4-weeks. In addition, 4 (29%) subjects had stable disease for a disease control rate of 57%. To date, median time on treatment is 14.4 weeks (range, 6.0 – 42.1+) with 3 subjects still active on treatment. Conclusions: Intravenously administered BDB001 in combination with pembrolizumab is well tolerated. Rapid and deep clinical responses were observed, supported by robust systemic immune activation. BDB001 in combination with pembrolizumab is a promising novel therapeutic option for patients with advanced solid tumors and is being evaluated in an ongoing dose expansion trial. Clinical trial information: NCT03486301.

TPS2673 Background: Immune checkpoint inhibitors directly targeting T cell activation have been successfully used in the treatment of various malignancies, nevertheless, the durable ORRs are low for certain indications. The low ORRs have been attributed to the immune suppressive tumor microenvironment (TME), composed of innate immune suppressive components such as tumor associated macrophages (TAM) and myeloid-derived suppression cells (MDSC). The potential contributions of innate immune modulation to anti-tumor immunity, suggest the need for the novel strategies to elicit a more efficient/robust immune response against the targeted malignant cells. Axl, Mer and CSF1R receptor tyrosine kinases play vital roles in promoting an immune suppressive TME by affecting TAM and MDSC populations and by decreasing antigen presentation on tumor cells. Q702 is a novel Axl/Mer/CSF1R inhibitor, able to modulate the TAM and MDSC population leading to CD8+ T cell activation and to increase antigen presentation of the tumor cells in syngeneic animal models. Q702, as a monotherapy, shows significant tumor growth inhibition in multiple syngeneic tumor models, and demonstrates synergistic effects with anti-PD-1 treatment particularly in high myeloid containing tumor models. Interestingly, intermittent administration of Q702 monotherapy demonstrates a more favorable immune cell population changes, possibly through preventing immune exhaustion secondary to negative feedback with continuous activation. These results suggest that Q702 monotherapy or in combination with existing therapies have a good potential to become a novel treatment strategy for patients with advanced solid tumors. Methods: “A Phase 1, Multicenter, Open-label, Dose-Escalation, Safety, Pharmacodynamic, Pharmacokinetic Study of Q702 with a Cohort Expansion at the RP2D in Patients with Advanced Solid Tumors. (NCT04648254)” is open and recruiting patients at 4 US investigative sites. Patients with histologically or cytologically confirmed advanced or metastatic solid tumors, that have progressed following SOC or for which there is no SOC which confers clinical benefit are being enrolled in this study. The study follows a standard dose escalation. The study will enroll up to 78 patients. The primary endpoint is to establish safety, PK profile and define the recommended phase 2 dose. The secondary and exploratory endpoints include establishing pharmacokinetic/pharmacodynamic relationship, potential biomarkers and preliminary anti-tumor activity. Clinical trial information: NCT04648254.

2552 Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokine that selectively binds the intermediate-affinity interleukin-2 receptor to preferentially activate CD8+ T and natural killer (NK) cells with minimal expansion of regulatory T cells (Tregs),designed for use as a cancer immunotherapy. ARTISTRY-2 (NCT03861793) is an ongoing phase 1/2 study evaluating the safety, efficacy, and pharmacokinetic and pharmacodynamic (PD) responses of subcutaneous (SC) nemvaleukin in combination with pembrolizumab in patients (pts) with advanced solid tumors. Methods: In phase 1, cohort-specific doses of SC nemvaleukin are administered on an every-7-day (q7d) or every-21-day (q21d) schedule during a 6-week monotherapy lead-in period, followed by combination with pembrolizumab 200 mg q21d. We present safety, PD effects, and preliminary clinical activity outcomes as of 12/02/2020. Results: 57 pts received nemvaleukin doses ranging from 0.3 mg to 6 mg q7d or 1 mg to 10 mg q21d. The most frequent tumor types (> 5 pts) were colorectal, pancreatic, ovarian, and lung; median number of prior therapies was 4. Treatment-related adverse events (TRAEs) in > 30% pts overall were pyrexia (43.9%), chills (38.6%), injection site erythema (33.3%), injection site reaction (33.3%), and fatigue (31.6%). 3 mg q7d (n = 7) had no drug-related dose reductions, discontinuations, or deaths during the monotherapy or combination periods. 6 mg was declared the maximum tolerated dose (MTD) for q7d dosing as 2 of 8 pts experienced dose-limiting toxicities (DLTs). For 6 mg q21d (n = 7), no drug-related dose reductions, discontinuations, or deaths have occurred during the monotherapy period; combination period data are not mature. 10 mg was declared the MTD for q21d dosing as 1 of 9 pts experienced DLTs and 3 had TRAEs leading to dose reductions. Systemic exposure to nemvaleukin increased with increasing dose. Increases in NK cells and CD8+ T cells of approximately 16-fold and 3-fold, respectively, at 3 mg q7d, and approximately 8-fold and 3-fold, respectively, at 6 mg q21d were observed, with minimal change in Tregs. 46 pts had at least 1 on-treatment scan as of the data cutoff date, and 30 (65%) had stable disease (SD) on the first scan. Of the 30 pts with ≥2 scans, 13 (43%) had 2+ consecutive scans of SD. 16 of 57 pts remain on therapy. Antitumor activity data for more recent cohorts are still maturing. Based on the totality of the safety, PD effects, and antitumor activity data, 3 mg q7d was selected as the RP2D for SC nemvaleukin. Conclusions: SC nemvaleukin 3 mg q7d was generally well tolerated as monotherapy and in combination with pembrolizumab, and demonstrated robust PD effects on NK cells and CD8+ T cells with minimal expansion of Tregs. These PD effects are similar to or greater than those observed with intravenous nemvaleukin. Thus, 3 mg q7d was selected as RP2D; phase 2 expansion cohorts for combination with pembrolizumab are enrolling. Clinical trial information: NCT03861793.

4635 Background: Glycolic and mitochondrial metabolism are aberrant in pancreatic cancer and translate into chemoresistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species, such as nab-paclitaxel. CPI- 613 is a novel antimitochondrial agent developed by Rafael Pharmaceuticals that showed promising clinical activity in combination with modified FOLFIRINOX in patients with stage IV pancreatic cancer. Preclinical data suggested possible synergy of CPI-613 with nab-paclitaxel. Methods: Single arm, open-label, phase I study of CPI-613 with gemcitabine and nab-paclitaxel in patients with locally advanced or metastatic pancreatic cancer to determine MTD, safety, and preliminary efficacy of CPI-613 in combination with chemotherapy. Key eligibility criteria included: histologically documented and measurable locally-advanced or metastatic, PDAC. ECOG performance status 0-2; and first line systemic treatment. CPI-613 was infused intravenously with a starting dose of 500 mg/m2 followed by modified dose nab-paclitaxel (100mg/m2) and gemcitabine ( 800 mg/m2) on Days 1, 8, and 15 of a 28-day cycle. The the primary endpoint, the MTD of CPI-613 was determined by a two-stage, dose-escalation schema, with 6-month treatment duration for patients exhibiting treatment response. Secondary endpoints were treatment-related adverse events, complete response (CR) and partial response (PR). Results: From February 2018 to 2020, 26 patients were screened, (23 metastatic and 3 locally advanced), 22 patients enrolled and 18 patients underwent a restaging scan. As of the time of submission 3 patients are still on active treatment. Patient demographics were: median age of 65, ECOG was 0-1, The MTD of CPI- 613 was determined to be 1500 mg/m2. The dose limiting toxicities were not achieved. Overall the treatment was well tolerated with toxicities mainly related to chemotherapy; most common grade 3 and 4 toxicities were hematologic toxicity and neuropathy. 1 patient achieved CR, 9 PR, 8 stable disease and 1 progressive disease for an objective response rate of 50% with a CR rate of 5.5%. Conclusions: The results demonstrate that CPI 613 can be safely administered with gemcitabine and nab-paclitaxel at doses up to 1,500 m/g2. Efficacy data suggest synergy with chemotherapy. Further clinical studies of CPI-613 efficacy in pancreatic cancer are in progress. Clinical trial information: NCT03435289 .

e16050 Background: The PI3K/mTOR pathway overactivation and loss of PTEN occur in 20-40% of mCRC pts. A recent phase 1/2 study in mCRC pts showed evidence that everolimus added to 1L SOC treatment improved outcomes, in particular in pts with PTEN loss (Gilcrease, 2019). This prospective, single-arm phase 1/2 study aims to identify the optimal dose and schedule of nab-sirolimus (ABI-009), an mTOR inhibitor, plus FB and evaluate the safety and preliminary efficacy of this regimen. Methods: Eligible pts have no prior therapy, ≥18 years old, ECOG performance status of 0-2. PTEN loss (by IHC) is evaluated for all pts. nab-Sirolimus IV starting dose and schedule was 30mg/m2 weekly for 3 weeks followed by a week of rest (on D1, 8, and 15 in a 28-day cycle, qw3/4) plus standard doses of FB on D1 and D15. Dose escalation to 45 and 60mg/m2 or de-escalation to 20 and 10mg/m2 followed the 3+3 design. Dose limiting toxicity (DLT) was assessed in cycle 1. Results: As of Jan 31, 2020, 24 pts were treated in the phase 1 study and 18 were evaluable for response. No DLTs were observed in the first 3 pts treated with nab-sirolimus at 30mg/m2 qw3/4; however, all 3 pts missed D8 doses (due to G2 thrombocytopenia and G3 neutropenia) and the cohort expanded to additional 3 pts for further observation. 5/6 pts missed D8 doses and a new dose cohort enrolled pts at 20mg/m2 qw3/4. No DLTs were observed and the cohort was expanded to 10 pts. A safety review of the first 18 pts observed that 9/18 pts missed doses on D8 and a new cohort was added to enroll pts at 20 mg/m2 q2w (D1 and D15, as for FB). This cohort enrolled 8 pts with no DLTs and represents the recommended-phase-2-dose (RP2D) and continues enrollment in phase 2. For all pts, 15/24 (63%) pts had G3-4 treatment-related adverse events (TRAEs); most common were neutropenia (6/24, 25%) and thrombocytopenia (4/24, 17%). At the RP2D 3/8 (38%) pts had G3-4 TRAEs (thrombocytopenia, weight loss, and hypertension, 1 pt each). Among 18 evaluable pts, best response was: 7/18 (39%) partial response, 10/18 (56%) stable disease, and 16/18 (89%) had tumor shrinkage. PTEN was assessed in 14 pts: 4/14 (29%) had PTEN loss, 2/4 (50%) PTEN loss pts responded, while 3/10 (30%) pts that were PTEN+ (WT) had a response. Conclusions: The RP2D of nab-sirolimus is 20mg/m2 q2w in combination with standard mFOLFOX+bevacizumab. The phase 2 portion of the study is ongoing. Clinical trial information: NCT03439462 .

Purpose: Few treatment options are available for patients with advanced or metastatic hepatocellular carcinoma (HCC). Based on preclinical and early clinical efficacy signals and lack of overlapping toxicity, we undertook this multicenter phase II trial to estimate efficacy and safety of everolimus and pasireotide in advanced HCC. Methods: Patients with advanced HCC not amenable to locoregional therapy and Child-Pugh A cirrhosis received everolimus 7.5 mg PO daily and pasireotide LAR 60 mg IM every 28 days. The primary endpoint was time to progression (TTP), with 26 events needed to evaluate if everolimus + pasireotide improved TTP from 2.8 to 4.4 months, with 80 % power and an alpha of 0.05. Secondary endpoints included response as measured by RECIST modified for HCC, treatment-emergent adverse events, and overall survival. Results: After 24 patients were enrolled, results of a randomized trial showing no benefit of everolimus in HCC were released prompting an unplanned interim analysis that found the conditional probability of rejecting the null hypothesis based on events in those patients was 0.08. Therefore accrual was halted. Patients had a median age of 59 years, 21 (88 %) had BCLC stage C cancer, and 11 (46 %) metastatic disease. Median TTP was 3.5 months (95 % CI 2–5.8) and median survival 6.7 months (95 % CI 6-infinity). Best response was stable disease in ten patients. Grade 3 hyperglycemia occurred in 6 (25 %). There were no grade 4 treatment-emergent events. Conclusion: Despite promising early efficacy signals, we found no benefit for the combination of everolimus and pasireotide in HCC.

Background: Cancers related to tobacco use and African-American ancestry are under-characterized by genomics. This gap in precision oncology research represents a major challenge in the health disparities in the United States. Methods: The Precision Oncology trial at the Wake Forest Baptist Comprehensive Cancer Center enrolled 431 cancer patients from March 2015 to May 2016. The composition of these patients consists of a high representation of tobacco-related cancers (e.g., lung, colorectal, and bladder) and African-American ancestry (13.5%). Tumors were sequenced to identify mutations to gain insight into genetic alterations associated with smoking and/or African-American ancestry. Results: Tobacco-related cancers exhibit a high mutational load. These tumors are characterized by high-frequency mutations in TP53, DNA damage repair genes (BRCA2 and ATM), and chromatin remodeling genes (the lysine methyltransferases KMT2D or MLL2, and KMT2C or MLL3). These tobacco-related cancers also exhibit augmented tumor heterogeneities. Smoking related genetic mutations were validated by The Cancer Genome Atlas dataset that includes 2,821 cases with known smoking status. The Wake Forest and The Cancer Genome Atlas cohorts (431 and 7,991 cases, respectively) revealed a significantly increased mutation rate in the TP53 gene in the African-American subgroup studied. Both cohorts also revealed 5 genes (e.g. CDK8) significantly amplified in the African-American population. Conclusions: These results provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer. TP53 mutations and key oncogene amplifications emerge as key factors contributing to cancer outcome disparities among different racial/ethnic groups.

The abundance and functional orientation of tumor-infiltrating lymphocytes in breast cancer is associated with distant metastasis-free survival, yet how this association is influenced by tumor phenotypic heterogeneity is poorly understood. Here, a bioinformatics approach defined tumor biologic attributes that influence this association and delineated tumor subtypes that may differ in their ability to sustain durable antitumor immune responses. A large database of breast tumor expression profiles and associated clinical data was compiled, from which the ability of phenotypic markers to significantly influence the prognostic performance of a classification model that incorporates immune cell–specific gene signatures was ascertained. Markers of cell proliferation and intrinsic molecular subtype reproducibly distinguished two breast cancer subtypes that we refer to as immune benefit-enabled (IBE) and immune benefit-disabled (IBD). The IBE tumors, comprised mostly of highly proliferative tumors of the basal-like, HER2-enriched, and luminal B subtypes, could be stratified by the immune classifier into significantly different prognostic groups, while IBD tumors could not, indicating the potential for productive engagement of metastasis-protective immunity in IBE tumors, but not in IBD tumors. The prognostic stratification in IBE was independent of conventional variables. Gene network analysis predicted the activation of TNFα/IFNγ signaling pathways in IBE tumors and the activation of the transforming growth factor-β pathway in IBD tumors. This prediction supports a model in which breast tumors can be distinguished on the basis of their potential for metastasis-protective immune responsiveness. Whether IBE and IBD represent clinically relevant contexts for evaluating sensitivity to immunotherapeutic agents warrants further investigation. Cancer Immunol Res; 4(7); 600–10. ©2016 AACR.

Pancreatic neuroendocrine tumors (PNETs) represent a group of diseases that pose diagnostic and therapeutic challenges due to their clinical and pathological heterogeneity as well as the limited number of patients available for clinical trials. Over the last couple of decades, a major progress in understanding tumor biology led to the discovery of new potential targets for the medical treatment of these tumors.There are numerous novel targeted agents in various stages of preclinical and clinical development that offer considerable promise as monotherapy or combination therapy for PNETs. The question of whether traditional clinical research methods are appropriate for the development of novel, targeted anticancer agents has been the subject of many discussions. Major challenges include identifying a valid target, the most effective agent within a target class, the right subset of population to benefit from the drug, and the most appropriate setting to use the drug. As new agents emerge, oncologists are faced with making clinical decisions sometimes before having a high level of evidence. In this review, we attempt to address some of the management steps involved in treating patients with pancreatic neuroendocrine tumors, particularly well to moderately differentiated tumors. The purpose of this review is to offer a therapeutic sequence including surgery, liver-directed therapy, chemotherapy, and targeted therapy for this disease.

TPS459 Background: Pancreatic cancer is the third leading cause of cancer death in the USA. The most effective treatments for first-line metastatic pancreatic cancer are FOLFIRINOX and gemcitabine plus nab-paclitaxel, which provide a median overall survival of 11·1 months and 8·5 months with moderate toxicity. Safer and more effective treatments are needed. The glycolic and mitochondrial metabolism are aberrant in pancreatic cancer and translate into chemoresistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species such as Nab-Paclitaxel. CPI- 613 is a novel antimitocondrial developed by Rafael Pharmaceuticals that showed preclinical activity in pancreatic cancer cell lines as well as promising clinical activity in combination with modified FOLFIRINOX in patients with stage IV pancreatic cancer. Preclinical data suggests possible synergy of CPI- 613 with nab-paclitaxel. Methods: This is a single arm, open-label, nonblinded phase I study of CPI-613 in combination with gemcitabine and nab-paclitaxel in patients with locally advanced or metastatic pancreatic cancer. Key eligibility criteria include: histologically or cytologically documented and measurable locally advanced or metastatic pancreatic adenocarcinoma, ECOG performance status 0-2, first line treatment for both locally advanced or metastatic. CPI-613 will be infused intravenously with a starting dose of 500 mg/m2 followed by 125 mg/m2 nab-paclitaxel and 1,000 mg/m2 gemcitabine on day 1, 8, 15 of a 28-day cycle. The study is comprised of a two-stage dose-escalation schema to evaluate the MTD of CPI-613. At least six months of treatment is planned for patients who have a response. Primary endpoint of the study is MTD of CPI 613 when combined with gemcitabine and nab-paclitaxel and secondary endpoints of the study are treatment related adverse events, CR and PR. This study was initiated in February 2018 at Atlantic Health System and within first seven months of the study, 11 out of 24 planned patients have been enrolled. Clinical trial information: NCT03435289.

TPS730 Background: Very few treatment options are available for pts with mCRC beside the standard of care (SOC), 5-FU based chemotherapy + bevacizumab. Immunotherapy is an option for pts with microsatellite instability (~5% of mCRC). The central role of the PI3K/mTOR pathway in cancer biology, including CRC, suggests that mTOR inhibition along with chemotherapy may improve antitumor activity in the metastatic setting. A recent phase I/II study showed promising antitumor activity of everolimus + SOC as 1L treatment for mCRC (96% progression-free [PF] rate at six months at the maximum tolerated dose (MTD), and 86% ORR for pts with PTEN loss (Gilcrease, ASCO 2012). The goal of this prospective, single arm phase I/II study is to evaluate the efficacy and safety of ABI-009, a novel mTOR inhibitor, + SOC as 1L treatment for mCRC. Methods: Eligible pts have an ECOG performance status of 0-2 and histologically confirmed measurable metastatic disease. PTEN loss (by IHC) and mutational status for PIK3CA, KRAS, NRAS, BRAF by NGS is evaluated for all pts. ABI-009 is given weekly x3 every four weeks starting at 30 mg/m2and can escalate to 45 and 60 mg/m2 (3+3 design); mFOLFOX6 + bevacizumab is given every two weeks. After six cycles of therapy, cycles may change to 21-days: ABI-009 weekly x2 every three weeks and mFOLFOX6 + bevacizumab every three weeks. Pts are treated until disease progression. Tumor response is assessed by CT at baseline then every eight weeks for one year, then every 12 weeks thereafter. Phase I will enroll up to 18 pts; the primary endpoints are dose-limiting toxicities and MTD, secondary endpoints include disease control rate (DCR). Phase II will enroll 40 pts; the primary endpoint is PF rate at six months, and secondary endpoints are median PF survival, overall survival, duration of response, and DCR in the intent-to-treat population and based on PTEN status. This study is now active, with first pt enrolled. The anticipated enrollment period is 12 months. This prospective phase I/II study may show evidence of efficacy and safety of ABI-009 combined with the SOC in pts with mCRC with or without PTEN loss to warrant a larger clinical study. Results: N/A. Conclusions: N/A. Clinical trial information: NCT03439462.

TPS479 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Current treatments using FOLFIRINOX and gemcitabine plus nab-paclitaxel, provide median survivals of 11.1 and 8.5 months, respectively. PDAC cells have altered metabolism. CPI-613 is a novel TCA cycle inhibitor that targets cancer cells. In a phase I study mFFX plus CPI-613 resulted in a 61% objective response rate with 3 of 18 patients achieving a complete response. Methods: Avenger 500 (NCT03504423) is an open-label randomized trial of CPI-613 plus mFFX versus FFX in untreated patients with metastatic PDAC. 500 patients will be randomized 1:1 between arms. The experimental arm comprises CPI-613 500 mg/m2 on day 1 and 3 of a 14-day cycle. The mFFX regimen is the standard dose and schedule of 5-Fluorouracil but reduced doses of oxaliplatin (65 mg/m²) and irinotecan (140 mg/m²). The control arm is standard dose FFX. There are two co-primary endpoints: Overall Response Rate (ORR, Complete Response + Partial Response). Best response within the first 12 cycles will be used for this determination, to be confirmed by independent, blinded, central review. Progression-Free Survival (PFS), is the second co-primary endpoint. Secondary endpoints are overall survival, duration of response and safety. Patient reported outcomes will be compared using the NCCN-FACT FHSI-18. An interim analysis will be done after 167 patients are evaluable for response. The difference in ORR will be tested using a Lan-DeMets Pocock type boundary for futility and efficacy. Futility will be declared if the difference in ORR between the arms is smaller than 5%, while efficacy will be declared if it is larger than 20%. The PFS hazard ratio will be tested using a Lan-DeMets O’Brien-Fleming type boundary. Efficacy will be declared if the hazard ratio is less than 0.48. The final analysis will be done with 500 patients randomized, when ~375 PFS events are available. Significance will be reached if the PFS hazard ratio is less than 0.80, or the difference in ORR is at least 11%. If the trial reaches significance for either primary endpoint, overall survival will be tested. Clinical trial information: NCT03504423.

e14548Background: Preclinical studies with muscadine grape extract (MGE) show anti-tumor activity and decreased systemic inflammation. This phase I study (NCT02583269) assessed safety and tolerabil...

Background Small cell lung cancer (SCLC) is a common lung cancer which presents with extensive stage disease at time of diagnosis in two-thirds of patients. For treatment of advanced disease, traditional platinum doublet chemotherapy induces response rates up to 80% but with few durable responses. CPI-613 is a novel anti-cancer agent that selectively inhibits the altered form of mitochondrial energy metabolism in tumor cells. Methods We evaluated CPI-613 with a single-arm, open-label phase II study in patients with relapsed or refractory SCLC. CPI-613 was given at a dose of 3,000 mg/m2 on days 1 and 4 of weeks 1–3 of 4 week cycle. The primary outcome was response rate as assessed by CT imaging using RECIST v1.1 criteria. Secondary outcomes were progression-free survival (PFS), overall survival (OS), and toxicity. Twelve patients were accrued (median age 57yo) who had previously received between 1 and 4 lines of chemotherapy (median 1) for SCLC with a treatment-free interval of less than 60 days in 9 of the 12 patients. Results No complete or partial responses were seen. Ten patients (83%) progressed as best response and 2 (17%) were not evaluable for response. Median time to progression was 1.7 months (range 0.7 to 1.8 months). Eleven patients (92%) died with median overall survival of 4.3 months (range 1.2 to 18.2 months). The study was closed early due to lack of efficacy. Of note, three out of three patients who progressed after CPI-613 and were subsequently treated with standard topotecan then demonstrated treatment response with survival for 18.2, 7.4, and 5.1 months. We conducted laboratory studies which found synergy in-vitro for CPI-613 with topotecan. Conclusions Single agent CPI-613 had no efficacy in this study. Further study of CPI 613 in combination with a topoisomerase inhibitor is warranted.

Introduction In this study, we assessed clinical outcomes of patients with brain metastases from a gastrointestinal (GI) primary cancer and patterns of failure after stereotactic radiosurgery including failure within the radiosurgical volume, distant failure and leptomeningeal failure (LMF). We also assessed other factors associated with the patients’ neurologic and extraneuraxial disease that may affect clinical outcomes. Methods We reviewed our institutional series of 62 consecutive patients with brain metastases treated with stereotactic radiosurgery, which included 17 patients with oesophageal, 44 patients with colorectal and one patient with anal canal primary. The median marginal dose to the radiosurgery volume was 17 Gy (range 10–24 Gy). Thirteen patients were treated with whole-brain radiotherapy (WBRT) prior to GKS. Results The median dose delivered to the margin of the tumour was 17 Gy (range: 10–24 Gy). The median largest tumour diameter was 2.7 cm (range: 0.60–6.1 cm). The median overall survival (OS) was 7.1 months with a median follow-up of 6.1 months and a range of 0–31.7 months. Freedom from local failure was 86.5% and 62.2% at 6 and 12 months respectively. Freedom from distant failure was 73.2% and 42.2% at 6 and 12 months, respectively, and 40% of patients died of neurologic death. LMF occurred in seven patients, all of whom had colorectal primaries. Multivariate analysis revealed that craniotomy for resection of brain metastasis (HR = 2.63, P

e15661 Background: Biliary duct carcinoma is a rare but highly fatal malignancy. The five-year survival rate for advanced bile duct cancer is 2%, per SEER data. As such, new treatment options are desperately needed. CPI-613, a novel anticancer agent that selectively inhibits mitochondrial metabolism in cancer cells, was employed in this study. Methods: This phase 1 study utilized a two-stage dose-escalation schema to determine the maximum-tolerated dose (MTD) and safety of single agent CPI-613 in patients with locally advanced or metastatic bile duct cancers. The 1st cohort enrolled 4 patients at 2300 mg/m2, with no dose-limiting toxicities (DLT) observed. The 2nd cohort enrolled patients at 1200 mg/m2/day for pre-cycle (days 1-5) and 3000 mg/m2 on days 1 and 4 weekly for 3 weeks (28 day cycle). The 5th and 6th patient experienced a DLT. The 3rd cohort was initiated at 600 mg/m2 pre-cycle and 3000 mg/m2 weekly with no other DLTs observed. Results: To-date, 14 patients have been enrolled in the study. The MTD was determined at 600 mg/m2/day pre-cycle and 3000 mg/m2 as per schedule. Once the MTD was determined, the cohort was expanded and, 8 patients have been treated at the MTD with no DLTs observed. Two additional patients are planned to be enrolled at this dose prior to trial completion. Of these 8 patients, 3 are still alive with 1 having prolonged survival (15 months) and the other 2 still on treatment. The most commonly observed toxicities were mild, such as anemia, anorexia, dehydration, fatigue, nausea and thrombocytopenia. Conclusions: Treatment with CPI-613 was well tolerated by patients with heavy tumor burden and refractory disease. CPI-613 has recently been shown to be well tolerated in combination with FOLFIRINOX in pancreatic cancer patients. Due to the low toxicity of CPI-613 in this study, even among highly symptomatic patients, it is anticipated that combination with other active agents is feasible in patients with advanced bile duct cancer. CPI-613 represents a novel treatment that could prove to be an exciting therapeutic alternative for patients with previously limited options and poor survival. Clinical trial information: NCT01766219.

Background Neoadjuvant chemotherapy for breast cancer leads to considerable variability in clinical responses, with only 10 to 20% of cases achieving complete pathologic responses (pCR). Biological and clinical factors that determine the extent of pCR are incompletely understood. Mounting evidence indicates that the patient’s immune system contributes to tumor regression and can be modulated by therapies. The cell types most frequently observed with this association are effector tumor infiltrating lymphocytes (TILs), such as cytotoxic T cells, natural killer cells and B cells. We and others have shown that the relative abundance of TILs in breast cancer can be quantified by intratumoral transcript levels of coordinately expressed, immune cell-specific genes. Through expression microarray analysis, we recently discovered three immune gene signatures, or metagenes, that appear to reflect the relative abundance of distinct tumor-infiltrating leukocyte populations. The B/P (B cell/plasma cell), T/NK (T cell/natural killer cell) and M/D (monocyte/dendritic cell) immune metagenes were significantly associated with distant metastasis-free survival of patients with highly proliferative cancer of the basal-like, HER2-enriched and luminal B intrinsic subtypes. Methods Given the histopathological evidence that TIL abundance is predictive of neoadjuvant treatment efficacy, we evaluated the therapy-predictive potential of the prognostic immune metagenes. We hypothesized that pre-chemotherapy immune gene signatures would be significantly predictive of tumor response. In a multi-institutional, meta-cohort analysis of 701 breast cancer patients receiving neoadjuvant chemotherapy, gene expression profiles of tumor biopsies were investigated by logistic regression to determine the existence of therapy-predictive interactions between the immune metagenes, tumor proliferative capacity, and intrinsic subtypes. Results By univariate analysis, the B/P, T/NK and M/D metagenes were all significantly and positively associated with favorable pathologic responses. In multivariate analyses, proliferative capacity and intrinsic subtype altered the significance of the immune metagenes in different ways, with the M/D and B/P metagenes achieving the greatest overall significance after adjustment for other variables. Conclusions Gene expression signatures of infiltrating immune cells carry both prognostic and therapy-predictive value that is impacted by tumor proliferative capacity and intrinsic subtype. Anti-tumor functions of plasma B cells and myeloid-derived antigen-presenting cells may explain more variability in pathologic response to neoadjuvant chemotherapy than previously recognized. Electronic supplementary material The online version of this article (doi:10.1186/s13073-014-0080-8) contains supplementary material, which is available to authorized users.

e14541Background: Casitas-B-lineage lymphoma protein-b (Cbl-b), an E3 ubiquitin ligase, is a major intracellular checkpoint limiting lymphocyte activation. Silencing Cbl-b enhances T cell and natur...

Objectives: We present a retrospective analysis of patients with pancreatic neuroendocrine tumors (PNETs) who have had Pancreatic Polypeptide testing in an attempt to better define Pancreatic Polypeptide producing tumors as an entity and the role of Pancreatic Polypeptide (PP) as a biomarker. To our knowledge, this is the first single center comprehensive review of Pancreatic Polypeptide producing tumors. Methods: A retrospective study of patients with pancreatic neuroendocrine tumors seen at our institution from 1980 to 2011. All patients that have had PP concentrations measured at least once were evaluated. Data relating to diagnosis, pathology, surgery, liver directed therapies, chemotherapy and survival outcome were noted. Results: 71 patients with PNETs fulfilled the inclusion criteria (8 PPomas, 22 PP producing tumors and 41 non -PP producing tumors). We identified a trend towards better survival for patients with PP producing tumors vs. non- PP producing tumors ( p =0.19). There was no correlation between survival and a diagnosis of PPoma in relation to other PP producing tumors or non-PP producing tumors. There was a borderline significant positive correlation of PP in association with Chromogranin A in a postoperative setting ( p =0.061). Conclusions: Pancreatic Polypeptide is a biomarker that is worth prospective investigation and a standardized assay. Our analysis investigating Pancreatic Polypeptide as a prognostic and or predictive biomarker reveals a trend towards showing these characteristics. Using a standardized test and investigating this biomarker prospectively could lead to the validation of Pancreatic Polypeptide as a biomarker.

264 Background: Stage IV pancreatic cancer is a lethal disease with limited treatment options. Current standard practice is combination chemotherapy with FOLFIRINOX or Gemcitabine + Abraxane. Despite these two new treatment options, the response rate and survival are limited in stage IV pancreatic cancer. The glycolic and mitochondrial metabolisms are aberrant in pancreatic cancer and translate into chemo-resistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species such as chemotherapy. CPI -613 is a novel anti-mitochondrial developed by Cornerstone Pharmaceuticals. Methods: A phase I clinical trial with mFOLFIRINOX+ CPI-613 in never treated for stage IV pancreatic cancer patients was initiated. The goals of this phase 1trial are: (1) To determine the Maximum Tolerated Dose (MTD) of CPI-613, when used in combination with mFOLFIRINOX, in patients with metastatic pancreatic cancer, (2) To assess the safety of CPI-613/ mFOLFIRINOX combination in patients with metastatic pancreatic cancer, and (3) To obtain preliminary data on efficacy of treatment with CPI-613/ mFOLFIRINOX Results: The MTD for CPI 613 was identified at 500mg/m2. The treatment combination is feasible and well-tolerated. The combination treatment was not found to have higher toxicity than FOLFIRINOX alone. The objective response rate was 53.9 % which is higher than FOLFIRINOX alone (reported as 31.6%). One patient has a complete radiologic and clinical response and two other patients have near complete responses. Conclusions: The preliminary efficacy data of this phase I clinical trial will inform a multi-institutional randomized phase II study of FOLFIRINOX vs. m FOLFIRINOX+ CPI613 in the near future. Clinical trial information: NCT01835041.

TPS773 Background: Treatment with Regorafenib (REGO) has shown significant clinical benefits in metastatic colorectal cancer (mCRC) patients (pts) as demonstrated in the CORRECT and CONCUR trials. Results from both studies suggest that subgroups have differential responses. Further research to identify these subgroups through the identification of molecular biomarkers is needed. Methods: Forty pts with refractory mCRC are being enrolled in this study. The primary objective is to prospectively identify tissue and serum-based biomarkers that can predict response to REGO. Secondary objectives are to determine molecular mechanisms by which REGO controls refractory mCRC, as well as molecular pathways involved in the acquisition of resistance. Tumor and blood samples are obtained prior to and 2 weeks after starting REGO. Blood samples are collected on day 1 of each cycle thereafter. Pts will receive 160 mg REGO daily for 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. Multi-omic based biomarker discovery approaches will be used to uncover predictive marker candidates with special attention to the tumor microenvironment. Laser capture microdissection will be used on tumor tissue to procure highly enriched populations of pt-matched epithelial and stromal/immune cell infiltrates. Each of these entities will be analyzed for RNA expression changes and protein signaling/drug target activation mapping. Protein signaling analysis will be performed by reverse phase protein array of key REGO-related proteins and phosphoproteins (e.g. phosphoVEGFR, Tie2, phosphoRET), as well as broad-scale mapping of mitogenic, survival, autophagy, inflammatory, motility, and signaling networks. Tumor profiling will include next-generation sequencing for 592 genes with 53 selected gene fusions, and IHC and FISH/CISH for selected biomarkers, including PDL1, HER2, MSI, TS, ERCC1, and TOPO1. Blood samples will undergo protein, miRNA, and mutated DNA analysis, as well as exosomal signature study via a proprietary synthetic polyligand multiplexed aptamer-based assay. Exploratory analysis of biomarkers will be used to determine correlations between the presence of, or change in, biomarker levels and clinical response. Clinical trial information: NCT01949194.

Background: Previous studies have suggested that immune infiltrates in colorectal cancer are of clinical importance. We now know that functional orientation, density and location of immune cells within colorectal tumors profoundly influence the clinical outcome irrespective of stage. The currently known prognostic markers are AJCC (American Joint Committee on Cancer) stage, tumor morphology, tumor molecular pathway, tumor gene signatures and tumor mutation status. The immunoscore is currently being validated in a large prospective study to enable its application in clinical practice. The cell types most frequently investigated as antitumor effector cells are tumor infiltrating lymphocytes (TILs) such as cytotoxic T cells (CTLs), natural killer (NK) cells and B cells. Through expression microarray analysis, we recently discovered three separate immune gene signatures, or metagenes, that appear to reflect the relative abundance of distinct tumor-infiltrating leukocyte populations. These metagenes, referred as the B/P (B-cell/Plasma cell), T/NK (T-cell/Natural Killer cell) and M/D (Monocyte/Dendritic cell) immune metagenes, were found to be significantly associated with the distant metastasis-free survival of breast cancer patients with highly proliferative cancer of the Basal-like, HER2-Enriched and Luminal B subtypes, in particular. Aim: Given the histopathological evidence that TIL abundance is prognostic of outcome in colorectal cancer we sought to evaluate the interaction between established clinical and pathologic factors and immune metagenes. We hypothesized that the immune gene signatures would recapitulate the known information and potentially add additional prognostic information. Methods: In a multi-institutional, meta-cohort analysis of 177 colon cancer tumor patients, gene expression profiles of colon tumor biopsies were investigated to determine the relationships between immune gene signatures and disease specific survival (DSS). In separate Cox proportional hazards regression models, B/P and TNK metagenes were both found to be associated with DSS, however M/D was not. Next, stepwise selection models were considered in which other prognostic factors (AJCC stage, grade, gender and age) and both B/P and TNK were considered for inclusion in the Cox proportional hazards regression model. In this analysis, AJCC stage was the first variable to enter the model, followed by B/P and then grade. Results: Age, gender and TNK were not significant predictors in this multivariate model. In the final multivariate model the hazard ratio for B/P was 0.746 with 95% confidence interval (0.61 to 0.91, p=0.0038) suggesting that as B/P signature increases the DSS risk decreases. These analyses support the finding that both TNK and B/P are predictive of DSS; however the impact of TNK was not an independent predictor of DSS once AJCC stage and grade were taken into account, while B/P remained an independent predictor. Further studies need to be conducted to determine whether the TNK effect would reach statistical significance in a multivariate model with a larger sample size. Conclusions: Our results suggest that the prognostic information provided by immune metagenes (B/P and TNK) will have the greatest clinical utility when used as a complement to known clinical predictors, especially AJCC stage. Citation Format: Angela Tatiana Alistar, Julia Chifman, Ralph D'Agostino, Jr., Lance D. Miller. Gene expression signatures of effector immune cell abundance are significantly associated with recurrence risk in colon cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A011.

e15252 Background: Albumin-bound paclitaxel plus gemcitabine (Gem/nab) and FOLFIRINOX are approved as first-line therapies for metastatic pancreatic cancer (PC). Optimal regimen sequence is unknown...

e21109 Background: Pancreatic neuroendocrine tumors (PNETs) represent tumors that secrete numerous proteins that could be used as biomarkers. We present a retrospective analysis of patients with PNETs who have had Pancreatic Polypeptide (PP) testing in an attempt to better define PP producing tumors as an entity and the role of PP as a biomarker. To our knowledge, this is the first single center comprehensive review of Pancreatic Polypeptide producing tumors. Methods: A retrospective study of patients with PNETs seen at Mount Sinai from 1980 to 2011. All patients that have had PP concentrations measured at least once were evaluated. Data relating to diagnosis, pathology, surgery, liver directed therapies, chemotherapy and survival outcome were noted. 71 patients with PNETs fulfilled the inclusion criteria. The 71 patients formed 4 subgroups. The 4 subgroups were evaluated and compared for survival: all 71 PP tested patients, 30 patients with PP producing tumors, 8 patients with PPomas, 22 patients with PP producing tumors that were non PP-omas and 41 patients with PP non-producing tumors Results: We identified a trend towards better survival for PNETs patients with PP producing tumors vs. non- PP producing tumors (p=0.19). There was no correlation between survival and a diagnosis of PPoma in relation to other PP producing tumors (p= 0.59) or non-PP producing tumors (p=0.58). Conclusions: Pancreatic Polypeptide is a biomarker that is worth prospective investigation and a standardized assay. Our analysis investigating Pancreatic Polypeptide as a prognostic and or predictive biomarker reveals a trend towards showing these characteristics. Using a standardized test and investigating this biomarker prospectively could lead to the validation of Pancreatic Polypeptide as a biomarker.

The abundance and functional orientation of tumor-infiltrating effector cells has long been observed to predict for reduced incidence of clinical metastasis and cancer-specific death. Using bioinformatics to mine large breast tumor microarray datasets, we and others have identified prognostic immune gene signatures, or metagenes. Robust evidence indicates that these metagenes are: 1) positively correlated with distant metastasis-free survival (DMFS) of patients, 2) comprised of genes that regulate immune cell-specific biology, and 3) reflective of the relative abundance of discernible populations of tumor infiltrating leukocytes. In recent work we have leveraged the statistical associations between the immune metagenes and the DMFS of breast cancer patients to explore the underlying phenotypes that differ in their ability to potentiate long-term, immune-mediated tumor rejection. Using a tumor classification model that combines the prognostic attributes of three distinct immune metagenes, termed the B/P, T/NK and M/D metagenes, we have identified molecular subtypes of breast cancer that either permit or prohibit prognostication by the immune metagenes. On this basis, we have delineated the phenotypic attributes of breast cancer that distinguish two novel immunogenic tumor subtypes, which we have defined as: immune benefit-enabled (IBE) and immune benefit-disabled (IBD). Phenotypically, IBE tumors comprise of Basal-like tumors and highly-proliferative HER2-Enriched and Luminal-B subtypes, while IBD tumors comprise of Claudin-Low, Luminal-A, and low-proliferative HER2-Enriched and Luminal-B tumors. Prognostically, IBE tumors (n = 666) can be stratified by the immune metagene model into prognostic subgroups with high statistical significance (P